Lesinurad Sodium;RDEA-594, -Drug Synthesis Database

【结构式】

【药物名称】Lesinurad Sodium;RDEA-594

【化学名称】2-[5-Bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylsulfanyl]acetic acid sodium salt

【CA登记号】

【分子式】C₁₇H₁₃BrN₃NaO₂S

【分子量】426.263

【开发单位】Ardea Biosciences, Inc. (US)

【药理作用】Solute Carrier Family 22 Member 12 (URAT1) Inhibitor；Uricosuric；Treatment of Gout

合成路线1 合成路线2

合成路线1

Cyclization of 4-cyclopropyl-1-naphthyl isothiocyanate (I) with aminoguanidine hydrochloride (II) using DIEA in DMF yields the naphthyl-1,2,4-triazole-3-thiol (III), which is then alkylated with methyl chloroacetate (IV) by means of K2CO3 in DMF to give the (triazolylsulfanyl)acetate (V). Diazotization of the amine (V) with NaNO2 and Cl2CHCOOH in the presence of BnEt3NBr or BnEt3NCl in CHBr3 gives rise to the 5-bromotriazole derivative (VI), which is hydrolyzed with LiOH in THF/EtOH/H2O to produce lesinurad (VII) , and is finally treated with NaOH in EtOH .
Also, coupling of the thiol (III) with the 2-chloroacetamide derivative (VIII) by means of K2CO3 in DMF yields the amide (IX), which is then brominated with CHBr3 in the presence of NaNO2, Cl2CHCOOH and BnEt3NBr or BnEt3NCl to give the 5-bromotriazole derivative (X) .Finally, hydrolysis of amide (X) with NaOH in refluxing EtOH affords lesinurad (VII) .

参考文献中间体

【1】 Miner, J., Quart, B.D., Girardet, J.-L. (Ardea Biosciences, Inc.). Treatment of gout. WO 201116852.
【2】 Quart, B.D., Girardet, J.-L., Gunic, E., Yeh, L.-T. (Ardea Biosciences, Inc.).Novel compounds and composition and methods of use. CA 2706858, CN 01918377, EP 2217577, JP 2011504935, KR 2010085195, US 2009197825, US 2011268801, WO 009070740.
【3】 Zamansky, I., Galvin, G., Girardet, J.-L. (Ardea Biosciences, Inc.). Polymorphic, crystalline and mesophase forms of sodium 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate, and uses thereof. WO 2011085009.

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)	68901	4-cyclopropyl-1-naphthyl isothiocyanate	878671-95-5	C₁₄H₁₁NS	详情	详情
(II)	68902	aminoguanidine hydrochloride;aminoguanidine monohydrochloride;Hydrazinecarboximidamide	1937-19-5	CH₆N₄.HCl	详情	详情
(III)	68903	5-amino-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole-3-thiol		C₁₅H₁₄N₄S	详情	详情
(IV)	10257	methyl 2-chloroacetate; methyl chloroacetate	96-34-4	C₃H₅ClO₂	详情	详情
(V)	68904	methyl 2-((5-amino-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-yl)thio)acetate		C₁₈H₁₈N₄O₂S	详情	详情
(VI)	68905	methyl 2-((5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-yl)thio)acetate		C₁₈H₁₆BrN₃O₂S	详情	详情
(VII)	68906	2-((5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-yl)thio)acetic acid		C₁₇H₁₄BrN₃O₂S	详情	详情
(VIII)	68907	2-chloro-N-(2-chloro-4-sulfamoylphenyl)acetamide		C₈H₈Cl₂N₂O₃S	详情	详情
(IX)	68908	2-((5-amino-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-yl)thio)-N-(2-chloro-4-sulfamoylphenyl)acetamide		C₂₃H₂₁ClN₆O₃S₂	详情	详情
(X)	68909	2-((5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-yl)thio)-N-(2-chloro-4-sulfamoylphenyl)acetamide		C₂₃H₁₉BrClN₅O₃S₂	详情	详情

合成路线2

Oxidation of (4-cyclopropyl-1-naphthyl)methanol (XI) by means of MnO2 in CH2Cl2 yields 4-cyclopropyl-1-naphthaldehyde (XII), which is then treated with NH2OH·HCl or (NH2OH)2SO4 in the presence of NaOMe (generated from Na in MeOH) to give 4-cyclopropyl-1-naphthaldehyde oxime (XIII). Bromination of oxime (XIII) with NBS in acetonitrile provides the corresponding oximidoyl bromide (XIV), which is finally treated with CS(NH2)2 in the presence of Et3N in THF (I) .
Chlorination of oxime (XIII) using 1,3-dichloro-5,5-dimethylhydantoin (DDH) or trichloroisocyanuric acid (TCCA) in acetonitrile affords 4-cyclopropyl-N-hydroxynaphthalene-1-carboximidoyl chloride (XV), which is then treated with CS(NH2)2 or CH3CSNH2 in the presence of Et3N in THF .
Coupling of 1-bromonaphthalene (XVI) with cyclopropylmagnesium bromide (XVII) in the presence of NiCl2(dppp) in THF gives 1-cyclopropylnaphthalene (XVIII), which is then nitrated with NaNO2 at 0 °C to produce 1-cyclopropyl-4-nitronaphthalene (XIX). Reduction of the nitronaphthalene derivative (XIX) by means of H2 over Pd/C in EtOH yields 4-cyclopropyl-1-naphthylamine (XX), which is finally treated with CSCl2 and DIEA in CH2Cl2 at 0 °C .

参考文献中间体

【1】 Miner, J., Quart, B.D., Girardet, J.-L. (Ardea Biosciences, Inc.). Treatment of gout. WO 201116852.
【2】 Quart, B.D., Girardet, J.-L., Gunic, E., Yeh, L.-T. (Ardea Biosciences, Inc.).Novel compounds and composition and methods of use. CA 2706858, CN 01918377, EP 2217577, JP 2011504935, KR 2010085195, US 2009197825, US 2011268801, WO 009070740.
【3】 Zamansky, I., Galvin, G., Girardet, J.-L. (Ardea Biosciences, Inc.). Polymorphic, crystalline and mesophase forms of sodium 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate, and uses thereof. WO 2011085009.
【4】 Liu, X., Hong, D., Wu, X. (Taizhou Hwasun Pharm. & Chem. Co., Ltd.). Method for preparing 4-cyclopropyl-1-isothiocyanonaphthalene and intermediate 4-cyclopropyl-1-naphthaldehyde oxime/halide. CN 102040546.

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)	68901	4-cyclopropyl-1-naphthyl isothiocyanate	878671-95-5	C₁₄H₁₁NS	详情	详情
(XI)	68910	(4-cyclopropyl-1-naphthyl)methanol		C₁₄H₁₄O	详情	详情
(XII)	68911	4-cyclopropyl-1-naphthaldehyde		C₁₄H₁₂O	详情	详情
(XIII)	68912	(Z)-4-cyclopropyl-1-naphthaldehyde oxime;4-cyclopropyl-1-naphthaldehyde oxime		C₁₄H₁₃NO	详情	详情
(XIV)	68914	(E)-4-cyclopropyl-N-hydroxy-1-naphthimidoyl bromide		C₁₄H₁₂BrNO	详情	详情
(XV)	68913	4-cyclopropyl-N-hydroxynaphthalene-1-carboximidoyl chloride;(E)-4-cyclopropyl-N-hydroxy-1-naphthimidoyl chloride		C₁₄H₁₂ClNO	详情	详情
(XVI)	10105	1-Bromonaphthalene	90-11-9	C₁₀H₇Br	详情	详情
(XVII)	12450	Bromo(cyclopropyl)magnesium;cyclopropylmagnesium bromide;cyclopropylmagnesiumbromide	23719-80-4	C₃H₅BrMg	详情	详情
(XVIII)	68915	1-cyclopropylnaphthalene	25033-19-6	C₁₃H₁₂	详情	详情
(XIX)	68916	1-cyclopropyl-4-nitronaphthalene		C₁₃H₁₁NO₂	详情	详情
(XX)	68917	4-cyclopropyl-1-naphthylamine	878671-94-4	C₁₃H₁₃N	详情	详情

Extended Information