2-Chloro-2-[3-ethoxy-4-(pentyloxy)phenyl]acetonitrile -Drug Synthesis Database

【结构式】

【分子编号】10405

【品名】2-Chloro-2-[3-ethoxy-4-(pentyloxy)phenyl]acetonitrile

【CA登记号】

【分子式】C₁₅H₂₀ClNO₂

【分子量】281.78204

【元素组成】C 63.94% H 7.15% Cl 12.58% N 4.97% O 11.36%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(VIII)

This compound can be obtained by three related ways: 1) The carboxylation of 3-ethoxy-4-pentyloxyiodobenzene (I) with CO2 and butyllithium in ether gives 3-ethoxy-4-pentyloxybenzoic acid (II), which is reduced with LiAlH4 in refluxing ether to yield the corresponding benzyl alcohol (III). The controlled oxidation of (III) with pyridinium chlorochromate in dichloromethane affords 3-ethoxy-4-pentyloxybenazldehyde (IV), which is treated wtih NaCN and acetic acid - water giving 2-(3-ethoxy-4-pentyloxyphenyl)-2-hydroxyacetonitrile (V). Finally, this compound is cyclized with thiourea (VI) and HCl in 2-methoxyethanol. 2) The alkylation of ethyl-vanilline (VII) with c and K2CO3 in hot DMF gives aldehyde (IV), which by reaction with NaCH in methanol - HCl yields the cyanohydrine (V). The reaction of (V) with SOCl2 in refluxing CHCl3 affords 2-chloro-2-(3-ethoxy-5-pentyloxyphenyl)acetonitrile (VIII), which is finally cyclized with thiourea (VI) in ethylene glycol monomethyl ether - HCl at 110 C in refluxing ethanol - HCl. 3) The cyclization of 2-(3-ethoxy-4-pentyloxyphenyl)-2-hydroxyacetic acid (IX) with thiourea (VI) under acidic conditions gives 5-(3-ethoxy-4-pentyloxyphenyl)-2-iminothiazolidin-4-one (X), which is then hydrolyzed to the desired product.

参考文献中间体

合成目标

【1】 Awata, T.; Maenaka, T.; Kawamatsu, Y. (Senju Pharmaceuticals Co., Ltd.); Ophthalmic topical agent for remedy of diseases of iris and ciliary body. EP 0170237; JP 1986043114; US 4602026 .
【2】 Kawamatsu, Y.; Yamamoto, Y. (Senju Pharmaceuticals Co., Ltd.; Takeda Chemical Industries, Ltd.); Thiazolidine derivs. and their production and use. EP 0033617 .
【3】 Imanishi, M.; Imamiya, E.; Kawamatsu, Y.; Hayashi, N.; Synthesis of 5-(3-ethoxy-4-pentyloxyphenyl)-2,4-[5-14C]thiazolidinedione ([14C]CT-112). J Takeda Res Lab 1983, 42, 3/4, 238-40.
【4】 Tawada, H.; Mizuno, K.; Meguro, K.; Sohda, T.; Imamiya, E.; Kawamatsu, Y.; Yamamoto, Y.; Studies on antidiabetic agents. III. 5-Arylthiazolidine-2,4-diones as potent aldose reductase inhibitors. Chem Pharm Bull 1982, 30, 10, 3601-16.
【5】 Prous, J.; Castaner, J.; CT-112. Drugs Fut 1991, 16, 10, 895.

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)	10398	2-Ethoxy-4-iodo-1-(pentyloxy)benzene; 2-Ethoxy-4-iodophenyl pentyl ether		C₁₃H₁₉IO₂	详情	详情
(II)	10399	3-Ethoxy-4-(pentyloxy)benzoic acid		C₁₄H₂₀O₄	详情	详情
(III)	10400	[3-Ethoxy-4-(pentyloxy)phenyl]methanol		C₁₄H₂₂O₃	详情	详情
(IV)	10401	3-Ethoxy-4-(pentyloxy)benzaldehyde		C₁₄H₂₀O₃	详情	详情
(V)	10402	2-[3-Ethoxy-4-(pentyloxy)phenyl]-2-hydroxyacetonitrile		C₁₅H₂₁NO₃	详情	详情
(VI)	10180	Thiourea	62-56-6	CH₄N₂S	详情	详情
(VII)	10404	Ethyl vanillin; 3-Ethoxy-4-hydroxybenzaldehyde	121-32-4	C₉H₁₀O₃	详情	详情
(VIII)	10405	2-Chloro-2-[3-ethoxy-4-(pentyloxy)phenyl]acetonitrile		C₁₅H₂₀ClNO₂	详情	详情
(IX)	10406	2-[3-Ethoxy-4-(pentyloxy)phenyl]-2-hydroxyacetic acid		C₁₅H₂₂O₅	详情	详情
(X)	10407	5-[3-Ethoxy-4-(pentyloxy)phenyl]-2-imino-1,3-thiazolidin-4-one		C₁₆H₂₂N₂O₃S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(II)

Reaction of the dicarboxylic acid (I) with thionyl chloride in hot toluene gives the di-acid chloride (II). Treatment of (II) with Cl2 in CH2Cl2 gives the sulfenyl chloride (III), which upon reaction with NH4OH affords the benzisothiazole (IV). Chlorination of (IV) in heat POCl3 yields the chlorobenzisothiazole (V). Reaction of (V) and piperazine (VI) in excess molten pipeazine gives the monosubstituted piperazine (VII). Reaction of (VII) with the dibromide (VIII) in refluxing ethanol yields the spiroquaternary (IX). Finally, BMY-13859-1 is obtained by treatment of (IX) with the glutarimide (X) in refluxing xylene followed by treatment with HCl in isopropanol.

参考文献中间体

合成目标

【1】 Eison, M.S.; Taylor, D.P.; New, J.S.; Minielli, J.L.; BMY-13859. Drugs Fut 1985, 10, 9, 731.

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)	10404	Ethyl vanillin; 3-Ethoxy-4-hydroxybenzaldehyde	121-32-4	C₉H₁₀O₃	详情	详情
(II)	10405	2-Chloro-2-[3-ethoxy-4-(pentyloxy)phenyl]acetonitrile		C₁₅H₂₀ClNO₂	详情	详情
(III)	28018	2-(chlorosulfanyl)benzoyl chloride		C₇H₄Cl₂OS	详情	详情
(IV)	16278	1,2-benzisothiazol-3(2H)-one; 1,2-Benzisothiazolin-3-one	2634-33-5	C₇H₅NOS	详情	详情
(V)	16279	3-chloro-1,2-benzisothiazole		C₇H₄ClNS	详情	详情
(VI)	10355	Diethylenediamine; Piperazine	110-85-0	C₄H₁₀N₂	详情	详情
(VII)	16280	3-piperazino-1,2-benzisothiazole; 1,2-Benzisothiazole-3-(1-piperazinyl)	87691-87-0	C₁₁H₁₃N₃S	详情	详情
(VIII)	11883	1,4-Dibromobutane; 1,4-Butylene bromide	110-52-1	C₄H₈Br₂	详情	详情
(IX)	28019	8-(1,2-benzisothiazol-3-yl)-8-aza-5-azoniaspiro[4.5]decane bromide		C₁₅H₂₀BrN₃S	详情	详情
(X)	28020	8-azaspiro[4.5]decane-7,9-dione	1075-89-4	C₉H₁₃NO₂	详情	详情

Extended Information