2-(3,4-dimethoxyphenyl)acetonitrile -Drug Synthesis Database

【结构式】

【分子编号】25857

【品名】2-(3,4-dimethoxyphenyl)acetonitrile

【CA登记号】93-17-4

【分子式】C₁₀H₁₁NO₂

【分子量】177.20288

【元素组成】C 67.78% H 6.26% N 7.9% O 18.06%

与该中间体有关的原料药合成路线共 4 条

合成路线1 合成路线2 合成路线3 合成路线4

合成路线1

该中间体在本合成路线中的序号：(IV)

Condensation of 2-chloro-2-(3,4-dimethoxyphenyl)acetonitrile (I) with p-thiocresol (II) in the presence of K2CO3 gave thioether (III). Alternatively, thioether (III) was obtained by reaction of the anion of (3,4-dimethoxyphenyl)acetonitrile (IV) with p-tolyl disulfide (V). Subsequent alkylation of (III) with 1-bromo-5-chloropentane using NaH in DMSO produced the 5-chloropentyl derivative (VI). This was finally condensed with tetrahydroisoquinoline (VII) to yield the title compound.

参考文献中间体

合成目标

【1】 Berger, D.; et al.; Novel multidrug resistance reversal agents. J Med Chem 1999, 42, 12, 2145.

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)	25855	2-chloro-2-(3,4-dimethoxyphenyl)acetonitrile	7537-07-7	C₁₀H₁₀ClNO₂	详情	详情
(III)	25856	2-(3,4-dimethoxyphenyl)-2-[(4-methylphenyl)sulfanyl]acetonitrile		C₁₇H₁₇NO₂S	详情	详情
(IV)	25857	2-(3,4-dimethoxyphenyl)acetonitrile	93-17-4	C₁₀H₁₁NO₂	详情	详情
(VI)	25858	7-chloro-2-(3,4-dimethoxyphenyl)-2-[(4-methylphenyl)sulfanyl]heptanenitrile		C₂₂H₂₆ClNO₂S	详情	详情
(VII)	25859	6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline; 6-methoxy-1,2,3,4-tetrahydro-7-isoquinolinyl methyl ether		C₁₁H₁₅NO₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(IV)

Condensation of alpha-chloro-(3,4-dimethoxyphenyl)acetonitrile (I) with p-thiocresol (II) in the presence of K2CO3 gave thioether (III). Alternatively, thioether (III) was obtained by reaction of the anion of (3,4-dimethoxyphenyl)acetonitrile (IV) with p-tolyl disulfide (V). Subsequent alkylation of (III) with 1-bromo-5-chloropentane using NaH in DMSO produced the 5-chloropentyl derivative (VI). This was then condensed with tetrahydroisoquinoline (VII) to yield the tertiary amine (VIII). Alkylation of the phenolic hydroxyl group of (VIII) with 2-chloroethyl tosylate produced the 2-chloroethyl ether (IX). Finally, reactionof (IX) with imidazole (X) and NaH in DMF furnished the title compound.

参考文献中间体

合成目标

【1】 Berger, D.; et al.; Novel multidrug resistance reversal agents. J Med Chem 1999, 42, 12, 2145.

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)	25855	2-chloro-2-(3,4-dimethoxyphenyl)acetonitrile	7537-07-7	C₁₀H₁₀ClNO₂	详情	详情
(III)	25856	2-(3,4-dimethoxyphenyl)-2-[(4-methylphenyl)sulfanyl]acetonitrile		C₁₇H₁₇NO₂S	详情	详情
(IV)	25857	2-(3,4-dimethoxyphenyl)acetonitrile	93-17-4	C₁₀H₁₁NO₂	详情	详情
(VI)	25858	7-chloro-2-(3,4-dimethoxyphenyl)-2-[(4-methylphenyl)sulfanyl]heptanenitrile		C₂₂H₂₆ClNO₂S	详情	详情
(VII)	25860	7-methoxy-1,2,3,4-tetrahydro-6-isoquinolinol		C₁₀H₁₃NO₂	详情	详情
(VIII)	25861	2-(3,4-dimethoxyphenyl)-7-[6-hydroxy-7-methoxy-3,4-dihydro-2(1H)-isoquinolinyl]-2-[(4-methylphenyl)sulfanyl]heptanenitrile		C₃₂H₃₈N₂O₄S	详情	详情
(IX)	25862	7-[6-(2-chloroethoxy)-7-methoxy-3,4-dihydro-2(1H)-isoquinolinyl]-2-(3,4-dimethoxyphenyl)-2-[(4-methylphenyl)sulfanyl]heptanenitrile		C₃₄H₄₁ClN₂O₄S	详情	详情
(X)	10255	Imidazole; 1H-Imidazole	288-32-4	C₃H₄N₂	详情	详情

合成路线3

该中间体在本合成路线中的序号：(I)

Acetonitrile derivative (I) is treated with BuLi and alkylated with 3-bromopropanol (A) to yield alcohol (II), which is further alkylated by means of LICKOR (n-BuLi/t-BuOK) and 1-chloro-3-bromopropane (B) to afford (III). Reaction of derivative (III) with secondary amine (VIII) in acetonitrile gives (IV). Amine (VIII) is obtained by trifluoroacetylation of azide (VI) with trifluoroacetic anhydride to yield (VII), which is then N-methylated by means of MeI and hydrolyzed with KOH. Finally, alcohol (IV) reacts with succinimido biotinate (V) in DMSO to provide the desired product.

参考文献中间体

合成目标

【1】 Teodori, E.; et al.; Synthesis and binding properties of photoactivable biotin-conjugated verapamil derivatives for the study of P-170 glycoprotein. Bioorg Med Chem 1999, 7, 9, 1873.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(A)	12573	3-Bromo-1-propanol; 3-Bromopropanol	627-18-9	C₃H₇BrO	详情	详情
(B)	19490	3-chloro-1-propanol	627-30-5	C₃H₇ClO	详情	详情
(I)	25857	2-(3,4-dimethoxyphenyl)acetonitrile	93-17-4	C₁₀H₁₁NO₂	详情	详情
(II)	42244	2-(3,4-dimethoxyphenyl)-5-hydroxypentanenitrile		C₁₃H₁₇NO₃	详情	详情
(III)	42245	5-chloro-2-(3,4-dimethoxyphenyl)-2-(3-hydroxypropyl)pentanenitrile		C₁₆H₂₂ClNO₃	详情	详情
(IV)	42249	5-[(2-azidophenethyl)(methyl)amino]-2-(3,4-dimethoxyphenyl)-2-(3-hydroxypropyl)pentanenitrile		C₂₅H₃₃N₅O₃	详情	详情
(V)	42250	1-([5-[(3aS,4S,6aR)-3a,4,6a-trimethyl-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl]pentanoyl]oxy)-2,5-pyrrolidinedione		C₁₇H₂₅N₃O₅S	详情	详情
(VI)	42246	2-azidophenethylamine; 2-(2-azidophenyl)-1-ethanamine		C₈H₁₀N₄	详情	详情
(VII)	42247	N-(2-azidophenethyl)-2,2,2-trifluoroacetamide		C₁₀H₉F₃N₄O	详情	详情
(VIII)	42248	N-(2-azidophenethyl)-N-methylamine; 2-(2-azidophenyl)-N-methyl-1-ethanamine		C₉H₁₂N₄	详情	详情

合成路线4

该中间体在本合成路线中的序号：(I)

The title compound has been synthesized by two closely related methods. Claisen condensation of 3,4-dimethoxyphenylacetonitrile (I) with ethyl formate produced the cyano aldehyde sodium enolate (II), which was further O-acylated with benzenesulfonyl chloride to afford (III). The aminothiophene derivative (V) was prepared by cyclization of (III) with methyl thioglycolate (IV) under basic conditions. A pyrrole ring was then introduced in (V) through a Paal-Knorr synthesis employing 2,5-dimethoxytetrahydrofuran (VI) in the presence of 4-chloropyridinium chloride, yielding (VII). Refluxing of ester (VII) in pyrrolidine (VIII) gave rise to amide (IX). The intramolecular cyclization of (IX) under Vilsmeier conditions furnished the tricyclic system (X). Finally, regioselective cleavage of the meta methoxy group of (X) by means of AlCl3 yielded the target compound.

参考文献中间体

合成目标

【1】 Caignard, D.-H.; Enghehard, C.; Robba, M.; Lancelot, J.-C.; Pierre, A.; Renard, P.; Rault, S.; Atassi, G. (ADIR et Cie.); Derivs. of the 8H-(2,3-b)-pyrrolizine-8-one, process for their preparation and pharmaceutical compsns. containing them. EP 0982308; FR 2781482; JP 2000044572; US 6071945 .

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)	25857	2-(3,4-dimethoxyphenyl)acetonitrile	93-17-4	C₁₀H₁₁NO₂	详情	详情
(II)	52226	sodium (Z)-2-cyano-2-(3,4-dimethoxyphenyl)-1-ethenolate		C₁₁H₁₀NNaO₃	详情	详情
(III)	52227	(Z)-2-cyano-2-(3,4-dimethoxyphenyl)ethenyl benzenesulfonate		C₁₇H₁₅NO₅S	详情	详情
(IV)	18838	methyl 2-sulfanylacetate	2365-48-2	C₃H₆O₂S	详情	详情
(V)	52228	methyl 3-amino-4-(3,4-dimethoxyphenyl)-2-thiophenecarboxylate		C₁₄H₁₅NO₄S	详情	详情
(VI)	12132	2,5-Dimethoxytetrahydrofuran; 5-Methoxytetrahydro-2-furanyl methyl ether	696-59-3	C₆H₁₂O₃	详情	详情
(VII)	52229	methyl 4-(3,4-dimethoxyphenyl)-3-(1H-pyrrol-1-yl)-2-thiophenecarboxylate		C₁₈H₁₇NO₄S	详情	详情
(VIII)	11376	Pyrrolidine	123-75-1	C₄H₉N	详情	详情
(IX)	52230	[4-(3,4-dimethoxyphenyl)-3-(1H-pyrrol-1-yl)-2-thienyl](1-pyrrolidinyl)methanone		C₂₁H₂₂N₂O₃S	详情	详情
(X)	52231	3-(3,4-dimethoxyphenyl)-8H-thieno[2,3-b]pyrrolizin-8-one		C₁₇H₁₃NO₃S	详情	详情

Extended Information