3-methoxy-4-[[(1R,2R)-2-(1-pyrrolidinyl)cyclohexyl]oxy]benzoyl chloride -Drug Synthesis Database

【结构式】

【分子编号】29178

【品名】3-methoxy-4-[[(1R,2R)-2-(1-pyrrolidinyl)cyclohexyl]oxy]benzoyl chloride

【CA登记号】

【分子式】C₁₈H₂₄ClNO₃

【分子量】337.8462

【元素组成】C 63.99% H 7.16% Cl 10.49% N 4.15% O 14.21%

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：(VI)

Opening of cyclohexene oxide (I) with pyrrolidine (II) in aqueous K2CO3 yielded the racemic trans-2-(1-pyrrolidinyl)cyclohexanol (III). Subsequent Mitsunobu coupling of (III) with phenol (IV) in the presence of DEAD and PPh3 produced ether (V). The intermediate acid chloride (VI) was then prepared by ester hydrolysis, followed by treatment with SOCl2.

参考文献中间体

合成目标

【1】 McCowan, J.R.; Sall, D.J.; Gifford-Moore, D.S.; Takeuchi, K.; Denney, M.L.; Kohn, T.J.; Smith, G.F.; Dibasic benzo[b]thiophene derivatives as a novel class of active site directed thrombin inhibitors: 4. SAR studies on the conformationally restricted C3-side chain of hydroxybenzo[b]thiophenes. Bioorg Med Chem Lett 1999, 9, 5, 759.

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)	17986	7-oxabicyclo[4.1.0]heptane; cyclohexene oxide	286-20-4	C₆H₁₀O	详情	详情
(II)	11376	Pyrrolidine	123-75-1	C₄H₉N	详情	详情
(III)	14637	(1R,2R)-2-(1-pyrrolidinyl)cyclohexanol		C₁₀H₁₉NO	详情	详情
(IV)	29176	methyl 4-hydroxy-3-methoxybenzoate	3943-74-6	C₉H₁₀O₄	详情	详情
(V)	29177	methyl 3-methoxy-4-[[(1R,2R)-2-(1-pyrrolidinyl)cyclohexyl]oxy]benzoate		C₁₉H₂₇NO₄	详情	详情
(VI)	29178	3-methoxy-4-[[(1R,2R)-2-(1-pyrrolidinyl)cyclohexyl]oxy]benzoyl chloride		C₁₈H₂₄ClNO₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VI)

Condensation of 4-(benzyloxy)benzaldehyde (VII) with N,N-dimethyl thioformamide (A) in the presence of LDA at -78 C generated the alpha-hydroxythioamide (VIII), which was cyclized by means of methanesulfonic acid to afford benzothiophene (IX). Friedel-Crafts acylation of (IX) with acid chloride (VI) upon heating in chlorobenzene yielded the 3-acyl benzothiophene (X). Subsequent displacement of the dimethylamino group of (X) by Grignard reagent (XI) produced the 2-aryl benzothiophene (XII). Deoxygenation of the keto group of (XII) was accomplished by the sequence of reduction to alcohol (XIII) with LiAlH4, followed by treatment with Et3SiH in trifluoroacetic acid to give (XIV). The benzyl ether of (XIV) was finally deprotected by hydrogenation over Pd/C to furnish the title compound.

参考文献中间体

合成目标

【1】 McCowan, J.R.; Sall, D.J.; Gifford-Moore, D.S.; Takeuchi, K.; Denney, M.L.; Kohn, T.J.; Smith, G.F.; Dibasic benzo[b]thiophene derivatives as a novel class of active site directed thrombin inhibitors: 4. SAR studies on the conformationally restricted C3-side chain of hydroxybenzo[b]thiophenes. Bioorg Med Chem Lett 1999, 9, 5, 759.

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)	29180	dimethylthioformamide	758-16-7	C₃H₇NS	详情	详情
(VI)	29178	3-methoxy-4-[[(1R,2R)-2-(1-pyrrolidinyl)cyclohexyl]oxy]benzoyl chloride		C₁₈H₂₄ClNO₃	详情	详情
(VII)	29179	4-(Benzyloxy)benzaldehyde	4397-53-9	C₁₄H₁₂O₂	详情	详情
(VIII)	29181	2-[4-(benzyloxy)phenyl]-2-hydroxy-N,N-dimethylethanethioamide		C₁₇H₁₉NO₂S	详情	详情
(IX)	29182	6-(benzyloxy)-N,N-dimethyl-1-benzothiophen-2-amine		C₁₇H₁₇NOS	详情	详情
(X)	29183	[6-(benzyloxy)-2-(dimethylamino)-1-benzothiophen-3-yl](3-methoxy-4-[[(1R,2R)-2-(1-pyrrolidinyl)cyclohexyl]oxy]phenyl)methanone		C₃₅H₄₀N₂O₄S	详情	详情
(XI)	29184	bromo[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]magnesium		C₁₂H₁₆BrMgNO	详情	详情
(XII)	29185	(6-(benzyloxy)-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]-1-benzothiophen-3-yl)(3-methoxy-4-[[(1R,2R)-2-(1-pyrrolidinyl)cyclohexyl]oxy]phenyl)methanone		C₄₅H₅₀N₂O₅S	详情	详情
(XIII)	29186	(6-(benzyloxy)-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]-1-benzothiophen-3-yl)(3-methoxy-4-[[(1R,2R)-2-(1-pyrrolidinyl)cyclohexyl]oxy]phenyl)methanol		C₄₅H₅₂N₂O₅S	详情	详情
(XIV)	29187	1-(2-[4-[6-(benzyloxy)-3-(3-methoxy-4-[[(1R,2R)-2-(1-pyrrolidinyl)cyclohexyl]oxy]benzyl)-1-benzothiophen-2-yl]phenoxy]ethyl)pyrrolidine		C₄₅H₅₂N₂O₄S	详情	详情

Extended Information