2-(3,4-dimethoxyphenyl)-1-ethanol -Drug Synthesis Database

【结构式】

【分子编号】38711

【品名】2-(3,4-dimethoxyphenyl)-1-ethanol

【CA登记号】7417-21-2

【分子式】C₁₀H₁₄O₃

【分子量】182.21936

【元素组成】C 65.92% H 7.74% O 26.34%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(III)

The esterification of 2(S)-hydroxy-3-methoxy-3,3-diphenylpropionic acid (I) with NaOMe and dimethyl sulfate gives the methyl ester (II), which is submitted to and acid (TsOH) catalyzed transetherification with 2-(3,4-dimethoxyphenyl)ethanol (III) to yield 3-[2-(3,4-dimethoxyphenyl)ethoxy-2(S)-hydroxy-3,3-diphenylpropionic acid methyl ester (IV). The hydrolysis of (IV) with KOH in methanol affords the corresponding free acid (V), which is finally condensed with 4,6-dimethyl-2-(methylsulfonyl)pyrimidine (VI) by means of lithium amide in DMF.

参考文献中间体

合成目标

【1】 Jansen, R.; Hillen, H.; Kettschau, G.; Unger, L.; Hergenröder, S.; Kling, A.; Raschack, M.; Klinge, D.; Riechers, H.; Amberg, W.; Discovery and synthesis of (S)-3-[2-(3,4-dimethoxyphenyl)ethoxy]-2-(4,6-dimethylpyrimidin-2-yloxy)-3,3-diphenylpropionic acid (LU 302872), a novel orally active mixed ETA/ETB receptor antagonist. J Med Chem 1999, 42, 16, 3026.

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)	21154	(2S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid		C₁₆H₁₆O₄	详情	详情
(II)	38710	methyl (2S)-2-hydroxy-3-methoxy-3,3-diphenylpropanoate		C₁₇H₁₈O₄	详情	详情
(III)	38711	2-(3,4-dimethoxyphenyl)-1-ethanol	7417-21-2	C₁₀H₁₄O₃	详情	详情
(IV)	38712	methyl (2S)-3-[(3,4-dimethoxyphenethyl)oxy]-2-hydroxy-3,3-diphenylpropanoate		C₂₆H₂₈O₆	详情	详情
(V)	38713	(2S)-3-[(3,4-dimethoxyphenethyl)oxy]-2-hydroxy-3,3-diphenylpropionic acid		C₂₅H₂₆O₆	详情	详情
(VI)	38714	4,6-dimethyl-2-(methylsulfonyl)pyrimidine; 4,6-dimethyl-2-pyrimidinyl methyl sulfone		C₇H₁₀N₂O₂S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XI)

Condensation of (1S,2R)-2-[2-(3,4-dimethoxyphenyl)ethoxy]cyclohexyl tosylate (I) with 3(R)-benzyloxypyrrolidine (II) provides vernakalant benzyl ether (III), which is then debenzylated by catalytic hydrogenolysis over Pd/C (1). In a more direct approach, tosylate (I) is condensed with 3(R)-hydroxypyrrolidine (IV) to provide vernakalant (1, 2). An alternative strategy consists of the cyclization of (1R,2R)-2-[2-(3,4-dimethoxyphenyl)ethoxy]cyclohexylamine (V) with (R )-2-acetoxysuccinic anhydride (VI) by means of acetyl chloride or with ethyl 4-chloro-3(R )-hydroxybutyrate (VII) to give, respectively, the cyclic imide (VIIIa) or the pyrrolidinone (VIIIb), which is subsequently reduced and deprotected by means of Red-Al to yield the title hydroxypyrrolidine derivative (2). The O-benzyl precursor of vernakalant (III) can alternatively be obtained by condensation of 2(R )-[3(R )-benzyloxy-1-pyrrolidinyl]cyclohexan-1(R )-ol (IX) with 3,4-dimethoxyphenethyl trichloroacetimidate (X) (prepared from dimethoxyphenethyl alcohol [XI] and trichloroacetonitrile) in the presence of trifluoromethanesulfonic acid (2, 3). A related strategy for preparing the succinimide precursor of vernakalant (VIIIa) consists of the condensation of 2(R)-acetoxy-N-[2(R)-hydroxy-1(R)-cyclohexyl]succinimide (XII) with imidate (X) in the presence of boron trifluoride etherate (4). Scheme 1.

参考文献中间体

合成目标

【1】 Beatch, G.N., Choi, L.S.L., Jung, G. et al. (Cardiome Pharma Corp.). Aminocyclohexyl ether compounds and uses thereof. EP 1560812, EP1666459, JP 2006525227, WO 2004099137.
【2】 Plouvier, B.M.C., Chou, D.T.H., Jung, G. et al. (Cardiome Pharma Corp.). Synthetic process for aminocyclohexyl ether compounds. WO 2006088525.
【3】 Machiya, K., Ike, K., Watanabe, M., Yoshino, T., Okamoto, T., Morinaga, Y., Mizobata, S. (Astellas Pharma, Inc.). Production method of optically active cyclohexane ether compounds. WO 2006075778.
【4】 Roth, C.J., Jung, G., Plouvier, B.M.C., Chou, D.T.H., Yee, J.G.K. (Cardiome Pharma Corp.). Synthetic processes for the preparation of aminocyclohexyl ether compounds. WO 2006138673.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VIIIa)	65269			C₂₂H₂₉NO₇	详情	详情
(VIIIb)	65270			C₂₀H₂₉NO₅	详情	详情
(I)	65263	(1S,2R)-2-[2-(3,4-dimethoxyphenyl)ethoxy]cyclohexyl tosylate		C₂₃H₃₀O₆S	详情	详情
(II)	65264	(3R)-benzyloxypyrrolidine		C₁₁H₁₅NO	详情	详情
(III)	65265	vernakalant benzyl ether		C₂₇H₃₇NO₄	详情	详情
(IV)	14490	(3R)tetrahydro-1H-pyrrol-3-ol; R-3-hydroxypyrrolidine	2799-21-5	C₄H₉NO	详情	详情
(V)	65266	(1R,2R)-2-[2-(3,4-dimethoxyphenyl)ethoxy]cyclohexylamine		C₁₆H₂₅NO₃	详情	详情
(VI)	65267	(2R)-acetoxysuccinic anhydride	79814-40-7	C₆H₆O₅	详情	详情
(VII)	65268	ethyl 4-chloro-(3R)-hydroxybutyrate;	90866-33-4	C₆H₁₁ClO₃	详情	详情
(IX)	65271	(2R)-[(3R)-benzyloxy-1-pyrrolidinyl]cyclohexan-(1R)-ol		C₁₆H₂₅NO₂	详情	详情
(X)	65272	3,4-dimethoxyphenethyl trichloroacetimidate		C₁₂H₁₄Cl₃NO₃	详情	详情
(XI)	38711	2-(3,4-dimethoxyphenyl)-1-ethanol	7417-21-2	C₁₀H₁₄O₃	详情	详情
(XII)	65273	(2R)-acetoxy-N-[(2R)-hydroxy-(1R)-cyclohexyl]succinimide		C₁₂H₁₇O₅	详情	详情

合成路线3

该中间体在本合成路线中的序号：(XI)

Several alternative routes to the intermediate amine (V) are shown in Scheme 4. The asymmetric reduction of ethyl 2-oxocyclohexanecarboxylate (XLII) gives the (1R,2S)-hydroxy ester (XLIII), which is converted to amide (XLIV) by treatment with aqueous ammonia and ammonium chloride. After activation of the hydroxyl group of (XLIV) as the corresponding mesylate (XLV), displacement with the potassium alkoxide of 3,4-dimethoxyphenethyl alcohol (XI) affords the trans-amide ether (XLVI). The target amine (V) is then obtained by Hofmann rearrangement of carboxamide (XLVI) employing NaOCl and NaOH. A different resolution method involves transesterification of ethyl 2-oxocyclohexanecarboxylate (XLII) with benzyl alcohol, followed by enzymatic reduction of the resulting benzyl keto ester (XLVII) with carbonyl reductase to provide the (1R,2R)-hydroxy ester (XLVIII). Coupling of (XLVIII) with imidate (X) furnishes the benzyl phenethoxycyclohexanecarboxylate (XLIX), which is subjected to benzyl group hydrogenolysis to provide acid (L). This compound can also be obtained by condensation of ethyl 2(R)-hydroxy-1(R)-cyclohexanecarboxylate (LI) with 3,4-dimethoxyphenethyl trichloroacetimidate (X), followed by alkaline hydrolysis of the obtained ethyl 2-phenethoxycyclohexanecarboxylate (LII). Optionally, the ethyl ester (LII) can be converted to amide (XLVI) by reaction with methanolic ammonia, or to hydrazide (LIII) by treatment with hydrazine hydrate in EtOH. Conversion of acid (L) to the target amine (V) can then be accomplished by Curtius rearrangement employing diphenylphosphoryl azide. Analogously, diazotization of hydrazide (LIII), followed by Curtius rearrangement of the intermediate acyl azide and alkaline hydrolysis results in the target amine (V) (2). Scheme 4.

参考文献中间体

合成目标

【2】 Plouvier, B.M.C., Chou, D.T.H., Jung, G. et al. (Cardiome Pharma Corp.). Synthetic process for aminocyclohexyl ether compounds. WO 2006088525.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(V)	65266	(1R,2R)-2-[2-(3,4-dimethoxyphenyl)ethoxy]cyclohexylamine		C₁₆H₂₅NO₃	详情	详情
(X)	65272	3,4-dimethoxyphenethyl trichloroacetimidate		C₁₂H₁₄Cl₃NO₃	详情	详情
(XI)	38711	2-(3,4-dimethoxyphenyl)-1-ethanol	7417-21-2	C₁₀H₁₄O₃	详情	详情
(XLII)	11889	ethyl 2-oxocyclohexanecarboxylate; Ethyl 2-cyclohexanonecarboxylate	1655-07-8	C₉H₁₄O₃	详情	详情
(XLIII)	15589	ethyl 2-hydroxycyclohexanecarboxylate; Ethyl cis-2-hydroxy-1-cyclohexanecarboxylate	6149-52-6	C₉H₁₆O₃	详情	详情
(XLIV)	65300	cis-2-Hydroxy-1-Cyclohexanecarboxamide; (1R,2S)-2-Hydroxy-1-Cyclohexanecarboxamide; Zinc01081409	73045-98-4	C₇H₁₃NO₂	详情	详情
(XLV)	65301			C₇H₁₂NaNO₂	详情	详情
(XLVI)	65302			C₁₇H₂₅NO₄	详情	详情
(XLVII)	65303			C₁₄H₁₆O₃	详情	详情
(XLVIII)	65304			C₁₄H₁₈O₃	详情	详情
(XLIX)	65305			C₂₄H₃₀O₅	详情	详情
(L)	65306			C₁₆H₂₄O₅	详情	详情
(LI)	65307	Ethyl trans-2-hydroxycyclohexanecarboxylate	3444-72-2	C₉H₁₆O₃	详情	详情
(LII)	65308			C₁₉H₂₈O₅	详情	详情
(LIII)	65309			C₁₇H₂₆N₂O₄	详情	详情

Extended Information