(1R)-1-[4-(benzyloxy)phenyl]-2-[(3,4-dimethoxyphenethyl)amino]-1-ethanol -Drug Synthesis Database

【结构式】

【分子编号】31687

【品名】(1R)-1-[4-(benzyloxy)phenyl]-2-[(3,4-dimethoxyphenethyl)amino]-1-ethanol

【CA登记号】

【分子式】C₂₅H₂₉NO₄

【分子量】407.5096

【元素组成】C 73.69% H 7.17% N 3.44% O 15.7%

与该中间体有关的原料药合成路线共 6 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5 合成路线6

合成路线1

该中间体在本合成路线中的序号：(VI)

The benzylation of 4-hydroxymandelic acid (I) with benzyl alcohol (II) and K2CO3 in methanol gives 4-benzyloxymandelic acid (III), which is condensed with 2-(3,4-dimethoxyphenyl)ethylamine (IV) by means of (C2H5O)2PON3 in THF to afford N-(3,4-dimethoxyphenylethyl)-4-benzyloxymandelamide (V). The reduction of (V) with diborane in THF yields the final product protected at the phenolic hydroxyl (VI) This compound is finally deprotected by hydrogenolysis with H2 over Pd/C.

参考文献中间体

合成目标

【1】 Noguchi, K.; Irie, K.; Preparation of optically active benzyl alcohol derivative. JP 54070231 .
【2】 Blancafort, P.; Castaner, J.; Serradell, M.N.; TA-064. Drugs Fut 1982, 7, 6, 407.

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)	31684	(2R)-4-Hydroxymandelic acid; (2R)-2-Hydroxy-2-(4-hydroxyphenyl)ethanoic acid	7198-10-9	C₈H₈O₄	详情	详情
(II)	18710	Benzyl alcohol; Phenylmethanol	100-51-6	C₇H₈O	详情	详情
(III)	31685	(2R)-2-[4-(benzyloxy)phenyl]-2-hydroxyethanoic acid; (2R)-4-benzyloxymandelic acid		C₁₅H₁₄O₄	详情	详情
(IV)	10098	2-(3,4-Dimethoxyphenyl)-1-ethanamine; 3,4-Dimethoxyphenethylamine; 2-(3,4-Dimethoxyphenyl)ethylamine	120-20-7	C₁₀H₁₅NO₂	详情	详情
(V)	31686	(2R)-2-[4-(benzyloxy)phenyl]-N-(3,4-dimethoxyphenethyl)-2-hydroxyethanamide		C₂₅H₂₇NO₅	详情	详情
(VI)	31687	(1R)-1-[4-(benzyloxy)phenyl]-2-[(3,4-dimethoxyphenethyl)amino]-1-ethanol		C₂₅H₂₉NO₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VII)

The condensation of 4-benzyloxybenzaldehyde (VII) with N-(3,4-dimethoxyphenylethyl)glycine (VIII) in refluxing pyridine also gives the protected product (VI).

参考文献中间体

合成目标

【1】 Ikezaki, M.; Umino, N.; Iwakuma, T.; Process for preparation of benzyl alcohol derivatives. JP 52051333 .
【2】 Blancafort, P.; Castaner, J.; Serradell, M.N.; TA-064. Drugs Fut 1982, 7, 6, 407.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VII)	29179	4-(Benzyloxy)benzaldehyde	4397-53-9	C₁₄H₁₂O₂	详情	详情
(VII)	31687	(1R)-1-[4-(benzyloxy)phenyl]-2-[(3,4-dimethoxyphenethyl)amino]-1-ethanol		C₂₅H₂₉NO₄	详情	详情
(VIII)	31688	N-(3,4-Dimethoxyphenylethyl)glycine; 2-[(3,4-Dimethoxyphenethyl)amino]acetic acid		C₁₂H₁₇NO₄	详情	详情

合成路线3

该中间体在本合成路线中的序号：(VI)

The condensation of 4-benzyloxyphenacyl chloride (XV) with the amine (IV) in refluxing CH2Cl2 gives N-(3,4-dimethoxyphenylethyl)-4-benzyloxyphenacylamine (XVI), which is reduced with NaSH4 in ethanol, also affording the protected product (VI).

参考文献中间体

合成目标

【1】 Ikezaki, M.; Ito, N.; Okazaki, Y.; Hoshiyama, M.; Nagao, T. (Tanabe Seiyaku Co., Ltd.); Benzyl alcohol, amine derivatives. AT 343628B; BE 0833731; DE 2542881; FR 2326182; GB 1499345; JP 50157327; JP 53010974; JP 7795620; JP 7795621; NL 7511564; US 4032575; US 4072759 .
【2】 Blancafort, P.; Castaner, J.; Serradell, M.N.; TA-064. Drugs Fut 1982, 7, 6, 407.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IV)	10098	2-(3,4-Dimethoxyphenyl)-1-ethanamine; 3,4-Dimethoxyphenethylamine; 2-(3,4-Dimethoxyphenyl)ethylamine	120-20-7	C₁₀H₁₅NO₂	详情	详情
(VI)	31687	(1R)-1-[4-(benzyloxy)phenyl]-2-[(3,4-dimethoxyphenethyl)amino]-1-ethanol		C₂₅H₂₉NO₄	详情	详情
(XV)	31689	4-Benzyloxyphenacyl chloride; 1-[4-(Benzyloxy)phenyl]-2-chloro-1-ethanone	39188-62-0	C₁₅H₁₃ClO₂	详情	详情
(XVI)	10100	1-[4-(Benzyloxy)phenyl]-2-[(3,4-dimethoxyphenethyl)amino]-1-ethanone; N-(3,4-Dimethoxyphenylethyl)-4-benzyloxyphenacylamine		C₂₅H₂₇NO₄	详情	详情

合成路线4

该中间体在本合成路线中的序号：(VI)

The formylation of 2-(4-hydroxyphenyl)glycine (IX) as usual gives N-formyl-2-(4-hydroxyphenyl)glycine (X), which by treatment with benzyl alcohol as before yields N-formyl-2-(4-benzyloxyphenyl)glycine (XI). The condensation of (XI) with the amine (IV) by means of butyl chloroformate affords the corresponding amide (XII), which is deformylated by treatment with HCl in methanol to give the glycinamide (XIII). The diazotation of (XIII) with NaNO2 in acetic acid affords N-(3,4-dimethoxyphenylethyl)-O-acetyl-4-benzyloxymandel-amide (XIV), which is finally reduced and deacetylated with LiAlH4 in THF yielding the protected product (VI).

参考文献中间体

合成目标

【1】 Noguchi, K.; Irie, K.; Preparation of optically active benzyl alcohol derivative. JP 54070232 .
【2】 Noguchi, K.; Irie, K.; Preparation of optically active benzyl alcohol derivative. JP 54070233 .
【3】 Blancafort, P.; Castaner, J.; Serradell, M.N.; TA-064. Drugs Fut 1982, 7, 6, 407.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IV)	10098	2-(3,4-Dimethoxyphenyl)-1-ethanamine; 3,4-Dimethoxyphenethylamine; 2-(3,4-Dimethoxyphenyl)ethylamine	120-20-7	C₁₀H₁₅NO₂	详情	详情
(VI)	31687	(1R)-1-[4-(benzyloxy)phenyl]-2-[(3,4-dimethoxyphenethyl)amino]-1-ethanol		C₂₅H₂₉NO₄	详情	详情
(IX)	31690	(2R)-2-amino-2-(4-hydroxyphenyl)ethanoic acid; (2R)-2-(4-hydroxyphenyl)glycine; D-(-)-p-Hydroxyphenylglycine; (R)-2-amino-2-(4-hydroxyphenyl)acetic acid	22818-40-2	C₈H₉NO₃	详情	详情
(X)	31691	(2R)-2-(formylamino)-2-(4-hydroxyphenyl)ethanoic acid		C₉H₉NO₄	详情	详情
(XI)	31692	N-formyl-2-(4-benzyloxyphenyl)glycine; (2R)-2-[4-(benzyloxy)phenyl]-2-(formylamino)ethanoic acid		C₁₆H₁₅NO₄	详情	详情
(XII)	31693	(2R)-2-[4-(benzyloxy)phenyl]-N-(3,4-dimethoxyphenethyl)-2-(formylamino)ethanamide		C₂₆H₂₈N₂O₅	详情	详情
(XIII)	31694	(2R)-2-amino-2-[4-(benzyloxy)phenyl]-N-(3,4-dimethoxyphenethyl)ethanamide		C₂₅H₂₈N₂O₄	详情	详情
(XIV)	31695	(1R)-1-[4-(Benzyloxy)phenyl]-2-[(3,4-dimethoxyphenethyl)amino]-2-oxoethyl acetate; N-(3,4-Dimethoxyphenylethyl)-O-acetyl-4-benzyloxymandel-amide		C₂₇H₂₉NO₆	详情	详情

合成路线5

该中间体在本合成路线中的序号：(VI)

The oxidation of 4-benzyloxyphenacyl chloride (XV) with KI and DMSO gives 4-benzyloxy-alpha-oxophenylacetaldehyde (XVII), which is condensed with the amine (IV) to afford the corresponding Schiff base (XVIII). Finally, this compound is reduced with NaBH4 yielding the protected product (VI), already obtained.

参考文献中间体

合成目标

【1】 Ikezaki, M.; Umino, N.; Iwakuma, T.; Process for preparation of benzyl alcohol derivatives. JP 52051334 .
【2】 Ikezaki, M.; Umino, N.; Iwakuma, T.; Process for preparation of benzyl alcohol derivatives. JP 52051335 .
【3】 Blancafort, P.; Castaner, J.; Serradell, M.N.; TA-064. Drugs Fut 1982, 7, 6, 407.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IV)	10098	2-(3,4-Dimethoxyphenyl)-1-ethanamine; 3,4-Dimethoxyphenethylamine; 2-(3,4-Dimethoxyphenyl)ethylamine	120-20-7	C₁₀H₁₅NO₂	详情	详情
(VI)	31687	(1R)-1-[4-(benzyloxy)phenyl]-2-[(3,4-dimethoxyphenethyl)amino]-1-ethanol		C₂₅H₂₉NO₄	详情	详情
(XV)	31689	4-Benzyloxyphenacyl chloride; 1-[4-(Benzyloxy)phenyl]-2-chloro-1-ethanone	39188-62-0	C₁₅H₁₃ClO₂	详情	详情
(XVII)	31696	2-[4-(benzyloxy)phenyl]-2-oxoacetaldehyde; 4-benzyloxy-alpha-oxophenylacetaldehyde		C₁₅H₁₂O₃	详情	详情
(XVIII)	31697	1-[4-(benzyloxy)phenyl]-2-[(3,4-dimethoxyphenethyl)imino]-1-ethanone		C₂₅H₂₅NO₄	详情	详情

合成路线6

该中间体在本合成路线中的序号：(V)

The enantioselective reduction of the phenacyl bromide (I) by means of a culture of Rhodotolule rubra in water gives the a(R)-hydroxy enantiomer (II), which is treated with K2CO3 in refluxing ethanol to yield the chiral epoxide (III). The condensation of (III) with 2-(3,4-dimethoxyphenyl)ethylamine (IV) by means of N,O-bis(trimethylsilyl)acetamide (TMSA) in hot DMSO affords the benzylated precursor (V), which is finally deprotected by means of HCl in water to provide the target Denopamine.

参考文献中间体

合成目标

【1】 Goswami, J.; et al.; A conventient stereoselective synthesis of (R)-(-)-denopamine and (R)-(-)-salmeterol. Tetrahedron Asymmetry 2001, 12, 24, 3343.

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)	36424	1-[4-(benzyloxy)phenyl]-2-bromo-1-ethanone		C₁₅H₁₃BrO₂	详情	详情
(II)	62589	(1R)-1-[4-(benzyloxy)phenyl]-2-bromo-1-ethanol		C₁₅H₁₅BrO₂	详情	详情
(III)	62590	(2R)-2-[4-(benzyloxy)phenyl]oxirane; benzyl 4-[(2R)oxiranyl]phenyl ether		C₁₅H₁₄O₂	详情	详情
(IV)	10098	2-(3,4-Dimethoxyphenyl)-1-ethanamine; 3,4-Dimethoxyphenethylamine; 2-(3,4-Dimethoxyphenyl)ethylamine	120-20-7	C₁₀H₁₅NO₂	详情	详情
(V)	31687	(1R)-1-[4-(benzyloxy)phenyl]-2-[(3,4-dimethoxyphenethyl)amino]-1-ethanol		C₂₅H₂₉NO₄	详情	详情

Extended Information