Michellamine B, NSC-661755, NSC-649324, -Drug Synthesis Database

【结构式】

【药物名称】Michellamine B, NSC-661755, NSC-649324

【化学名称】(1S,1'R,3S,3'R)-2,2'-Bis[4-(6,8-dihydroxy-1,3-dimethyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-1-hydroxy-8-methoxy-6-methylnaphthalene]

【CA登记号】137893-48-2

【分子式】C₄₆H₄₈N₂O₈

【分子量】756.90406

【开发单位】National Cancer Institute (Originator), Hauser (Licensee)

【药理作用】AIDS Medicines, Anti-HIV Agents, ANTIINFECTIVE THERAPY

合成路线1 合成路线2 合成路线3

合成路线1

The isoquinoline intermediate (IX) has been synthesized as follows: The reduction of methyl 3,5-dimethoxybenzoate (I) with LiAlH4 gives the benzyl alcohol (II), which is treated with Swern oxidant to yield the benzaldehyde (III). The treatment of (III) with the sequence outlined in the scheme the chiral secondary amine is obtained. The cyclization of (IV) with ammonium formate catalyzed by Pd, followed by a treatment with acetic anhydride and POCl3 afforded the dihydroisoquinoline (V), which is reduced with LiAlH4 to the tetrahydro derivative (VI). Cleavage of the methoxy groups of (VI) with BBr3 affords the dihydroxycompound (VII), which is benzylated with benzyl bromide and Cs2CO3 providing the fully benzylated tetrahydroisoquinoline (VIII). Finally, this compound is iodinated with I2 and Ag2SO4 furnishing the desired isoquinoline intermediate (IX).

参考文献中间体

【1】 Hoye, T.R.; et al.; Total synthesis of michellamines A-C, korupensamines A-D, and ancistrobrevine B. J Org Chem 1999, 64, 19, 7184.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	12912	1-(Bromomethyl)benzene; Alpha-bromotoluene	100-39-0	C₇H₇Br	详情	详情
	40727	2-phenyl-2-propanamine; 1-methyl-1-phenylethylamine	585-32-0	C₉H₁₃N	详情	详情
(I)	37841	methyl 3,5-dimethoxybenzoate	2150-37-0	C₁₀H₁₂O₄	详情	详情
(II)	35424	(3,5-dimethoxyphenyl)methanol	705-76-0	C₉H₁₂O₃	详情	详情
(III)	21720	3,5-dimethoxybenzaldehyde	7311-34-4	C₉H₁₀O₃	详情	详情
(IV)	37842	(2R)-1-(3,5-dimethoxyphenyl)-N-(1-methyl-1-phenylethyl)-2-propanamine; N-[(1R)-2-(3,5-dimethoxyphenyl)-1-methylethyl]-N-(1-methyl-1-phenylethyl)amine		C₂₀H₂₇NO₂	详情	详情
(V)	37843	(3R)-6-methoxy-1,3-dimethyl-3,4-dihydro-8-isoquinolinyl methyl ether; (3R)-6,8-dimethoxy-1,3-dimethyl-3,4-dihydroisoquinoline		C₁₃H₁₇NO₂	详情	详情
(VI)	37844	(1R,3R)-6-methoxy-1,3-dimethyl-1,2,3,4-tetrahydro-8-isoquinolinyl methyl ether; (1R,3R)-6,8-dimethoxy-1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline		C₁₃H₁₉NO₂	详情	详情
(VII)	37845	(1R,3R)-1,3-dimethyl-1,2,3,4-tetrahydro-6,8-isoquinolinediol		C₁₁H₁₅NO₂	详情	详情
(VIII)	37846	benzyl (1R,3R)-2-benzyl-6-(benzyloxy)-1,3-dimethyl-1,2,3,4-tetrahydro-8-isoquinolinyl ether; (1R,3R)-2-benzyl-6,8-bis(benzyloxy)-1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline		C₃₂H₃₃NO₂	详情	详情
(IX)	37847	benzyl (1R,3R)-2-benzyl-6-(benzyloxy)-5-iodo-1,3-dimethyl-1,2,3,4-tetrahydro-8-isoquinolinyl ether; (1R,3R)-2-benzyl-6,8-bis(benzyloxy)-5-iodo-1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline		C₃₂H₃₂INO₂	详情	详情

合成路线2

The intermediate naphthaleneboronic acid (XIX) has been obtained as follows: The bromination of the 3-methylphenyl methoxymethyl ether (X) with NBS gives the dibromo compound (XI), which is treated with sodium phenylsulfinate to afford the sulfone (XII). The condensation of (XII) with methyl crotonate (XIII) by means of LDA and KOH gives the butyric acid (XIV), which is cyclized to the tetralone (XV) by means of trifluoroacetic anhydride (TFAA). The aromatization of (XV) by means of t-BuOK or NaOH yields the 5-bromo-8-(methoxymethoxy)-3-methyl-1-naphthol (XVI), which is methylated with dimethyl sulfate to afford the methyl ether (XVII). The reaction of (XVII) with trimethyl borate and n-BuLi gives the boronic ester (XVIII), which is hydrolyzed with water and ammonium chloride yielding the desired naphthaleneboronic acid (XIX). Alternatively, the naphthaleneboronic acid (XIX) has been obtained as follows: The reaction of 2,4-dibromophenol methoxymethyl ether (XX) with n-BuLi and cyclohexyl(isopropyl)amine gives the benzyne intermediate (XXI), which, without isolation is cyclized with the lithium enolate of 3-methylcrotonic acid dimethylamide (XXII) to afford the previously described naphthol (XVI), which is purified by chromatography.

参考文献中间体

【1】 Hoye, T.R.; et al.; Total synthesis of michellamines A-C, korupensamines A-D, and ancistrobrevine B. J Org Chem 1999, 64, 19, 7184.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(X)	37848	1-(methoxymethoxy)-3-methylbenzene; methoxymethyl 3-methylphenyl ether		C₉H₁₂O₂	详情	详情
(XI)	37849	[4-bromo-3-(bromomethyl)phenoxy]methyl methyl ether; 1-bromo-2-(bromomethyl)-4-(methoxymethoxy)benzene		C₉H₁₀Br₂O₂	详情	详情
(XII)	37850	2-bromo-5-(methoxymethoxy)benzyl phenyl sulfone; [2-bromo-5-(methoxymethoxy)benzyl](dioxo)phenyl-lambda(6)-sulfane		C₁₅H₁₅BrO₄S	详情	详情
(XIII)	26361	methyl (E)-2-butenoate	623-43-8	C₅H₈O₂	详情	详情
(XIV)	37851	4-[2-bromo-5-(methoxymethoxy)phenyl]-3-methyl-4-(phenylsulfonyl)butyric acid		C₁₉H₂₁BrO₆S	详情	详情
(XV)	37852	5-bromo-8-(methoxymethoxy)-3-methyl-4-(phenylsulfonyl)-3,4-dihydro-1(2H)-naphthalenone		C₁₉H₁₉BrO₅S	详情	详情
(XVI)	37853	5-bromo-8-(methoxymethoxy)-3-methyl-1-naphthol		C₁₃H₁₃BrO₃	详情	详情
(XVII)	37854	5-bromo-8-(methoxymethoxy)-3-methyl-1-naphthyl methyl ether; 5-bromo-1-methoxy-8-(methoxymethoxy)-3-methylnaphthalene		C₁₄H₁₅BrO₃	详情	详情
(XVIII)	37855	dimethyl 5-methoxy-4-(methoxymethoxy)-7-methyl-1-naphthylboronate		C₁₆H₂₁BO₅	详情	详情
(XIX)	37856	5-methoxy-4-(methoxymethoxy)-7-methyl-1-naphthylboronic acid		C₁₄H₁₇BO₅	详情	详情
(XX)	37857	(2,4-dibromophenoxy)methyl methyl ether; 2,4-dibromo-1-(methoxymethoxy)benzene		C₈H₈Br₂O₂	详情	详情
(XXI)	37858	1-bromo-4-(methoxymethoxy)-1,3-cyclohexadien-5-yne; 4-bromo-1,3-cyclohexadien-5-yn-1-yl methoxymethyl ether		C₈H₇BrO₂	详情	详情
(XXII)	37859			C₈H₁₄LiNO	详情	详情

合成路线3

The condensation of the isoquinoline intermediate (IX) with the naphthaleneboronic acid intermediate (XIX) by means of palladium tetrakis(triphenylphosphine) and NaHCO3 in refluxing ethanol/toluene gives a 5:4 mixture of the (S) and (R) atropaisomers (XXIII), which, without separation, are treated with methanolic HCl to eliminate the methoxymethyl protecting groups and yield a mixture of (S) and (R) (XXIV). The dimerization of this mixture by means of silver oxide in dichloromethane affords a mixture of the (R,R), (R,S) and (S,S) dimers (XXV), which is deprotected with H2 over Pd/C in methanol/dichloromethane and submitted to HPLC to obtain the target (R,S) atropaisomer.

参考文献中间体

【1】 Hoye, T.R.; et al.; Total synthesis of michellamines A-C, korupensamines A-D, and ancistrobrevine B. J Org Chem 1999, 64, 19, 7184.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(S)-(XXIV)	37861	4-[(1R,3R)-2-benzyl-6,8-bis(benzyloxy)-1,3-dimethyl-1,2,3,4-tetrahydro-5-isoquinolinyl]-8-methoxy-6-methyl-1-naphthol	C₄₄H₄₃NO₄	详情	详情
(S)-(XXIII)	38319	(1R,3R)-2-benzyl-6,8-bis(benzyloxy)-5-(4,5-dimethoxy-7-methyl-1-naphthyl)-1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline; benzyl (1R,3R)-2-benzyl-6-(benzyloxy)-5-(4,5-dimethoxy-7-methyl-1-naphthyl)-1,3-dimethyl-1,2,3,4-tetrahydro-8-isoquinolinyl ether	C₄₆H₄₇NO₅	详情	详情
(R)-(XXIII)	63435	2-benzyl-6,8-bis(benzyloxy)-5-[5-methoxy-4-(methoxymethoxy)-7-methyl-1-naphthyl]-1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline; benzyl 2-benzyl-6-(benzyloxy)-5-[5-methoxy-4-(methoxymethoxy)-7-methyl-1-naphthyl]-1,3-dimethyl-1,2,3,4-tetrahydro-8-isoquinolinyl ether	C₄₆H₄₇NO₅	详情	详情
(R)-(XXIV)	63438	4-{1,3-dimethyl-2-(phenylmethyl)-6,8-bis[(phenylmethyl)oxy]-1,2,3,4-tetrahydro-5-isoquinolinyl}-6-methyl-8-(methyloxy)-1-naphthalenol	C₄₄H₄₃NO₄	详情	详情
(IX)	37847	benzyl (1R,3R)-2-benzyl-6-(benzyloxy)-5-iodo-1,3-dimethyl-1,2,3,4-tetrahydro-8-isoquinolinyl ether; (1R,3R)-2-benzyl-6,8-bis(benzyloxy)-5-iodo-1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline	C₃₂H₃₂INO₂	详情	详情
(XIX)	37856	5-methoxy-4-(methoxymethoxy)-7-methyl-1-naphthylboronic acid	C₁₄H₁₇BO₅	详情	详情
(XXV)	37862		C₈₈H₈₂N₂O₈	详情	详情

Extended Information