Cepharanthine, BRN 0075231, LS-52756, -Drug Synthesis Database

【结构式】

【药物名称】Cepharanthine, BRN 0075231, LS-52756

【化学名称】(14S,27R)-22,33-Dimethoxy-13,28-dimethyl-2,5,7,20-tetraoxa-13,28-diazaoctacyclo[25.6.2.2(16,19).1(3,10).1(21,25).0(4,8).0(14,39).0(31,35)]nonatriaconta-1(33),3,8,10(39),16,18,21(38),22,24,31,34,36-dodecaene

【CA登记号】481-49-2

【分子式】C₃₇H₃₈N₂O₆

【分子量】606.72521

【开发单位】

【药理作用】AIDS Medicines, Antibiotics and Alkaloids, Anti-HIV Agents, ANTIINFECTIVE THERAPY, ONCOLYTIC DRUGS, Apoptosis Inducers, NF-kappaB (NFKB) Activation Inhibitors

合成路线1 合成路线2 合成路线3

合成路线1

The condensation of 3,4-methylenedioxy-5-[2-methoxy-4-(N-carbobenzoxyaminoethyl)phenoxy]phenylethylamine (I) with 4-[2-methoxy-5-(methoxycarbonylmethyl)phenoxyphenylacetic acid (II) by means of dicyclohexylcarbodiimide in methylene chloride gives the amide (III), which is hydrolyzed with aqueous Na2CO3 to the corresponding free acid (IV). The cyclization of (IV) by the p-nitrophenyl ester method yields the cyclobisamide (V), which by a Bischler-Napieralski reaction with POCl3 in chloroform is converted into the bis(3,4-dihydroisoquinoline) (VI). The hydrogenation of (VI) with H2 over Pt affords the bis(tetrahydroisoquinoline) derivative (VII), which without isolation is finally methylated with formalin and NaBH4.

参考文献中间体

【1】 Tomita, M.; et al.; Synthesis of di-cepharanthine. Tetrahedron Lett 1967, 1201-06.
【2】 Kondo, H.; et al.; US 2206407 .
【3】 Serradell, M.N.; Blancafort, P.; Mealy, N.; Castañer, J.; Cepharanthine. Drugs Fut 1979, 4, 7, 481.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	39554	benzyl 4-[[6-(2-aminoethyl)-1,3-benzodioxol-4-yl]oxy]-3-methoxyphenethylcarbamate	C₂₆H₂₈N₂O₆	详情	详情
(II)	39555	2-[4-[2-methoxy-5-(2-methoxy-2-oxoethyl)phenoxy]phenyl]acetic acid	C₁₈H₁₈O₆	详情	详情
(III)	39556	methyl 2-[3-(4-[2-[(2-[7-[4-(2-[[(benzyloxy)carbonyl]amino]ethyl)-2-methoxyphenoxy]-1,3-benzodioxol-5-yl]ethyl)amino]-2-oxoethyl]phenoxy)-4-methoxyphenyl]acetate	C₄₄H₄₄N₂O₁₁	详情	详情
(IV)	39557	2-[3-(4-[2-[(2-[7-[4-(2-[[(benzyloxy)carbonyl]amino]ethyl)-2-methoxyphenoxy]-1,3-benzodioxol-5-yl]ethyl)amino]-2-oxoethyl]phenoxy)-4-methoxyphenyl]acetic acid	C₄₃H₄₂N₂O₁₁	详情	详情
(V)	39558	22,33-dimethoxy-2,5,7,20-tetraoxa-13,28-diazahexacyclo[29.2.2.2(16,19).1(3,10).1(21,25).0(4,8)]nonatriaconta-1(33),3,8,10(39),16,18,21(38),22,24,31,34,36-dodecaene-14,27-dione	C₃₅H₃₄N₂O₈	详情	详情
(VI)	39559	22,33-dimethoxy-2,5,7,20-tetraoxa-13,28-diazaoctacyclo[25.6.2.2(16,19).1(3,10).1(21,25).0(4,8).0(14,39).0(31,35)]nonatriaconta-1(33),3,8,10(39),13,16,18,21(38),22,24,27,31,34,36-tetradecaene; 22-methoxy-2,5,7,20-tetraoxa-13,28-diazaoctacyclo[25.6.2.2(16,19).1(3,10).1(21,25).0(4,8).0(14,39).0(31,35)]nonatriaconta-1(33),3,8,10(39),13,16,18,21(38),22,24,27,31,34,36-tetradecaen-33-yl methyl ether	C₃₅H₃₀N₂O₆	详情	详情
(VII)	39560	(14S,27R)-22,33-dimethoxy-2,5,7,20-tetraoxa-13,28-diazaoctacyclo[25.6.2.2(16,19).1(3,10).1(21,25).0(4,8).0(14,39).0(31,35)]nonatriaconta-1(33),3,8,10(39),16,18,21(38),22,24,31,34,36-dodecaene; (14S,27R)-22-methoxy-2,5,7,20-tetraoxa-13,28-diazaoctacyclo[25.6.2.2(16,19).1(3,10).1(21,25).0(4,8).0(14,39).0(31,35)]nonatriaconta-1(33),3,8,10(39),16,18,21(38),22,24,31,34,36-dodecaen-33-yl methyl ether	C₃₅H₃₄N₂O₆	详情	详情

合成路线2

The starting phenylethylamine (I) is prepared by condensation of N-formyl-5-bromo-3,4-methylenedioxyphenylethylamine (VIII) with N-carbobenzoxy-3-methoxy-4-hydroxyphenylethylamine (IX) through an Ullman condensation catalysed by CuO, followed by elimination of the formyl group with HCl in methanol. Compound (VIII) is prepared as follows: 3,4-dihydroxy-5-bromobenzaldehyde (X) is methylenated with methylene bromide (A) and CuO in DMF giving 3,4-methylenedioxy-5-bromobenzaldehyde (XI), which is condensed with nitromethane (B) in acetic acid containing ammonium acetate affording 3,4-methylenedioxy-5-bromo-beta-nitrostyrene (XII). The reduction of (XII) under Clemensen conditions yields 3,4-methylenedioxy-5-bromophenylethylamine (XIII), which is finally formylated with formic acid in decalin. Compound (IX) is prepared as follows: 3-methoxy-4-hydroxy-beta-nitrostyrene (XIV) is treated with ethyl chloroformate (C) in pyridine yielding the corresponding ethoxycarbonyl derivative (XV), which is reduced under Clemensen conditions to 3-methoxy-4-ethoxycarbonyloxyphenylethylamine (XVI). Finally, this compound is treated first with benzyloxycarbonyl chloride and then with aqueous NaHCO3.

参考文献中间体

【1】 Tomita, M.; et al.; Synthesis of di-cepharanthine. Tetrahedron Lett 1967, 1201-06.
【2】 Serradell, M.N.; Blancafort, P.; Mealy, N.; Castañer, J.; Cepharanthine. Drugs Fut 1979, 4, 7, 481.
【3】 Kondo, H.; et al.; US 2206407 .

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)	10252	1,2-Dibromoethane; Ethylene dibromide	106-93-4	C₂H₄Br₂	详情	详情
(B)	39563	nitromethane	75-52-5	CH₃NO₂	详情	详情
(I)	39554	benzyl 4-[[6-(2-aminoethyl)-1,3-benzodioxol-4-yl]oxy]-3-methoxyphenethylcarbamate		C₂₆H₂₈N₂O₆	详情	详情
(VIII)	39566	2-(7-bromo-1,3-benzodioxol-5-yl)ethylformamide		C₁₀H₁₀BrNO₃	详情	详情
(IX)	39570	benzyl 3-hydroxy-4-methoxyphenethylcarbamate		C₁₇H₁₉NO₄	详情	详情
(X)	39561	3-bromo-4,5-dihydroxybenzaldehyde	16414-34-9	C₇H₅BrO₃	详情	详情
(XI)	39562	7-bromo-1,3-benzodioxole-5-carbaldehyde		C₈H₅BrO₃	详情	详情
(XII)	39564	4-bromo-6-[(E)-2-nitroethenyl]-1,3-benzodioxole		C₉H₆BrNO₄	详情	详情
(XIII)	39565	2-(7-bromo-1,3-benzodioxol-5-yl)ethylamine; 2-(7-bromo-1,3-benzodioxol-5-yl)-1-ethanamine		C₉H₁₀BrNO₂	详情	详情
(XIV)	39567	2-methoxy-5-[(E)-2-nitroethenyl]phenol		C₉H₉NO₄	详情	详情
(XV)	39568	ethyl 2-methoxy-5-[(E)-2-nitroethenyl]phenyl carbonate		C₁₂H₁₃NO₆	详情	详情
(XVI)	39569	5-(2-aminoethyl)-2-methoxyphenyl ethyl carbonate		C₁₂H₁₇NO₄	详情	详情
(C)	11229	1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate	541-41-3	C₃H₅ClO₂	详情	详情

合成路线3

The starting phenylacetic acid (II) is prepared by an Ullman condensation between tert-butyl-4-hydroxyphenylacetate (XVII) and methyl 3-bromo-4-methoxyphenylacetate (XVIII) catalysed by CuO, followed by treatment with p-toluenesulfonic acid in benzene. Compound (XVII) is prepared by esterification of 4-benzyloxyphenylacetic acid (XIX) to the corresponding tart butyl ester (XX), followed by hydrogenolysis with H2 over Pd/C. Compound (XVIII) is prepared by methylation of methyl 3-bromo-4-hydroxyphenylacetate (XXI) with dimethyl sulfate and K2CO3 in DMF.

参考文献中间体

【1】 Kondo, H.; et al.; US 2206407 .
【2】 Tomita, M.; et al.; Synthesis of di-cepharanthine. Tetrahedron Lett 1967, 1201-06.
【3】 Serradell, M.N.; Blancafort, P.; Mealy, N.; Castañer, J.; Cepharanthine. Drugs Fut 1979, 4, 7, 481.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(II)	39555	2-[4-[2-methoxy-5-(2-methoxy-2-oxoethyl)phenoxy]phenyl]acetic acid		C₁₈H₁₈O₆	详情	详情
(XVII)	39573	4-hydroxybenzyl pivalate		C₁₂H₁₆O₃	详情	详情
(XVIII)	39575	methyl 2-(3-bromo-4-methoxyphenyl)acetate		C₁₀H₁₁BrO₃	详情	详情
(XIX)	39571	2-[4-(benzyloxy)phenyl]acetic acid	6547-53-1	C₁₅H₁₄O₃	详情	详情
(XX)	39572	4-(benzyloxy)benzyl pivalate		C₁₉H₂₂O₃	详情	详情
(XXI)	39574	methyl 2-(3-bromo-4-hydroxyphenyl)acetate		C₉H₉BrO₃	详情	详情

Extended Information