beta-Lapachone, ARQ-501, CO-501, -Drug Synthesis Database

【结构式】

【药物名称】beta-Lapachone, ARQ-501, CO-501

【化学名称】2,2-Dimethyl-3,4-dihydro-2H-benzo[h]-1-benzopyran-5,6-dione

【CA登记号】4707-32-8

【分子式】C₁₅H₁₄O₃

【分子量】242.27703

【开发单位】ArQule (Proprietary), Cyclis Pharmaceuticals (Proprietary), Beth Israel Deaconess Medical Center (Originator), Dana-Farber Cancer Institute (Originator), CoPharma (Licensee)

【药理作用】Oncolytic Drugs, Solid Tumors Therapy, Apoptosis Inducers, DNA Topoisomerase I Inhibitors, DNA Topoisomerase II Inhibitors

合成路线1 合成路线2

合成路线1

Oxidative cleavage of methylindene (I) by means of Na2Cr2O7 produces 2-acetylphenylacetic acid (II). Fischer esterification of keto acid (II) gives keto ester (III), which is subjected to intramolecular Claisen condensation and air oxidation, yielding the hydroxy naphthoquinone (IV) (1). Alkylation of (IV) with prenyl bromide (V) leads to a mixture of lapachol (VII) and minor amounts of the prenyl ether isomer (VI) (1-3). Finally, cyclization of (VII) in concentrated H2SO4 gives rise to the target compound.

参考文献中间体

【1】 Sun, J.S.; Geiser, A.H.; Frydman, B.; A preparative synthesis of lapachol and related naphthoquinones. Tetrahedron Lett 1998, 39, 8221.
【2】 Schaffner-Sabba, K.; Schmidt-Ruppin, K.H..; Wehrli, W.; Schuerch, A.R.; Wasley, J.W.F.; beta-Lapachone: Synthesis of derivatives and activities in tumor models. J Med Chem 1984, 27, 8, 990.
【3】 Boothman, D.A.; Frydman, B.J.; Witiak, D.T. (Wisconsin Alumni Research Foundation); Novel synthesis and use of beta-lapachone analogs. US 5763625; WO 9633988 .
【4】 Jiang, Z.; Hogeland, J. (Dana-Farber Cancer Institute); Synthesis of beta-lapachone and its intermediates. WO 0259103 .

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)	60264	3-methyl-1H-indene		C₁₀H₁₀	详情	详情
(II)	60265	2-(2-acetylphenyl)acetic acid		C₁₀H₁₀O₃	详情	详情
(III)	60266	ethyl 2-(2-acetylphenyl)acetate		C₁₂H₁₄O₃	详情	详情
(IV)	60267	2-hydroxy-1,4-naphthalenedione		C₁₀H₆O₃	详情	详情
(V)	51796	Prenyl Chloride; 1-Chloro-3-methyl-2-butene	503-60-6	C₅H₉Cl	详情	详情
(VI)	60268	2-[(3-methyl-2-butenyl)oxy]-1,4-naphthalenedione		C₁₅H₁₄O₃	详情	详情
(VII)	60269	2-hydroxy-3-(3-methyl-2-butenyl)-1,4-naphthalenedione		C₁₅H₁₄O₃	详情	详情

合成路线2

Esterification of 1-naphthol (I) with 3-methylcrotonic acid chloride (II) provides ester (III), which subsequently rearranges to the hydroxy ketone (IV). Cyclization of (IV) under acidic conditions provides the tricyclic system (V). Keto group reduction in (V) by means of LiAlH4 leads to alcohol (VI), which upon acidic treatment is dehydrated to olefin (VII). Further catalytic hydrogenation of (VII) in the presence of Pd/C yields the dihydro naphthopyran (VIII). Electrophilic nitration of (VIII) provides (IX). After reduction of nitro derivative (IX) to the corresponding amine (X) by means of Sn/HCl, acylation with acetic anhydride furnishes acetamide (XI). Finally, oxidation of (XI) with concentrated nitric acid gives rise to the target ortho-quinone .

参考文献中间体

【1】 Amaral, A.C.F.; Barnes, R.A.; The total synthesis of beta-lapachone. J Heterocycl Chem 1992, 29, 1457.

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)	22935	alpha-naphthol; 1-naphthol	90-15-3	C₁₀H₈O	详情	详情
(II)	17810	3-methyl-2-butenoyl chloride; 3,3-Dimethylacryloyl chloride	3350-78-5	C₅H₇ClO	详情	详情
(III)	60270	1-naphthalenyl 3-methyl-2-butenoate		C₁₅H₁₄O₂	详情	详情
(IV)	60271	1-(1-hydroxy-2-naphthalenyl)-3-methyl-2-buten-1-one		C₁₅H₁₄O₂	详情	详情
(V)	60272	2,2-dimethyl-2,3-dihydro-4H-benzo[h]chromen-4-one		C₁₅H₁₄O₂	详情	详情
(VI)	60273	2,2-dimethyl-3,4-dihydro-2H-benzo[h]chromen-4-ol		C₁₅H₁₆O₂	详情	详情
(VII)	60274	2,2-dimethyl-2H-benzo[h]chromene		C₁₅H₁₄O	详情	详情
(VIII)	60275	2,2-dimethyl-3,4-dihydro-2H-benzo[h]chromene		C₁₅H₁₆O	详情	详情
(IX)	60276	2,2-dimethyl-6-nitro-3,4-dihydro-2H-benzo[h]chromene		C₁₅H₁₅NO₃	详情	详情
(X)	60277	2,2-dimethyl-3,4-dihydro-2H-benzo[h]chromen-6-amine; 2,2-dimethyl-3,4-dihydro-2H-benzo[h]chromen-6-ylamine		C₁₅H₁₇NO	详情	详情
(XI)	60278	N-(2,2-dimethyl-3,4-dihydro-2H-benzo[h]chromen-6-yl)acetamide		C₁₇H₁₉NO₂	详情	详情

Extended Information