1,4-cyclohexadiene -Drug Synthesis Database

【结构式】

【分子编号】31516

【品名】1,4-cyclohexadiene

【CA登记号】628-41-1

【分子式】C₆H₈

【分子量】80.12952

【元素组成】C 89.94% H 10.06%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(VIII)

The title compound was originally isolated from the culture broths of Verticillum sp. The synthesis of this compound has been further described. The unsaturated lactone (I) was isomerized at the C-4 hydroxyl group, and subsequently protected as the methoxymethyl ether (II). Condensation of (II) with benzoate ester (III) in a tandem Michael addition-Dieckmann cyclization reaction afforded the tricyclic compound (IV), which was aromatized to the naphthopyranone (V) by treatment with cyclohexene and Pd/C. Protection of the hydroxyl group of (V) with benzyl bromide and K2CO3 gave benzyl ether (VI). After reduction of the lactone function of (VI) to the corresponding lactol by means of DIBAL, further deoxygenation with triethylsilane and trifluoroacetic acid provided the cyclic ether (VII). The benzyl group of (VII) was removed by hydrogenolysis with cyclohexadiene (VIII) and Pd/C, and the resulting hydroxynaphthopyran (IX) was oxidatively dimerized, affording (X) as a diasteromeric mixture. Aromatization of (X) by NaOH produced the bisnaphthol (XI).

参考文献中间体

合成目标

【1】 Yamazaki, T.; Yoshimoto, T.; Tatsuta, K.; Synthesis and biological evaluation of the analogs of bioxanthracenes ES-242s, N-methyl-D-aspartate antagonists. J Antibiot 1998, 51, 3, 383.
【2】 Yamazaki, T.; Nagai, T.; Tamura, T.; Tatsuta, K.; Mase, T.; Synthesis of an N-methyl-D-aspartate receptor antagonist, ES-242-5, and its analogs. J Antibiot 1999, 52, 4, 422.
【3】 Nakamura, H.; Absolute and atropisomeric structure of ES-242s, N-methyl-D-aspartate receptor antagonists. J Antibiot 1999, 52, 4, 433.

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)	31509	(5R,6S)-5-hydroxy-6-methyl-5,6-dihydro-2H-pyran-2-one		C₆H₈O₃	详情	详情
(II)	31510	(5S,6S)-5-(methoxymethoxy)-6-methyl-5,6-dihydro-2H-pyran-2-one		C₈H₁₂O₄	详情	详情
(III)	31511	methyl 2,4-dimethoxy-6-methylbenzoate	6110-37-8	C₁₁H₁₄O₄	详情	详情
(IV)	31512	(3S,4S,4aR)-10-hydroxy-7,9-dimethoxy-4-(methoxymethoxy)-3-methyl-3,4,4a,5-tetrahydro-1H-benzo[g]isochromen-1-one		C₁₈H₂₂O₇	详情	详情
(V)	31513	(3S,4S)-10-hydroxy-7,9-dimethoxy-4-(methoxymethoxy)-3-methyl-3,4-dihydro-1H-benzo[g]isochromen-1-one		C₁₈H₂₀O₇	详情	详情
(VI)	31514	(3S,4S)-10-(benzyloxy)-7,9-dimethoxy-4-(methoxymethoxy)-3-methyl-3,4-dihydro-1H-benzo[g]isochromen-1-one		C₂₅H₂₆O₇	详情	详情
(VII)	31515	(3S,4S)-10-(benzyloxy)-7,9-dimethoxy-4-(methoxymethoxy)-3-methyl-3,4-dihydro-1H-benzo[g]isochromene; benzyl (3S,4S)-7,9-dimethoxy-4-(methoxymethoxy)-3-methyl-3,4-dihydro-1H-benzo[g]isochromen-10-yl ether		C₂₅H₂₈O₆	详情	详情
(VIII)	31516	1,4-cyclohexadiene	628-41-1	C₆H₈	详情	详情
(IX)	31517	(3S,4S)-7,9-dimethoxy-4-(methoxymethoxy)-3-methyl-3,4-dihydro-1H-benzo[g]isochromen-10-ol		C₁₈H₂₂O₆	详情	详情
(X)	31518	5,5'-Bis[7,9-dimethoxy-4(S)-(methoxymethoxy)-3(S)-methyl-3,4,5,10-tetrahydro-1H-naphtho[2,3-c]pyran-10-one]		C₃₆H₄₂O₁₂	详情	详情
(XI)	31519	5,5'-Bis[7,9-dimethoxy-4(S)-(methoxymethoxy)-3(S)-methyl-3,4-dihydro-1H-naphtho[2,3-c]pyran-10-ol]		C₃₆H₄₂O₁₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：

Combining (3-aminopropyl)carbamic acid benzyl ester (CBZ-protected propylene diamine) (I) with 2-oxoethylphosphonic acid diethyl ester under reductive amination conditions in the presence of sodium cyanoborohydride gives the CBZ-protected phosphonoethyl-substituted propylene diamine (II). The condensation of (II) with 3,4-diethoxy-3-cyclobutene-1,2-dione at room temperature in ethanol leads to the squaric acid analog (III). Removal of the CBZ protecting group under catalytic transfer hydrogenation conditions followed by spontaneous cyclization provides the penultimate diethylphosphonate ester (IV), which is hydrolyzed in the presence of bromotrimethylsilane in refluxing 1,2-dichloroethane to yield the final product in 15% overall yield.

参考文献中间体

合成目标

【1】 Zaleska, M.M.; Childers, W.E. Jr.; Abou-Gharbia, M.A.; Moyer, J.A.; EAA-090. Drugs Fut 2002, 27, 7, 633.
【2】 Kowal, D.M.; Abou-Gharbia, M.; Schmid, J.; Bramlett, D.R.; Miller, T.L.; Tasse, R.P.; Zaleska, M.M.; Moyer, J.A.; Garrison, D.T.; Kinney, W.A.; Design and synthesis of [2-(8,9-dioxo-2, 6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid (EAA-090), a potent N-methyl-D-aspartate antagonist, via the use of 3-cyclobutene-1,2-dione as an achiral alpha-amino acid bioisostere. J Med Chem 1998, 41, 2, 236.
【3】 Kinney, W.A.; Garrison, D.C. (Wyeth); [[(2-Amino-3, 4-dioxo-1-cyclo-buten-1-yl)amino]alkyl]-acid derivs.. EP 0496561; JP 1992321654; US 5168103 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	30975	3,4-diethoxy-3-cyclobutene-1,2-dione	5231-87-8	C₈H₁₀O₄	详情	详情
	31516	1,4-cyclohexadiene	628-41-1	C₆H₈	详情	详情
	54139	Diethyl (formylmethyl)phosphonate	1606-75-3	C₆H₁₃O₄P	详情	详情
(I)	54138	ethyl 3-aminopropylcarbamate	n/a	C₆H₁₄N₂O₂	详情	详情
(II)	54140	diethyl 2-({3-[(ethoxycarbonyl)amino]propyl}amino)ethylphosphonate	n/a	C₁₂H₂₇N₂O₅P	详情	详情
(III)	54141	diethyl 2-[{3-[(ethoxycarbonyl)amino]propyl}(2-ethoxy-3,4-dioxo-1-cyclobuten-1-yl)amino]ethylphosphonate	n/a	C₁₈H₃₁N₂O₈P	详情	详情
(IV)	54142	diethyl 2-[8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl]ethylphosphonate	n/a	C₁₃H₂₁N₂O₅P	详情	详情

Extended Information