2,3,5-trimethyl-1,4-benzenediol -Drug Synthesis Database

【结构式】

【分子编号】26357

【品名】2,3,5-trimethyl-1,4-benzenediol

【CA登记号】700-13-0

【分子式】C₉H₁₂O₂

【分子量】152.19308

【元素组成】C 71.03% H 7.95% O 21.03%

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：(V)

The chlorination of myrcene (I) with Cl2 in refluxing pentane gives the choromyrcene (II), and the hydrochlorination of (I) catalyzed by CuCl yields a mixture of geranyl/neryl chloride (III). The reductive coupling of (II) and (III) by means of Mg and CuCl affords beta-springene (IV), which is condensed with 2,3,6-trimethylhydroquinone (V) by means of cyclooctadienyl rhodium chloride dimer [RhCl(COD)]2 and K2CO3 in refluxing toluene to provide the adduct (VI). The cyclization of (VI) by means of MeAlCl2 of Ts-OH in refluxing hexane furnishes the tocotrienol (VII), which is finally hydrogenated with H2 over Pd/C in ethanol to give the target (rac)-vitamin E.

参考文献中间体

合成目标

【1】 Bienayme, H.; et al.; Rhodium(I)-catalyzed addition of phenols to dienes. A new convergent synthesis of vitamin E. Tetrahedron Lett 2000, 41, 18, 3339.

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)	49619	Myrcene; 7-Methyl-3-methylene-1,6-octadiene; beta-Myrcene	123-35-3	C₁₀H₁₆	详情	详情
(II)	49620	3-chloro-2-methyl-6-methylene-1,7-octadiene		C₁₀H₁₅Cl	详情	详情
(III)	49621	Geranyl chloride; trans-1-chloro-3,7-dimethyl-2,6-octadiene		C₁₀H₁₇Cl	详情	详情
(IV)	49622	(6E,10E)-7,11,15-trimethyl-3-methylene-1,6,10,14-hexadecatetraene		C₂₀H₃₂	详情	详情
(V)	26357	2,3,5-trimethyl-1,4-benzenediol	700-13-0	C₉H₁₂O₂	详情	详情
(VI)	49623	2,3,5-trimethyl-6-[(2E,6E,10E)-3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraenyl]-1,4-benzenediol		C₂₉H₄₄O₂	详情	详情
(VII)	49624	2,5,7,8-tetramethyl-2-[(3E,7E)-4,8,12-trimethyl-3,7,11-tridecatrienyl]-6-chromanol		C₂₉H₄₄O₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(IV)

A new short synthesis of troglitazone has been described: Condensation of the bromoacetal (I) with 4-hydroxybenzaldehyde (II) by means of K2CO3 and NaI in refluxing acetone gives the unsaturated ether (III), which is cyclized with trimethylhydroquinone (IV) by means of bis(trifluoromethylsulfonyl)imide in dichloromethane to yield the 6-hydroxybenzopyran (V). Acylation of (V) with acetic anhydride and DMAP in THF affords the expected acetoxybenzopyran (VI), which is condensed with thiazolidine-2,4-dione (VII) by means of piperidine in toluene to provide the 6-benzylidene-thiazolidine (VIII). The hydrogenation of (VIII) with H2 over Pd/C in methanol gives the corresponding benzyl derivative (IX), which is finally deacetylated with AcOH/HCl/water (3:1:1) in MeOH.

参考文献中间体

合成目标

【1】 Cossy, J.; et al.; A short synthesis of troglitazone: An antidiabetic drug for treating insulin resistance. Bioorg Med Chem Lett 1999, 9, 24, 3439.

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)	40477	(E)-4-bromo-1-methoxy-3-methyl-2-butenyl methyl ether; (E)-4-bromo-1,1-dimethoxy-3-methyl-2-butene		C₇H₁₃BrO₂	详情	详情
(II)	13433	4-Hydroxybenzaldehyde; p-Hydroxybenzaldehyde	123-08-0	C₇H₆O₂	详情	详情
(III)	40478	4-[[(E)-4,4-dimethoxy-2-methyl-2-butenyl]oxy]benzaldehyde		C₁₄H₁₈O₄	详情	详情
(IV)	26357	2,3,5-trimethyl-1,4-benzenediol	700-13-0	C₉H₁₂O₂	详情	详情
(V)	40479	4-[(6-hydroxy-2,5,7,8-tetramethyl-2H-chromen-2-yl)methoxy]benzaldehyde		C₂₁H₂₂O₄	详情	详情
(VI)	40480	2-[(4-formylphenoxy)methyl]-2,5,7,8-tetramethyl-2H-chromen-6-yl acetate		C₂₃H₂₄O₅	详情	详情
(VII)	10883	1,3-Thiazolane-2,4-dione; 2,4-Thiazolidinedione	2295-31-0	C₃H₃NO₂S	详情	详情
(VIII)	40481	2-([4-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]phenoxy]methyl)-2,5,7,8-tetramethyl-2H-chromen-6-yl acetate		C₂₆H₂₅NO₆S	详情	详情
(IX)	40482	2-([4-[(2,4-dioxo-1,3-thiazolidin-5-yl)methyl]phenoxy]methyl)-2,5,7,8-tetramethyl-2H-chromen-6-yl acetate		C₂₆H₂₇NO₆S	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 reaction of pimelic acid monoester (I) with refluxing SOCl2 gives the corresponding acid chloride (II), which by a Friedel-Craft's condensation with benzene (AlCl3 as catalyst) is converted into 6-benzoylhexanoic acid ethyl ester (III). The reduction of (III) with NaBH4 in methanol affords 7-hydroxy-7-phenylheptanoic acid ethyl ester (IV), which is hydrolyzed with NaOH in hot THF - water to yield the corresponding free acid (V). Finally, this compound is condensed with trimethylhydroquinone (VI) by means of boron trifluoride ethearate in hot toluene.

参考文献中间体

合成目标

【1】 Terao, S.; Maki, Y. (Takeda Chemical Industries, Ltd.); Quinone amides, their production and use. EP 0232089; JP 1987246545 .
【2】 Terao, S.; Maki, Y. (Takeda Chemical Industries, Ltd.); Quinone derivs., their production and use. AU 8545615; EP 0171251; ES 8704870; JP 1986044840; JP 1991072444; JP 1991081248; JP 1991086841; US 5180742; WO 8600887; WO 8604058 .
【3】 Shiraishi, M.; Kato, K.; Terao, S.; Ashida, Y.; Terashita, Z.-I.; Kito, G.; Quinones. 4. Novel eicosanoid antagonists: Synthesis and pharmacological evaluation. J Med Chem 1989, 32, 9, 2214-21.
【4】 Terao, S.; Quinone derivatives: Synthesis and structure-activity relations of a novel class of eicosanoid antagonists, AA-2414 and its analogs. Advances in Prostaglandin, Thromboxane and Leukotriene Research 1989, 19, 651-654.
【5】 Prous, J.; Castaner, J.; AA-2414. Drugs Fut 1990, 15, 8, 783.

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)	13364	Benzene	71-43-2	C₆H₆	详情	详情
(I)	31145	7-ethoxy-7-oxoheptanoic acid	33018-91-6	C₉H₁₆O₄	详情	详情
(II)	31146	ethyl 7-chloro-7-oxoheptanoate	14794-32-2	C₉H₁₅ClO₃	详情	详情
(III)	31147	ethyl 7-oxo-7-phenylheptanoate		C₁₅H₂₀O₃	详情	详情
(IV)	31148	ethyl 7-hydroxy-7-phenylheptanoate		C₁₅H₂₂O₃	详情	详情
(V)	31149	7-hydroxy-7-phenylheptanoic acid		C₁₃H₁₈O₃	详情	详情
(VI)	26357	2,3,5-trimethyl-1,4-benzenediol	700-13-0	C₉H₁₂O₂	详情	详情

合成路线4

该中间体在本合成路线中的序号：(I)

Raxofelast has been synthesized by a short route involving Friedel-Crafts alkylation of trimethylhydroquinone (I) by methyl 4-bromocrotonate (II). The crude reaction mixture containing methyl 4-(2,5-dihydroxy-3,4,6-trimethylphenyl)-2(E)-butenoate (III) was directly submitted to a hydrolytic cyclization in alkaline environment in the presence of a strong reducing agent to afford (±)-2,3-dihydro-5-hydroxy-4,6,7-trimethyl-2-benzofuranacetic acid (IV) (IRFI-005). Acetylation of phenolic hydroxyl by routine methods, followed by recrystallization by isopropyl acetate, gave the final product.

参考文献中间体

合成目标

【1】 De Vellis, P.; Scuri, R.; Zanarella, S.; Ceccarelli, S.; Synthesis of novel 2-substituted 5-oxycoumarans via a direct route to 2,3-dihydro-5-hydroxy-2-benzofuranacetic acids. J Heterocycl Chem 1993, 30, 679.
【2】 Cuzzocrea, S.; Ceccarelli, S.; Raxofelast. Drugs Fut 1999, 24, 7, 735.

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)	26357	2,3,5-trimethyl-1,4-benzenediol	700-13-0	C₉H₁₂O₂	详情	详情
(II)	26358	methyl (E)-4-bromo-2-butenoate	1117-71-1	C₅H₇BrO₂	详情	详情
(III)	26359	methyl (E)-4-(2,5-dihydroxy-3,4,6-trimethylphenyl)-2-butenoate		C₁₄H₁₈O₄	详情	详情
(IV)	26360	2-(5-hydroxy-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-2-yl)acetic acid		C₁₃H₁₆O₄	详情	详情
(V)	26361	methyl (E)-2-butenoate	623-43-8	C₅H₈O₂	详情	详情

合成路线5

该中间体在本合成路线中的序号：(I)

Condensation of trimethylhydroquinone (I) with 4-chloro-1-butanol (II) in the presence of phosphomolybdic acid in refluxing toluene yielded the chlorobutyl ether (III). Benzhydrylpiperazine (VI), (prepared from chlorodiphenylmethane (IV) and piperazine (V)), was then condensed with chloride (III) to give the target compound, which was isolated as the dihydrochloride salt.

参考文献中间体

合成目标

【1】 Kawasaki, N.; Satoh, T.; Nagai, H.; Nishiki, M.; Matsumoto, H.; Inagaki, N.; Miyataka, H.; Synthesis of trimethylhydroquinone derivatives as anti-allergic agents with anti-oxidative actions. Chem Pharm Bull 1999, 47, 2, 177.

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)	26357	2,3,5-trimethyl-1,4-benzenediol	700-13-0	C₉H₁₂O₂	详情	详情
(II)	22336	4-chloro-1-butanol	928-51-8	C₄H₉ClO	详情	详情
(III)	27973	4-(4-chlorobutoxy)-2,3,6-trimethylphenol		C₁₃H₁₉ClO₂	详情	详情
(IV)	27974	Benzhydrylchloride; 1,1-Diphenylchloromethane; Dibenzyl chloride; Alpha-Chlorodiphenylmethane; Chlorodiphenylmethane; Diphenylchloromethane; 1-[chloro(phenyl)methyl]benzene	90-99-3	C₁₃H₁₁Cl	详情	详情
(V)	10355	Diethylenediamine; Piperazine	110-85-0	C₄H₁₀N₂	详情	详情
(VI)	20796	N-(Benzhydryl)piperazine; 1-Benzhydrylpiperazine; 1-(dibenzyl)piperazine	841-77-0	C₁₇H₂₀N₂	详情	详情

合成路线6

该中间体在本合成路线中的序号：(I)

The target product can be obtained by condensation of trimethylhydroquinone (I) with diol (II) by means of phosphomolybdic acid in refluxing toluene followed by recrystallization from n-hexane/ethyl acetate.

参考文献中间体

合成目标

【1】 Satoh, T.; Miyataka, H.; Nishiki, M.; Hirano, T.; Kawasaki, N.; Antioxidative and 5-lipoxygenase inhibiting activities of novel bis(4-hydroxy-2,3,5-trimethylphenoxy)alkyl derivatives. Chem Pharm Bull 2001, 49, 2, 225.

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)	26357	2,3,5-trimethyl-1,4-benzenediol	700-13-0	C₉H₁₂O₂	详情	详情
(II)	15471	1,5-pentanediol	111-29-5	C₅H₁₂O₂	详情	详情

Extended Information