5-(1,1-dimethylheptyl)-1,3-benzenediol -Drug Synthesis Database

【结构式】

【分子编号】20233

【品名】5-(1,1-dimethylheptyl)-1,3-benzenediol

【CA登记号】

【分子式】C₁₅H₂₄O₂

【分子量】236.35436

【元素组成】C 76.23% H 10.23% O 13.54%

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：(II)

The condensation of diethyl 2-acetylglutarate (I) with 5-(1,1-dimethylheptyl)resorcinol (II) by means of POCl3 gives ethyl 7-(1,1-dimethylheptyl)-5-hydroxy-4-methyl-2-oxo-2H-1-benzopyran-3-propionate (III), which is cyclized by means of NaH in DMSO yielding 3-(1,1-dimethylheptyl)-7,10-dihydro-1-hydroxy-6H-dibenzo[b,d]pyran-6,9-(8H)-dione (IV). The ketalization of (IV) with ethylene glycol (A) and p-toluenesulfonic acid affords the ketal (V), which by a Grignard reaction with methylmagnesium iodide in refluxing ether is converted into dl-3-(1,1-dimethylheptyl)-6,6a,7,8-tetrahydro-1-hydroxy-6,6-dimethyl-9H-dibenzo[b,d]pyran-9-one (VI). Finally, this compound is reduced with Li in liquid ammonia.

参考文献中间体

合成目标

【1】 Archer, R.A.; Hexahydro-dibenzo[b,d]pyran-9-ones as analgesic drugs. US 3944673 .
【2】 Archer, R.A.; Dihydroxyhexahydrodibenzo[b,d]pyrans. DE 2451934; ES 431674; FR 2249664; GB 1487637; JP 50071678; US 3968125 .
【3】 Archer, R.A.; Hexahydro-dibenzo[b,d]pyran-9-ones as an anti-anxiety drug. DE 2451932; ES 431675; FR 2249663; GB 1487636; JP 50082073; NL 7414437; US 3928598 .
【4】 Archer, R.A.; Hexahydro-dibenzo[b,d]pyran-9-ones as psychotropic, particularly anti-depressant drugs. US 3953603 .
【5】 Castaner, J.; Weetman, D.F.; Nabilone. Drugs Fut 1978, 3, 3, 207.

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)	11295	Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol	107-21-1	C₂H₆O₂	详情	详情
(I)	15865	Diethyl 2-acetylglutarate; diethyl 2-acetylpentanedioate	1501-06-0	C₁₁H₁₈O₅	详情	详情
(II)	20233	5-(1,1-dimethylheptyl)-1,3-benzenediol		C₁₅H₂₄O₂	详情	详情
(III)	33507	ethyl 3-[7-(1,1-dimethylheptyl)-5-hydroxy-4-methyl-2-oxo-2H-chromen-3-yl]propanoate		C₂₄H₃₄O₅	详情	详情
(IV)	33508	3-(1,1-dimethylheptyl)-1-hydroxy-7,10-dihydro-6H-benzo[c]chromene-6,9(8H)-dione		C₂₂H₂₈O₄	详情	详情
(V)	33509	3-(1,1-Dimethylheptyl)-9,9-(ethylenedioxy)-1-hydroxy-7,8,9,10-tetrahydro-6H-dibenzo[b,d]pyran-6-one		C₂₄H₃₂O₅	详情	详情
(VI)	33510	3-(1,1-dimethylheptyl)-1-hydroxy-6,6-dimethyl-6,6a,7,8-tetrahydro-9H-benzo[c]chromen-9-one		C₂₄H₃₄O₃	详情	详情
(VII)	20225	iodo(methyl)magnesium	917-64-6	CH₃IMg	详情	详情

合成路线2

该中间体在本合成路线中的序号：(X)

The Grignard reaction of ethyl heptanoate (I) with deuterated methylmagnesium iodide (II) in ether gives deuterated 2-methyl-2-octanol (III), which is treated with deuterium oxide to yield heptadeuterated 2-methyl-2-octanol (IV). The condensation of (IV) with monodeuterated 2,6-dimethoxyphenol (V) (obtained by treatment of 2,6-dimethoxyphenol (VI) with deuterium oxide) by means of deuterated trifluoromethylsulfonic acid affords the alkylated phenol (VII), which is phosphorylated with diethyl phosphite and triethylamine giving the phosphate (VIII). The reduction of (VIII) with Li/NH3 yields the deuterated dimethoxybenzene (IX), which is demethylated with boron tribromide in dichloromethane to afford the deuterated resorcinol (X). The condensation of (X) with alpha-pinene-3,10-diol 10-O-pivalic ester (XI) by means of boron trifluoride etherate in methylene chloride gives the deuterated target compound as its monopivalic ester (XII), which is finally treated with LiAlH4 in THF to eliminate the ester group.

参考文献中间体

合成目标

【1】 Pop, E.; et al.; Synthesis of deuterated dexanabinol, a nonpsychotropic cannabinoid with neuroprotective properties. J Label Compd Radiopharm 1998, 41, 10, 885.

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)	20224	ethyl heptanoate	106-30-9	C₉H₁₈O₂	详情	详情
(II)	20225	iodo(methyl)magnesium	917-64-6	CH₃IMg	详情	详情
(II)	63794	iodo(methyl)magnesium		CH₃IMg	详情	详情
(III)	20226	2-methyl-2-octanol		C₉H₂₀O	详情	详情
(III)	63795	2-methyl-2-octanol		C₉H₂₀O	详情	详情
(IV)	20226	2-methyl-2-octanol		C₉H₂₀O	详情	详情
(IV)	63796	2-methyl-2-octanol		C₉H₂₀O	详情	详情
(V)	20228	2,6-dimethoxyphenol	91-10-1	C₈H₁₀O₃	详情	详情
(V)	63797	2,6-dimethoxyphenol	91-10-1	C₈H₁₀O₃	详情	详情
(VI)	20228	2,6-dimethoxyphenol	91-10-1	C₈H₁₀O₃	详情	详情
(VII)	20230	4-(1,1-dimethylheptyl)-2,6-dimethoxyphenol		C₁₇H₂₈O₃	详情	详情
(VII)	63798	4-(1,1-dimethylheptyl)-2,6-dimethoxyphenol		C₁₇H₂₈O₃	详情	详情
(VIII)	20231	4-(1,1-dimethylheptyl)-2,6-dimethoxyphenyl diethyl phosphate		C₂₁H₃₇O₆P	详情	详情
(VIII)	63799	4-(1,1-dimethylheptyl)-2,6-dimethoxyphenyl diethyl phosphate		C₂₁H₃₇O₆P	详情	详情
(IX)	20232	1-(1,1-dimethylheptyl)-3,5-dimethoxybenzene; 3-(1,1-dimethylheptyl)-5-methoxyphenyl methyl ether		C₁₇H₂₈O₂	详情	详情
(IX)	63800	3-(1,1-dimethylheptyl)-5-methoxyphenyl methyl ether; 1-(1,1-dimethylheptyl)-3,5-dimethoxybenzene		C₁₇H₂₈O₂	详情	详情
(X)	20233	5-(1,1-dimethylheptyl)-1,3-benzenediol		C₁₅H₂₄O₂	详情	详情
(X)	63601	methyl (3aR,4R,5S,5aR,10bR,13aR)-4-(acetyloxy)-3a-ethyl-9-[(13S,15S)-17-ethyl-13-(methoxycarbonyl)-1,11-diazatetracyclo[13.3.1.0~4,12~.0~5,10~]nonadeca-4(12),5,7,9,17-pentaen-13-yl]-5-hydroxy-8-methoxy-6-methyl-3a,4,5,5a,6,11,12,13a-octahydro-1H-indolizino[8,1-cd]carbazole-5-carboxylate		C₄₆H₅₆N₄O₈	详情	详情
(XI)	20234	(4-hydroxy-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)methyl pivalate		C₁₅H₂₄O₃	详情	详情
(XII)	20235	[(6aS,10aS)-3-(1,1-dimethylheptyl)-1-hydroxy-6,6-dimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-9-yl]methyl pivalate		C₃₀H₄₆O₄	详情	详情
(XII)	63802	[(6aS,10aS)-3-(1,1-dimethylheptyl)-1-hydroxy-6,6-dimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-9-yl]methyl pivalate		C₃₀H₄₆O₄	详情	详情

合成路线3

该中间体在本合成路线中的序号：(I)

The aromatic portion of the molecule is generated by the condensation of 1,6-dimethoxyphenol with 1,1-dimethylheptanol in the presence of methanesulfonic acid at 50 C. The crude product is then esterified with diethyl phosphite and triethylamine with cooling to yield the diethyl phosphate derivative. Reduction with lithium in liquid ammonia produces 1-(1',1'-dimethylheptyl)-3,5-hydroxybenzene (I) which is processed crude to the next step. This involves the condensation of the p-menthenediol (II) with the dimethylheptyl resorcinol (I) catalyzed by p-toluenesulfonic acid to give the dimethylheptyl analog of DELTA8-THC (III). Following acetylation of the phenolic group, the allylic methyl group is oxidized to the aldehyde (IV) using selenium dioxide. Further oxidation to the carboxylic acid is accomplished by the use of sodium chlorite. Finally, ajulemic acid is obtained by removal of the acetyl group with sodium carbonate in aqueous methanol.

参考文献中间体

合成目标

【1】 Burnstein, S.; Ajulemic Acid. Drugs Fut 2001, 26, 4, 342.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	20233	5-(1,1-dimethylheptyl)-1,3-benzenediol	C₁₅H₂₄O₂	详情	详情
(II)	46586	(1S,4R)-4-(1-hydroxy-1-methylethyl)-1-methyl-2-cyclohexen-1-ol	C₁₀H₁₈O₂	详情	详情
(III)	46587	(6aR,10aR)-3-(1,1-dimethylheptyl)-6,6,9-trimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-1-yl acetate	C₂₇H₄₀O₃	详情	详情
(IV)	46588	(6aR,10aR)-3-(1,1-dimethylheptyl)-9-formyl-6,6-dimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-1-yl acetate	C₂₇H₃₈O₄	详情	详情

合成路线4

该中间体在本合成路线中的序号：(III)

参考文献中间体

合成目标

【1】 Tremblay, N.; Labelle, M.; Rochette, C.; Dufresne, C.; Gallant, M.; Gareau, Y.; Metters, K.M.; Sawyer, N.; Slipetz, D.M.; Weech, P.K.; Structure activity relatioships of tetrahydrocannabibol analogues on human cannabinoid receptors. Bioorg Med Chem Lett 1996, 6, 2, 189.

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)	34542	(2E)-3,7-dimethyl-2,6-octadienal	5392-40-5	C₁₀H₁₆O	详情	详情
(II)	34543	4,6,6-trimethylbicyclo[3.1.1]hept-3-en-2-ol		C₁₀H₁₆O	详情	详情
(III)	20233	5-(1,1-dimethylheptyl)-1,3-benzenediol		C₁₅H₂₄O₂	详情	详情
(IV)	31571	3-(1,1-dimethylheptyl)-6,6,9-trimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-1-ol		C₂₅H₃₈O₂	详情	详情

合成路线5

该中间体在本合成路线中的序号：(III)

The cyclization of aldehyde (I) or verbenol (II) with resorcinol (III) by means of BF3 in dichloromethane gives the tetrahydrocannabiol analoge (IV) after column chromatography purification. The methylation of (IV) by means of methyl iodide and K2CO3 in refluxing DMF yields the methyl ether (V), which is treated with anhydrous ZnCl2 and HCl in chloroform affording the HCl adduct (VI). Finally, this compound is dehydrochlorinated to the target compound by means of potassium tricyclopentylcarbinolate (K-tcpc) in refluxing toluene.

参考文献中间体

合成目标

【1】 Teshima, K.; et al.; J Org Chem 1971, 36, 5, 721.
【2】 Tremblay, N.; Labelle, M.; Rochette, C.; Dufresne, C.; Gallant, M.; Gareau, Y.; Metters, K.M.; Sawyer, N.; Slipetz, D.M.; Weech, P.K.; Structure activity relatioships of tetrahydrocannabibol analogues on human cannabinoid receptors. Bioorg Med Chem Lett 1996, 6, 2, 189.

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)	34542	(2E)-3,7-dimethyl-2,6-octadienal	5392-40-5	C₁₀H₁₆O	详情	详情
(II)	34543	4,6,6-trimethylbicyclo[3.1.1]hept-3-en-2-ol		C₁₀H₁₆O	详情	详情
(III)	20233	5-(1,1-dimethylheptyl)-1,3-benzenediol		C₁₅H₂₄O₂	详情	详情
(IV)	31571	3-(1,1-dimethylheptyl)-6,6,9-trimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-1-ol		C₂₅H₃₈O₂	详情	详情
(V)	34544	3-(1,1-dimethylheptyl)-6,6,9-trimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-1-yl methyl ether; 3-(1,1-dimethylheptyl)-1-methoxy-6,6,9-trimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromene		C₂₆H₄₀O₂	详情	详情
(VI)	34545	9-chloro-3-(1,1-dimethylheptyl)-1-methoxy-6,6,9-trimethyl-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromene; 9-chloro-3-(1,1-dimethylheptyl)-6,6,9-trimethyl-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-1-yl methyl ether		C₂₆H₄₁ClO₂	详情	详情

合成路线6

该中间体在本合成路线中的序号：(VI)

Esterification of (1S,5R)-myrtenol (I) with pivalyl chloride (II) yields ester (III), which is then oxidized with Na2CrO4 in HOAc-Ac2O to give 4-oxo-myrtenyl pivalate (IV). Reduction of (IV) with lithium tri-t-butoxyaluminohydride in THF affords 4-hydroxymyrtenyl pivalate (V), which is then condensed with 5-(1,1-dimethylheptyl)resorcinol (VI) in the presence of p-TsOH in CH2Cl2 to furnish compound (VII). Treatment of (VII) with K2CO3 in MeOH provides methyl ether derivative (VIII), which is finally reduced with LiAlH4.

参考文献中间体

合成目标

【1】 Mechoulam, R.; et al.; Synthesis of the individual, pharmacologically distinct, enantiomers of a tetrahydrocannabinol derivative. Tetrahedron Asymmetry 1990, 1, 5, 315.
【2】 Goldenberg, D.; Horowitz, M.; Hanus, L.; Breuer, A.; Ross, R.A.; Pertwee, R.G.; Mechoulam, R.; Shiloah, S.; Tchilibon, S.; Fride, E.; HU - 308: A specific agonist for CB2, a peripheral cannabinoid receptor. Proc Natl Acad Sci USA 1999, 96(25): 14228 1999, 96, 25, 14228.

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)	44155	(6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)methanol	515-00-4	C₁₀H₁₆O	详情	详情
(II)	13597	2,2-Dimethylpropanoyl chloride; Pivaloyl chloride	3282-30-2	C₅H₉ClO	详情	详情
(III)	44156	(6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)methyl pivalate		C₁₅H₂₄O₂	详情	详情
(IV)	44157	(6,6-dimethyl-4-oxobicyclo[3.1.1]hept-2-en-2-yl)methyl pivalate		C₁₅H₂₂O₃	详情	详情
(V)	44158	[(4R)-4-hydroxy-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl]methyl pivalate		C₁₅H₂₄O₃	详情	详情
(VI)	20233	5-(1,1-dimethylheptyl)-1,3-benzenediol		C₁₅H₂₄O₂	详情	详情
(VII)	44159	[(4R)-4-[4-(1,1-dimethylheptyl)-2,6-dihydroxyphenyl]-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl]methyl pivalate		C₃₀H₄₆O₄	详情	详情
(VIII)	44160	[(4R)-4-[4-(1,1-dimethylheptyl)-2,6-dimethoxyphenyl]-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl]methyl pivalate		C₃₂H₅₀O₄	详情	详情

Extended Information