新产品编号:1286675
Chemical Name: (6aR,10aR)-3-[1(S),2(R)-Dimethylheptyl]-9-(hydroxymethyl)-6,6-dimethyl-6a,7,10,10a-tetrahydro-6H-dibenzo[b,d]pyran-1-ol
项目整合开发状态: Preclinical
项目研究机构: Clemson University (Originator), Virginia Commonwealth University (Originator)
合成路线:The Horner-Emmons condensation of 3,5-dimethoxybenzaldehyde (I) with triethyl phosphonopropionate (II) gives the cinnamate ester (III),which is hydrolyzed,treated with SOCl2 and condensed with the chiral auxiliary acylsultam (IV) to yield the adduct (V).The enantioselective methylation of (V) with Me2CuLi gives compound (VI) as the major diastereomer.Subsequent hydrolysis of (VI) with LiOH furnishes carboxylic acid (VII).The reduction of (VII) with LiAlH4 gives alcohol (VIII).The reaction of (VIII) with Ts-Cl and pyridine affords the tosylate (IX),which is condensed with butylmagnesium bromide (X) by means of Li2CuCl4 in THF to provide the adduct (XI).The demethylation of (XI) with BBr3 in dichloromethane gives the resorcinol derivative (XII),which is condensed with 4-hydroxy-myrtenyl pivalate (XIII) by means of BF3-Et2O to yield the cannabinoid pivalate ester (XIV).Finally,the reductive cleavage of the ester group of (XIV) with LiAlH4 yields the target cannabinoid.
📌 参考资料/链接：
参考文献标题:Synthesis and pharmacology of the 1',2'-dimethylheptyl-DELTA8-THC isomers: Exceptionally potent cannabinoids
文献作者:Duncan,S.G.Jr.; Huffman,J.W.
参考来源:Bioorg Med Chem Lett 1997,7(21),2799
📄 详细内容
合成路线:The Horner-Emmons condensation of 3,5-dimethoxybenzaldehyde (I) with triethyl phosphonopropionate (II) gives the cinnamate ester (III),which is hydrolyzed,treated with SOCl2 and condensed with the chiral auxiliary acylsultam (IV) to yield the adduct (V).The enantioselective methylation of (V) with Me2CuLi gives compound (VI) as the major diastereomer.Subsequent hydrolysis of (VI) with LiOH furnishes carboxylic acid (VII).The reduction of (VII) with LiAlH4 gives alcohol (VIII).The reaction of (VIII) with Ts-Cl and pyridine affords the tosylate (IX),which is condensed with butylmagnesium bromide (X) by means of Li2CuCl4 in THF to provide the adduct (XI).The demethylation of (XI) with BBr3 in dichloromethane gives the resorcinol derivative (XII),which is condensed with 4-hydroxy-myrtenyl pivalate (XIII) by means of BF3-Et2O to yield the cannabinoid pivalate ester (XIV).Finally,the reductive cleavage of the ester group of (XIV) with LiAlH4 yields the target cannabinoid.
合成路线:The intermediate 4-hydroxy-myrtenyl pivalate (XIII) has been obtained as follows: The reaction of (1R,5S)-myrtenol (XV) with pivaloyl chloride (XVI) and pyridine in dichloromethane gives the pivalate ester (XVII),which by an allylic oxidation with CrO3 and 3,5-dimethylpyrazole in dichloromethane yields 4-oxo-myrtenyl pivalate (XVIII).Finally,this compound is reduced with LiAlH(OBu)3 in THF to afford the target 4-hydroxy-myrtenyl pivalate (XIII) intermediate.
参考文献标题:Enantioselective synthesis of 11-hydroxy-(1'S,2'R)-dimethylheptyl-DELTA8-THC,a very potent CB1 agonist
文献作者:Huffman,J.W.; Liddle,J.
参考来源:Tetrahedron 2001,57(36),7607