-Drug Synthesis Database

【结构式】

【药物名称】

【化学名称】(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

【CA登记号】

【分子式】C₂₅H₃₈O₃

【分子量】386.57981

【开发单位】Clemson University (Originator), Virginia Commonwealth University (Originator)

【药理作用】Cannabinoid CB1 Agonists

合成路线1 合成路线2

合成路线1

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.

参考文献中间体

【1】 Huffman, J.W.; Liddle, J.; Enantioselective synthesis of 11-hydroxy-(1'S,2'R)-dimethylheptyl-DELTA8-THC, a very potent CB1 agonist. Tetrahedron 2001, 57, 36, 7607.
【2】 Duncan, S.G. Jr.; Huffman, J.W.; Synthesis and pharmacology of the 1',2'-dimethylheptyl-DELTA8-THC isomers: Exceptionally potent cannabinoids. Bioorg Med Chem Lett 1997, 7, 21, 2799.

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)	21720	3,5-dimethoxybenzaldehyde	7311-34-4	C₉H₁₀O₃	详情	详情
(II)	18816	ethyl 2-(diethoxyphosphoryl)propanoate	3699-66-9	C₉H₁₉O₅P	详情	详情
(III)	24400	ethyl (E)-3-(3,5-dimethoxyphenyl)-2-methyl-2-propenoate		C₁₄H₁₈O₄	详情	详情
(IV)	24401	1,7,7-Trimethylbicyclo[2,2,1]heptane-1',2-sultam; (1S)-(-)-2,10-Camphorsultam		C₁₀H₁₇NO₂S	详情	详情
(V)	24402	4-[(E)-3-(3,5-dimethoxyphenyl)-2-methyl-2-propenoyl]-10,10-dimethyl-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione		C₂₂H₂₉NO₅S	详情	详情
(VI)	24403	4-[(2S,3S)-3-(3,5-dimethoxyphenyl)-2-methylbutanoyl]-10,10-dimethyl-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione		C₂₃H₃₃NO₅S	详情	详情
(VII)	24404	(2S,3S)-3-(3,5-dimethoxyphenyl)-2-methylbutyric acid		C₁₃H₁₈O₄	详情	详情
(VIII)	24405	(2S,3S)-3-(3,5-dimethoxyphenyl)-2-methyl-1-butanol		C₁₃H₂₀O₃	详情	详情
(IX)	51421	(2S,3S)-3-(3,5-dimethoxyphenyl)-2-methylbutyl 4-methylbenzenesulfonate		C₂₀H₂₆O₅S	详情	详情
(X)	42802	bromo(butyl)magnesium	693-03-8	C₄H₉BrMg	详情	详情
(XI)	51422	3-[(1S,2R)-1,2-dimethylheptyl]-5-methoxyphenyl methyl ether; 1-[(1S,2R)-1,2-dimethylheptyl]-3,5-dimethoxybenzene		C₁₇H₂₈O₂	详情	详情
(XII)	24406	5-[(1S,2R)-1,2-dimethylheptyl]-1,3-benzenediol		C₁₅H₂₄O₂	详情	详情
(XIII)	24407	[(1R,5S)-4-hydroxy-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl]methyl pivalate		C₁₅H₂₄O₃	详情	详情
(XIV)	24408	[(6aR,10aR)-3-[(1S,2R)-1,2-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2

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.

参考文献中间体

【1】 Huffman, J.W.; Liddle, J.; Enantioselective synthesis of 11-hydroxy-(1'S,2'R)-dimethylheptyl-DELTA8-THC, a very potent CB1 agonist. Tetrahedron 2001, 57, 36, 7607.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XIII)	24407	[(1R,5S)-4-hydroxy-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl]methyl pivalate		C₁₅H₂₄O₃	详情	详情
(XV)	51423	[(1R,5R)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl]methanol		C₁₀H₁₆O	详情	详情
(XVI)	13597	2,2-Dimethylpropanoyl chloride; Pivaloyl chloride	3282-30-2	C₅H₉ClO	详情	详情
(XVII)	51424	[(1R,5R)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl]methyl pivalate		C₁₅H₂₄O₂	详情	详情
(XVIII)	51425	[(1R,5S)-6,6-dimethyl-4-oxobicyclo[3.1.1]hept-2-en-2-yl]methyl pivalate		C₁₅H₂₂O₃	详情	详情

Extended Information