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【结 构 式】 
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【分子编号】42802 【品名】bromo(butyl)magnesium 【CA登记号】693-03-8 |
【 分 子 式 】C4H9BrMg 【 分 子 量 】161.32446 【元素组成】C 29.78% H 5.62% Br 49.53% Mg 15.07% |
合成路线1
该中间体在本合成路线中的序号：(II)The reaction of sec-butyl crotonate (I) with butylmagnesium bromide (II) by means of Cu2Cl2 in refluxing ether gives sec-butyl 3-methylheptanoate (III), wich is condensed with dimethyl methylphosphonate (IV) by means of butyllithium in THF at -70 C to afford dimethyl 2-oxo-4-methylphosphonate (V). The Wittig condensation of (V) with 1alpha-acetoxy-2alpha-(6-methoxycarbonylhexyl)-3beta-formyl-4alpha(tetrahydropyranyloxy)cyclopentane (VI) by means of NaH inTHF yields methyl 9alpha-acetoxy-11alpha-(tetrahydropyranyloxy)-15-oxo-17,20-dimethylprost-trans-13-enoate (VII), which is reduced with NaBH4 in methanol to the 15-hydroxy compound (VIII). Selective hydrolysis of (VIII) with p-toluenesufonic acid in methanol gives the 11, 15-dihydroxy derivate (IX), which is then treated with dihydropyran and p-toluenesulfonic acid in methylene chloride to afford the bis-tetrahydropyranyloxy compound (X). The reactin of (X) with diphenydiselenide (XI) by means of butyllithium and diisopropylamine in THF at -70º affords the 2-phenylseleno compound (XII), which by treatment with H2O2 and NaHCO3 in ethyl acetate - THF is converted into methyl 9alpha-hidroxy-11alpha, 15lpha-bis(tetrahydropyranyloxy)-17S, 20-dimethylprosta-trans-2, trans-13-dienoate (XIII). The hydrolysis of (XIII) with KOH in ethanol gives the corresponding free acid (XIV), which is oxidized with CrO3 - H2SO4 - MnSO4 in water - ether to afford 9-oxo-11alpha, 15alpha-bis(tetrahydropyranyloxy)-17S, 20-dimethylprosta-trans-2, trans-13-dienoic acid (XV). Finally this compound is deprotected by treatment with hot aqueous acetic acid.
| 【1】 Hayashi, M.; Kori, S. Kori, S.; Ohyama, I.; Iguchi, S.; Okada, T. (Ono Pharmaceutical Co., Ltd.); GB 1545213 . |
| 【2】 Hayashi, M.; Iguchi, S.; Okada, T. (Ono Pharmaceutical Co., Ltd.); DE 3002677 DE 3002677; FR 2447375; GB 2041368; JP 80100360 . |
| 【3】 Castaner, J.; Hillier, K.; Ono-1206. Drugs Fut 1982, 7, 2, 116. |
| 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) | 59729 | sec-butyl (E)-2-butenoate | C8H14O2 | 详情 | 详情 | |
| (II) | 42802 | bromo(butyl)magnesium | 693-03-8 | C4H9BrMg | 详情 | 详情 |
| (III) | 59730 | sec-butyl 3-methylheptanoate | C12H24O2 | 详情 | 详情 | |
| (IV) | 13607 | dimethyl methylphosphonate | 756-79-6 | C3H9O3P | 详情 | 详情 |
| (V) | 59733 | C11H23O4P | 详情 | 详情 | ||
| (VI) | 59732 | methyl 7-{(1R)-5-(acetyloxy)-2-formyl-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl}heptanoate | C22H36O7 | 详情 | 详情 | |
| (VII) | 59731 | methyl 7-{(1R)-5-(acetyloxy)-2-[(E)-5-methyl-3-oxo-1-nonenyl]-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl}heptanoate | C31H52O7 | 详情 | 详情 | |
| (VIII) | 59734 | methyl 7-{(1R)-5-(acetyloxy)-2-[(E,3S)-3-hydroxy-5-methyl-1-nonenyl]-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl}heptanoate | C31H54O7 | 详情 | 详情 | |
| (IX) | 59735 | methyl 7-{(1R)-5-(acetyloxy)-3-hydroxy-2-[(E,3S)-3-hydroxy-5-methyl-1-nonenyl]cyclopentyl}heptanoate | C25H44O6 | 详情 | 详情 | |
| (X) | 59736 | methyl 7-{(1R)-5-(acetyloxy)-2-{(E,3S)-5-methyl-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-nonenyl}-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl}heptanoate | C37H64O8 | 详情 | 详情 | |
| (XI) | 39170 | 1,2-diphenyldiselane | 1666-13-3 | C12H10Se2 | 详情 | 详情 |
| (XII) | 59737 | methyl 7-{(1R)-5-(acetyloxy)-2-{(E,3S)-5-methyl-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-nonenyl}-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl}-2-(phenylselanyl)heptanoate | C43H68O8Se | 详情 | 详情 | |
| (XIII) | 59738 | methyl (E)-7-{(1R)-5-hydroxy-2-{(E,3S)-5-methyl-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-nonenyl}-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl}-2-heptenoate | C35H60O7 | 详情 | 详情 | |
| (XIV) | 59739 | (E)-7-{(1R)-5-hydroxy-2-{(E,3S)-5-methyl-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-nonenyl}-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl}-2-heptenoic acid | C34H58O7 | 详情 | 详情 | |
| (XV) | 59740 | (E)-7-{(1R)-2-{(E,3S)-5-methyl-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-nonenyl}-5-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl}-2-heptenoic acid | C34H56O7 | 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 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.
| 【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3
该中间体在本合成路线中的序号：(II)Butylmagnesium bromide (II) was added to the Weinreb amide of Boc-L-leucine (I), yielding ketone (III), which was further reduced with NaBH4 to give alcohol (IV) as a diastereomeric mixture. The Boc protecting group of (IV) was removed employing trifluoroacetic acid in CH2Cl2, and the resulting amino alcohol (V) was coupled with N-Boc-L-histidine (VI) by means of BOP reagent to afford amide (VII). Deprotection of the Boc group of (VII) with trifluoroacetic acid then furnished the target C-terminal fragment (VIII).
| 【1】 Cristau, M.; et al.; Synthesis and biological evaluation of bombesin constrained analogues. J Med Chem 2000, 43, 12, 2356. |
| 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) | 40395 | tert-butyl (1S)-1-[[methoxy(methyl)amino]carbonyl]-3-methylbutylcarbamate | C13H26N2O4 | 详情 | 详情 | |
| (II) | 42802 | bromo(butyl)magnesium | 693-03-8 | C4H9BrMg | 详情 | 详情 |
| (III) | 42803 | tert-butyl (1S)-1-isobutyl-2-oxohexylcarbamate | C15H29NO3 | 详情 | 详情 | |
| (IV) | 42804 | tert-butyl (1S)-2-hydroxy-1-isobutylhexylcarbamate | C15H31NO3 | 详情 | 详情 | |
| (V) | 42805 | (4S)-4-amino-2-methyl-5-nonanol | C10H23NO | 详情 | 详情 | |
| (VI) | 42808 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-(1H-imidazol-5-yl)propionic acid | 17791-52-5 | C11H17N3O4 | 详情 | 详情 |
| (VII) | 42806 | tert-butyl (1S)-2-[[(1S)-2-hydroxy-1-isobutylhexyl]amino]-1-(1H-imidazol-5-ylmethyl)-2-oxoethylcarbamate | C21H38N4O4 | 详情 | 详情 | |
| (VIII) | 42807 | (2S)-2-amino-N-[(1S)-2-hydroxy-1-isobutylhexyl]-3-(1H-imidazol-5-yl)propanamide | C16H30N4O2 | 详情 | 详情 |