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【结 构 式】 
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【分子编号】40516 【品名】methyl (1R,5R)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene-2-carboxylate 【CA登记号】 |
【 分 子 式 】C10H15NO2 【 分 子 量 】181.23464 【元素组成】C 66.27% H 8.34% N 7.73% O 17.66% |
合成路线1
该中间体在本合成路线中的序号：(XVIII)The condensation of 4-(benzyloxy)benzaldehyde (XII) with phosphonium salt (V) by means of TMG as before gives the acrylic ester (XIII), which is hydrogenated with H2 over Rh/C in methanol to yield the propionic ester (XIV). The hydrolysis of (XIV) with LiOH in dioxane/water affords the corresponding acid (XV) as a racemic mixture, which is condensed with (R)-phenylglycinol (IX) by means of EDC, HOBt and DIEA in dichloromethane to provide the amide (XVI) as a diastereomeric mixture that is separated by crystallization and chromatography. The desired (S)-isomer (XVII) is treated with H2SO4 in hot dioxane/water to furnish the chiral propionic acid (XVIII), which is esterified with EtOH and HCl to give the ethyl propionate (XIX). The hydrogenolysis of the benzyl ether group of (XIX) with H2 over Pd/C in ethyl acetate yields the phenolic derivative (XX), which is condensed with the bis-methanesulfonate by means of K2CO3 in acetonitrile to afford the adduct (XXI). Finally, the ester group of (XXI) is hydrolyzed with LiOH in THF/water to provide the target propionic acid.
| 【1】 McIntyre, J.A.; Castaner, J.; Bayes, M.; Tesaglitazar. Drugs Fut 2003, 28, 10, 959. |
| 【2】 Andersson, K.; Boije, M.; Inghardt, T.; Lindstedt Alstermark, E.-L.; Gottfries, J.; Li, L. (AstraZeneca plc); New 3-aryl-2-aryl propionic acid derivs. and analogs. EP 1084101; EP 1084102; EP 1084103; WO 9962870; WO 9962871; WO 9962872 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 50403 | 4-[2-[(methylsulfonyl)oxy]ethyl]phenyl methanesulfonate | C10H14O6S2 | 详情 | 详情 | |
| (V) | 50405 | (Ethoxy(ethoxycarbonyl)methyl)triphenylphosphonium chloride | C24H26ClO3P | 详情 | 详情 | |
| (IX) | 14376 | (2R)-2-amino-2-phenyl-1-ethanol; (R)-(-)-2-phenylglycinol; (R)-2-amino-2-phenyl-1-ethanol | 56613-80-0 | C8H11NO | 详情 | 详情 |
| (XII) | 29179 | 4-(Benzyloxy)benzaldehyde | 4397-53-9 | C14H12O2 | 详情 | 详情 |
| (XIII) | 50411 | ethyl (E)-3-[4-(benzyloxy)phenyl]-2-ethoxy-2-propenoate | C20H22O4 | 详情 | 详情 | |
| (XIV) | 50412 | ethyl 3-[4-(benzyloxy)phenyl]-2-ethoxypropanoate | C20H24O4 | 详情 | 详情 | |
| (XV) | 50413 | 3-[4-(benzyloxy)phenyl]-2-ethoxypropionic acid | C18H20O4 | 详情 | 详情 | |
| (XVI) | 50414 | 3-[4-(benzyloxy)phenyl]-2-ethoxy-N-[(1R)-2-hydroxy-1-phenylethyl]propanamide | C26H29NO4 | 详情 | 详情 | |
| (XVII) | 50415 | (2S)-3-[4-(benzyloxy)phenyl]-2-ethoxy-N-[(1R)-2-hydroxy-1-phenylethyl]propanamide | C26H29NO4 | 详情 | 详情 | |
| (XVIII) | 40516 | methyl (1R,5R)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene-2-carboxylate | C10H15NO2 | 详情 | 详情 | |
| (XIX) | 50417 | ethyl (2S)-3-[4-(benzyloxy)phenyl]-2-ethoxypropanoate | C20H24O4 | 详情 | 详情 | |
| (XX) | 50418 | ethyl (2S)-2-ethoxy-3-(4-hydroxyphenyl)propanoate | C13H18O4 | 详情 | 详情 | |
| (XXI) | 50419 | ethyl (2S)-2-ethoxy-3-[4-([4-[(methylsulfonyl)oxy]phenethyl]oxy)phenyl]propanoate | C22H28O7S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)The reaction of anhydroecgonine methyl ester (I) with 4-methylphenylmagnesium bromide (II) in ethyl ether gives 3beta-(4-methylphenyl)tropane-2beta-carboxylic acid methyl ester (III), which is demethylated by reaction with 2,2,2-trichloroethyl chloroformate (IV) yielding the carbamate (V), followed by reduction with Zn/AcOH to afford the nortropane derivative (VI). The alkylation of (VI) with the tributylstannane (VII), TEA and iodine in ethanol provides the adduct (VIII), which is finally brominated with NBS in THF.
| 【1】 Clarke, R.L.; et al.; Compounds affecting the central nervous system. 4. 3beta-Phenyltropane-2-carboxylic esters and analogs. J Med Chem 1973, 16, 1, 1260-67. |
| 【2】 Carroll, F.I.; Gao, Y.; Rahman, M.A.; Abraham, P.; Parham, K.; Lewin, A.H.; Boja, J.W.; Kuhar, M.J.; Synthesis, ligand binding, QSAR, and CoMFA study of 3beta-(p-substitutedphenyl)tropane-2beta-carboxylic acid methyl esters. J Med Chem 1991, 34, 9, 2719. |
| 【3】 Helfenbein, J.; et al.; Synthesis of (E)-N-(3-bromoprop-2-enyl)-2 beta-carbomethoxy-3 beta-(4 '-tolyl) nortropane (PE2Br) and radiolabelling of [Br-76]PE2Br: A potential ligand for exploration of the dopamine transporter by PET. J Label Compd Radiopharm 1999, 42, 6, 581. |
| 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) | 40516 | methyl (1R,5R)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene-2-carboxylate | C10H15NO2 | 详情 | 详情 | |
| (II) | 35657 | bromo(4-methylphenyl)magnesium | 4294-57-9 | C7H7BrMg | 详情 | 详情 |
| (III) | 40517 | methyl (1R,2S,3S,5R)-8-methyl-3-(4-methylphenyl)-8-azabicyclo[3.2.1]octane-2-carboxylate | C17H23NO2 | 详情 | 详情 | |
| (IV) | 13664 | 1,1,1-Trichloro-2-[(chlorocarbonyl)oxy]ethane; 2,2,2-Trichloroethyl chloroformate | 17341-93-4 | C3H2Cl4O2 | 详情 | 详情 |
| (V) | 40518 | 2-methyl 8-(2,2,2-trichloroethyl) (1R,2S,3S,5R)-3-(4-methylphenyl)-8-azabicyclo[3.2.1]octane-2,8-dicarboxylate | C19H22Cl3NO4 | 详情 | 详情 | |
| (VI) | 40519 | methyl (1R,2S,3S,5R)-3-(4-methylphenyl)-8-azabicyclo[3.2.1]octane-2-carboxylate | C16H21NO2 | 详情 | 详情 | |
| (VII) | 40520 | tributyl[(E)-3-chloro-2-propenyl]stannane | C15H31ClSn | 详情 | 详情 | |
| (VIII) | 40521 | methyl (1R,2S,3S,5R)-3-(4-methylphenyl)-8-[(E)-3-(tributylstannyl)-1-propenyl]-8-azabicyclo[3.2.1]octane-2-carboxylate | C31H51NO2Sn | 详情 | 详情 |