|
【结 构 式】 
|
【分子编号】51229 【品名】1-(2,4-dihydroxyphenyl)-2-(4-hydroxyphenyl)-1-ethanone 【CA登记号】 |
【 分 子 式 】C14H12O4 【 分 子 量 】244.24688 【元素组成】C 68.85% H 4.95% O 26.2% |
合成路线1
该中间体在本合成路线中的序号：(III)Friedel-Crafts reaction between 4-hydroxyphenylacetic acid (I) and resorcinol (II) by means of BF3.Et2O provides trihydroxydeoxy benzoin (III), which is then protected with dihydropyran (IV) in the presence of TsOH to give the bis-THP ether (V). Knoevenagel reaction of (V) with 4-hydroxybenzaldehyde (VI) in the presence of piperidine in refluxing benzene, followed by alkylation with 1-(2-chloroethyl)piperidine (VII) in the presence of Cs2CO3 in refluxing acetone:H2O to yield chromanone (VIII). Alternatively, (VIII) can be synthesized by reaction of (V) with compound (IX) (obtained in turn from reaction between aldehyde (VI) and chloro derivative (VII) with K2CO3 in DMF) by means of piperidine in refluxing toluene, followed by treatment with NaOAc in refluxing MeOH. Chromanone (VIII) is then alkylated either with MeLi or with methylmagnesium bromide in THF and then dehydrated and deprotected in HOAc furnishing chromene (X). Racemic compound (X) is then resolved to afford enantiomer (XI) either by preparative chiral HPLC or by chemical resolution of the corresponding diastereomeric salt obtained by reaction with (+)-CSA in DMF/CH2Cl2, and treatment of the resulting salt with saturated K2CO3 . Finally, the target product is obtained by acylation of (XI) by reaction with pivaloyl chloride (XII) and Et3N in CH2Cl2.
| 【1】 Caron, B.; Cloutier, J.; Gauthier, S.; (S)-(+)-4-[7-(2, 2-Dimethyl-1-oxopropoxy)-4-methyl-2-[4-[2-(1-piperidinyl)ethoxy]phenyl]-2H-1-benzopyran-3-yl]phenyl 2, 2-dimethylpropanoate (EM-800): A highly potent, specific, and orally active nonsteroidal antiestrogen. J Med Chem 1997, 40, 14, 2117. |
| 【2】 Labrie, F.; Merand, Y.; Gauthier, S. (Endorecherche Inc.); Benzopyran-containing cpds. and method for their use. EP 0811006; EP 1167364; JP 1999500133; WO 9626201 . |
| 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) | 18430 | 2-(4-Hydroxyphenyl)acetic acid; 4-Hydroxyphenylacetic acid | 156-38-7 | C8H8O3 | 详情 | 详情 |
| (II) | 10361 | 1,3-Dihydroxybenzene; m-Dihydroxybenzene; Resorcinol; Resorcin; 1,3-Benzenediol | 108-46-3 | C6H6O2 | 详情 | 详情 |
| (III) | 51229 | 1-(2,4-dihydroxyphenyl)-2-(4-hydroxyphenyl)-1-ethanone | C14H12O4 | 详情 | 详情 | |
| (IV) | 13684 | 3,4-Dihydro-2H-pyran;2,3-Dihydro-4H-pyran; 5,6-Dihydro-4H-pyran;Dihydropyran | 110-87-2 | C5H8O | 详情 | 详情 |
| (V) | 51230 | 1-[2-hydroxy-4-(tetrahydro-2H-pyran-2-yloxy)phenyl]-2-[4-(tetrahydro-2H-pyran-2-yloxy)phenyl]-1-ethanone | C24H28O6 | 详情 | 详情 | |
| (VI) | 13433 | 4-Hydroxybenzaldehyde; p-Hydroxybenzaldehyde | 123-08-0 | C7H6O2 | 详情 | 详情 |
| (VII) | 10117 | 1-(2-Chloroethyl)piperidine; N-(2-Chloroethyl)piperidine | 1932-03-2 | C7H14ClN | 详情 | 详情 |
| (VIII) | 51231 | 2-[4-[2-(1-piperidinyl)ethoxy]phenyl]-7-(tetrahydro-2H-pyran-2-yloxy)-3-[4-(tetrahydro-2H-pyran-2-yloxy)phenyl]-2,3-dihydro-4H-chromen-4-one | C38H45NO7 | 详情 | 详情 | |
| (IX) | 35795 | 4-[2-(1-piperidinyl)ethoxy]benzaldehyde | 26815-04-3 | C14H19NO2 | 详情 | 详情 |
| (X) | 51232 | 3-(4-hydroxyphenyl)-4-methyl-2-[4-[2-(1-piperidinyl)ethoxy]phenyl]-2H-chromen-7-ol | C29H31NO4 | 详情 | 详情 | |
| (XI) | 51233 | (2S)-3-(4-hydroxyphenyl)-4-methyl-2-[4-[2-(1-piperidinyl)ethoxy]phenyl]-2H-chromen-7-ol | C29H31NO4 | 详情 | 详情 | |
| (XII) | 13597 | 2,2-Dimethylpropanoyl chloride; Pivaloyl chloride | 3282-30-2 | C5H9ClO | 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 1-(2,4-dihydroxyphenyl)-2-(4-hydroxyphenyl)-ethanone (I) with DHP and Ts-OH in ethyl acetate gives the bis-tetrahydropyranyl ether (II), which is condensed with the benzaldehyde (III) by means of piperidine in 2-butanol to yield a mixture of the propenone (IV) and the benzopyranone (V). This mixture, without isolation, is treated with DBU to convert (IV) into (V). The methylation of (V) with MeLi in tert-butyl methyl ether affords the benzopyran-4-ol (VI), which is treated with (S)-(+)-camphorsulfonic acid (VII) to provide the dehydrated benzopyran camphorsulfonate (VIII) as a diastereomeric mixture that is separated by crystallization. The desired isomer (IX) is treated with TEA to give the title compound (X) as free base that is finally treated with HCl in EtOH/water to yield the desired hydrochloride.
| 【1】 Gauthier, S.; et al.; Synthesis and structure-activity relationships of analogs of EM-652, a pure selective estrogen receptor modulator. Part 1: Study of nitrogen substitution. 223rd ACS Natl Meet (April 7 2002, Orlando) 2002, Abst MEDI 224. |
| 【2】 Lu, Y.; Draper, R.W.; Iyer, R.V.; Vater, E.J. (Schering Corp.); Enantioselective synthesis. US 6262270 . |
| 【3】 Lu, Y.; Draper, R.W.; Iyer, R.V.; Vater, E.J. (Schering Corp.); Enantioselective synthesis. WO 0009493 . |
| 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) | 51229 | 1-(2,4-dihydroxyphenyl)-2-(4-hydroxyphenyl)-1-ethanone | C14H12O4 | 详情 | 详情 | |
| (II) | 51230 | 1-[2-hydroxy-4-(tetrahydro-2H-pyran-2-yloxy)phenyl]-2-[4-(tetrahydro-2H-pyran-2-yloxy)phenyl]-1-ethanone | C24H28O6 | 详情 | 详情 | |
| (III) | 35795 | 4-[2-(1-piperidinyl)ethoxy]benzaldehyde | 26815-04-3 | C14H19NO2 | 详情 | 详情 |
| (IV) | 53981 | (E)-1-[2-hydroxy-4-(tetrahydro-2H-pyran-2-yloxy)phenyl]-3-{4-[2-(1-piperidinyl)ethoxy]phenyl}-2-[4-(tetrahydro-2H-pyran-2-yloxy)phenyl]-2-propen-1-one | n/a | C38H45NO7 | 详情 | 详情 |
| (V) | 53982 | (2R,3S)-5-hydroxy-2-{4-[2-(1-piperidinyl)ethoxy]phenyl}-7-(tetrahydro-2H-pyran-2-yloxy)-3-[4-(tetrahydro-2H-pyran-2-yloxy)phenyl]-2,3-dihydro-4H-chromen-4-one | n/a | C38H45NO8 | 详情 | 详情 |
| (VI) | 53983 | (2R,3S)-4-methyl-2-{4-[2-(1-piperidinyl)ethoxy]phenyl}-7-(tetrahydro-2H-pyran-2-yloxy)-3-[4-(tetrahydro-2H-pyran-2-yloxy)phenyl]-3,4-dihydro-2H-chromene-4,5-diol | n/a | C39H49NO8 | 详情 | 详情 |
| (VII) | 53984 | (+/-)-Camphor-10-sulphonic acid; (?-10-Camphorsulfonic acid; DL-Camphor-10-sulfonic acid; DL-10-Camphorsulfonic acid; DL-Camphor-10-sulfonic acid; DL-Oxo-10-Bornanesulfonic acid | 5872-08-2 | C10H16O4S | 详情 | 详情 |
| (VIII) | 53985 | 1-(2-{4-[5,7-dihydroxy-3-(4-hydroxyphenyl)-4-methyl-2H-chromen-2-yl]phenoxy}ethyl)piperidinium (7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl)methanesulfonate | n/a | C39H47NO9S | 详情 | 详情 |
| (IX) | 53986 | 1-(2-{4-[(2S)-5,7-dihydroxy-3-(4-hydroxyphenyl)-4-methyl-2H-chromen-2-yl]phenoxy}ethyl)piperidinium (7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl)methanesulfonate | n/a | C39H47NO9S | 详情 | 详情 |
| (X) | 53987 | (2S)-3-(4-hydroxyphenyl)-4-methyl-2-{4-[2-(1-piperidinyl)ethoxy]phenyl}-2H-chromene-5,7-diol | n/a | C29H31NO5 | 详情 | 详情 |