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【结 构 式】 
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【分子编号】10361 【品名】1,3-Dihydroxybenzene; m-Dihydroxybenzene; Resorcinol; Resorcin; 1,3-Benzenediol 【CA登记号】108-46-3 |
【 分 子 式 】C6H6O2 【 分 子 量 】110.11244 【元素组成】C 65.45% H 5.49% O 29.06% |
合成路线1
该中间体在本合成路线中的序号：(I)The method of synthesis for 2,4,6-triiodoresorcine comprises a stage of resorcin (I) iodination with iodine chloride in the presence of hydrochloric acid as a catalyzer. The reaction mixture is allowed to stand for 1 h at the temperature of 20-5 C. The precipitate is filtered and dried at 50 C. Triiodoresorcine yield is 93.6% (crystallized from CCl4).
合成路线2
该中间体在本合成路线中的序号：(VII)The total synthesis of picumast dihydrochloride has been described: The alkylation of piperazine (I) with 4-chlorobenzyl chloride (II) in ethanol gives 1-(4-chlorobenzyl)piperazine (III), which is alkylated again with 1-bromo-3-chloropropane (IV) by means of triethylamine in a suitable solvent to yield 1-(4-chlorobenzyl)-4-(3-chloropropyl)piperazine (V). Finally, this compound is condensed with 7-hydroxy-3,4-dimethylcoumarin (VI) by means of K2CO3 in refluxing butanone. Compound (VI) is obtained by cyclization of resorcinol (VII) with ethyl 2-methylacetoacetate (VIII) by means of refluxing acetic acid containing HCl.
| 【1】 Witte, E.-C.; Chemical synthesis of picumast dihydrochloride. Arzneim-Forsch Drug Res 1989, 39, 10a, 1309. |
| 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) | 10355 | Diethylenediamine; Piperazine | 110-85-0 | C4H10N2 | 详情 | 详情 |
| (II) | 10356 | 1-Chloro-4-(chloromethyl)benzene; 4-Chlorobenzyl chloride | 104-83-6 | C7H6Cl2 | 详情 | 详情 |
| (III) | 10357 | 1-(4-Chlorobenzyl)piperazine; N-(4-Chlorobenzyl)piperazine | C11H15ClN2 | 详情 | 详情 | |
| (IV) | 10358 | 1-Bromo-3-chloropropane | 109-70-6 | C3H6BrCl | 详情 | 详情 |
| (V) | 10359 | 1-(4-Chlorobenzyl)-4-(3-chloropropyl)piperazine | C14H20Cl2N2 | 详情 | 详情 | |
| (VI) | 10360 | 3,4-Dimethylumbelliferone; 7-Hydroxy-3,4-dimethyl-2H-chromen-2-one | 2107-78-0 | C11H10O3 | 详情 | 详情 |
| (VII) | 10361 | 1,3-Dihydroxybenzene; m-Dihydroxybenzene; Resorcinol; Resorcin; 1,3-Benzenediol | 108-46-3 | C6H6O2 | 详情 | 详情 |
| (VIII) | 10362 | ethyl 2-methyl-3-oxobutanoate; ethyl 2-methylacetoacetate | 609-14-3 | C7H12O3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：2,4-Dihydroxyacetophenone (I) is formed by the Friedel-Crafts acetylation of resorcinol. This compound is condensed with diethyl oxalate in sodium ethoxide solution, affording (II). Disodium cromproxate (IV) is conveniently prepared from (II) by treatment with epichlorohydrine in aqueous ethanolic alkaline solution. It is recrystallized from hot water.
| 【1】 Ruyun, J.; Disodium Cromproxate. Drugs Fut 1991, 16, 5, 422. |
| 【2】 Liang, X.; Qi, J.; Lu, Y.; A simplified synthesis of 1,3-bis-(2-carboxychromone-7-oxy)-2-hydroxypropane disodium salt (78012). Acta Pharm Sin 1982, 17, 2, 143-5. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10146 | Epichlorohydrin; 2-(Chloromethyl)oxirane | 106-89-8 | C3H5ClO | 详情 | 详情 | |
| 10361 | 1,3-Dihydroxybenzene; m-Dihydroxybenzene; Resorcinol; Resorcin; 1,3-Benzenediol | 108-46-3 | C6H6O2 | 详情 | 详情 | |
| (I) | 13961 | Resacetophenone; 1-(2,4-Dihydroxyphenyl)-1-ethanone | 89-84-9 | C8H8O3 | 详情 | 详情 |
| (II) | 13962 | ethyl 7-hydroxy-4-oxo-4H-chromene-2-carboxylate | C12H10O5 | 详情 | 详情 | |
| (III) | 13963 | ethyl 7-(3-[[2-(ethoxycarbonyl)-4-oxo-4H-chromen-7-yl]oxy]-2-hydroxypropoxy)-4-oxo-4H-chromene-2-carboxylate | C27H24O11 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)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5
该中间体在本合成路线中的序号：(I)Pechmann condensation of resorcinol (I) with ethyl 2-methylacetylacetate (II) in concentrated sulfuric acid at room temperature provided coumarine (III). Further treatment with one equivalent of sodium hydride and an excess of sulfamoyl chloride yielded the target sulfamate.
| 【1】 Woo, L.W.C.; et al.; Steroidal and nonsteroidal sulfamates as potent inhibitors of steroid sulfatase. J Med Chem 1998, 41, 7, 1068. |
| 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) | 10361 | 1,3-Dihydroxybenzene; m-Dihydroxybenzene; Resorcinol; Resorcin; 1,3-Benzenediol | 108-46-3 | C6H6O2 | 详情 | 详情 |
| (II) | 10362 | ethyl 2-methyl-3-oxobutanoate; ethyl 2-methylacetoacetate | 609-14-3 | C7H12O3 | 详情 | 详情 |
| (III) | 10360 | 3,4-Dimethylumbelliferone; 7-Hydroxy-3,4-dimethyl-2H-chromen-2-one | 2107-78-0 | C11H10O3 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(IV)Friedel Crafts condensation of p-dimethoxybenzene (I) with dichloromaleic anhydride (II) in a molten mixture of AlCl3 and NaCl yielded dichloronaphthazarin (III). Finally, treatment of (III) with resorcinol (IV) and Na2CO3 in DMSO at room temperature furnished the target compound.
| 【1】 Chang, H.-X.; Chou, T.C.; Savaraj, N.; Liu, L.F.; Yu, C.; Cheng, C.C.; Design of antineoplastic agents based on the "2-phenylnaphthalene-type" structural pattern. 4. Synthesis and biological activity of 2-chloro-3-(substituted phenoxy)-1,4-naphthoquinones and related 5,8-dihydroxy-1,4-naphthoquinones. J Med Chem 1999, 42, 3, 405. |
| 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) | 21946 | 1,4-dimethoxybenzene; 4-methoxyphenyl methyl ether | 150-78-7 | C8H10O2 | 详情 | 详情 |
| (II) | 21947 | 3,4-dichloro-2,5-furandione | 1122-17-4 | C4Cl2O3 | 详情 | 详情 |
| (III) | 21948 | 2,3-dichloro-5,8-dihydroxynaphthoquinone | 14918-69-5 | C10H4Cl2O4 | 详情 | 详情 |
| (IV) | 10361 | 1,3-Dihydroxybenzene; m-Dihydroxybenzene; Resorcinol; Resorcin; 1,3-Benzenediol | 108-46-3 | C6H6O2 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(XI)Methyl [6-hydroxy-2,3-dihydro-1-benzofuran-3(S)-yl]acetate (VII) is synthesized as follows:
Cyclization of resorcinol (XI) with ethyl 4-chloroacetoacetate (XII) by means of H2SO4 gives 4-(chloromethyl)-7-hydroxychromen-2-one (XIII), which by treatment with NaOH at reflux affords (6-hydroxybenzofuran-3-yl)acetic acid (XIV). Esterification of carboxylic acid (XIV) with MeOH in the presence of H2SO4 at reflux yields the corresponding methyl ester (XV), which is hydrogenated over Pd/C in MeOH to provide (±)-methyl (6-hydroxy-2,3-dihydro-1-benzofuran-3-yl)acetate (XVI) . Finally, the (S)-enantiomer (VII) is isolated by preparative HPLC .
Alternatively, intermediate (XV) can be reduced by H2 in the presence of bis(1,5-cyclooctadiene)rhodium trifluoromethanesulfonate and (S,S)-Et-ferrotane in the presence of NaOMe in MeOH .
| 【1】 Negoro, N., Sasaki, S., Mikami, S. et al. Discovery of TAK-875: A potent, selective, and orally bioavailable GPR40 agonist. ACS Med Chem Lett 2010, 1: 290-4. |
| 【2】 Yasuma, T., Negoro, N., Yamashita, M., Itou, M. (Takeda Pharmaeutical Co., Ltd.). Fused cyclic compounds. CA 2656003, EP 2041123, EP 2248812, JP 2009280585, JP 2009542580, US 2010004312, US 7732626, WO 2008001931. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VII) | 68881 | methyl [6-hydroxy-2,3-dihydro-1-benzofuran-3(S)-yl]acetate;(S)-methyl 2-(6-hydroxy-2,3-dihydrobenzofuran-3-yl)acetate | C11H12O4 | 详情 | 详情 | |
| (XI) | 10361 | 1,3-Dihydroxybenzene; m-Dihydroxybenzene; Resorcinol; Resorcin; 1,3-Benzenediol | 108-46-3 | C6H6O2 | 详情 | 详情 |
| (XII) | 23541 | ethyl 4-chloro-3-oxobutanoate；Ethyl 4-chloro-3-oxobutanoate；Ethyl 4-chloroacetoacetate | 638-07-3 | C6H9ClO3 | 详情 | 详情 |
| (XIII) | 68882 | 4-(chloromethyl)-7-hydroxychromen-2-one;4-(chloromethyl)-7-hydroxy-2H-1-Benzopyran-2-one;4-(Chloromethyl)-7-hydroxycoumarin;4-Chloromethyl-7-hydroxy-2H-chromen-2-one;7-Hydroxy-4-(chloromethyl)coumarin | 25392-41-0 | C10H7ClO3 | 详情 | 详情 |
| (XIV) | 68883 | (6-hydroxybenzofuran-3-yl)acetic acid;2-(6-hydroxybenzofuran-3-yl)acetic acid | C10H8O4 | 详情 | 详情 | |
| (XV) | 68884 | methyl 2-(6-hydroxybenzofuran-3-yl)acetate | C11H10O4 | 详情 | 详情 | |
| (XVI) | 68885 | methyl 2-(6-hydroxy-2,3-dihydrobenzofuran-3-yl)acetate；(±)-methyl (6-hydroxy-2,3-dihydro-1-benzofuran-3-yl)acetate | C11H12O4 | 详情 | 详情 |