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【结 构 式】 
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【分子编号】14139 【品名】2-(5-Ethyl-2-pyridinyl)-1-ethanol 【CA登记号】5223-06-3 |
【 分 子 式 】C9H13NO 【 分 子 量 】151.20836 【元素组成】C 71.49% H 8.67% N 9.26% O 10.58% |
合成路线1
该中间体在本合成路线中的序号：(I)Two new related syntheses of pioglitazone hydrochloride have been described: 1) The condensation of 2-(5-ethylpyridin-2-yl)ethanol (I) with 4-hydroxybenzaldehyde (II) by means of benzyltributylammonium chloride, NaOH and tosyl chloride gives 4-[2-(5-ethylpyridin-2-yl)ethoxy]benzaldehyde (III), which is condensed with thiazolidine-2,4-dione (IV) in basic medium to afford 5-[-4-[2-(5-ethylpyridin-2-yl)ethoxy]benzylidene]thiazolidine-2,4-dione (V). Finally, this compound is hydrogenated in the usual way. 2) The condensation of alcohol (I) with 4-fluorobenzonitrile (VI) by means of NaH gives 4-[2-(5-ethylpyridin-2-yl)ethoxy]benzonitrile (VII), which is reduced with Raney Nickel and formic acid to the aldehyde (III), already obtained.
| 【1】 Momose, Y.; Sohda, T.; Meguro, K.; Hatanaka, C.; Ikeda, H.; Oi, S.; Studies on antidiabetic agents: Synthesis and biological activities of pioglitazone and related compounds. 11th Symp Med Chem (Dec 4-5, Tokushima) 1990, Abst P-11. |
| 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) | 14139 | 2-(5-Ethyl-2-pyridinyl)-1-ethanol | 5223-06-3 | C9H13NO | 详情 | 详情 |
| (II) | 13433 | 4-Hydroxybenzaldehyde; p-Hydroxybenzaldehyde | 123-08-0 | C7H6O2 | 详情 | 详情 |
| (III) | 14141 | 4-[2-(5-Ethyl-2-pyridinyl)ethoxy]benzaldehyde | C16H17NO2 | 详情 | 详情 | |
| (IV) | 10883 | 1,3-Thiazolane-2,4-dione; 2,4-Thiazolidinedione | 2295-31-0 | C3H3NO2S | 详情 | 详情 |
| (V) | 14143 | 5-((E)-[4-[2-(5-Ethyl-2-pyridinyl)ethoxy]phenyl]methylidene)-1,3-thiazolane-2,4-dione | 144809-28-9 | C19H18N2O3S | 详情 | 详情 |
| (VI) | 14144 | 4-Fluorobenzonitrile | 1194-02-1 | C7H4FN | 详情 | 详情 |
| (VII) | 14145 | 4-[2-(5-Ethyl-2-pyridinyl)ethoxy]benzonitrile | C16H16N2O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)This compound has been obtained by several different methods. The reaction of 2-(5-ethyl-2-pyridyl)ethanol (I) with Ts-Cl and NaOH in THF gives the corresponding tosylate (II), which is condensed with 4-hydroxybenzaldehyde (IV) by means of BnNBu3Cl and NaOH or K2CO3 to yield the aryl ether (V) (1-3). The condensation of (V) with thiazolidine-2,4-dione (VI) in refluxing ethanol affords the 5-benzylidenethiazolidinedione (VII), which is finally reduced with H2 over Pd/C in DMF or dioxane. The reaction of 2-(5-ethyl-2-pyridyl)ethanol (I) with Ms-Cl and TEA in dichloromethane THF gives the corresponding mesylate (III), which is condensed with 4-hydroxybenzaldehyde (IV) by means of K2CO3 to yield the already reported aryl ether (V). The condensation of 2-(5-ethyl-2-pyridyl)ethanol (I) with 4-fluorobenzonitrile (VIII) by means of NaH gives 4-[2-(5-ethyl-2-pyridyl)ethoxy]benzonitrile (IX), which is reduced with RaNi and HCOOH to yield the already reported 4-ethoxybenzaldehyde derivative (V).
| 【1】 Saito, Y.; Yamashita, M.; Mizufune, H. (Takeda Chemical Industries, Ltd.); Process for preparing 4-(2-(2-pyridyl)ethoxy)benzaldehyde derivs.. EP 0816340 . |
| 【2】 Mizuno, Y.; Arita, M. (Takeda Chemical Industries, Ltd.); Method for producing ethers. EP 0506273 . |
| 【3】 Meguro, K.; Momose, Y.; Sohda, T.; Oi, S.; Ikeda, H.; Hatanaka, C.; Studies on antidiabetic agents. X. Synthesis and biological activities of pioglitazone and related compounds. Chem Pharm Bull 1991, 39, 6, 1440-5. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 14139 | 2-(5-Ethyl-2-pyridinyl)-1-ethanol | 5223-06-3 | C9H13NO | 详情 | 详情 |
| (II) | 62865 | 2-(5-ethyl-2-pyridinyl)ethyl 4-methylbenzenesulfonate | C16H19NO3S | 详情 | 详情 | |
| (III) | 62866 | 2-(5-ethyl-2-pyridinyl)ethyl methanesulfonate | C10H15NO3S | 详情 | 详情 | |
| (IV) | 13433 | 4-Hydroxybenzaldehyde; p-Hydroxybenzaldehyde | 123-08-0 | C7H6O2 | 详情 | 详情 |
| (V) | 14141 | 4-[2-(5-Ethyl-2-pyridinyl)ethoxy]benzaldehyde | C16H17NO2 | 详情 | 详情 | |
| (VI) | 10883 | 1,3-Thiazolane-2,4-dione; 2,4-Thiazolidinedione | 2295-31-0 | C3H3NO2S | 详情 | 详情 |
| (VII) | 14143 | 5-((E)-[4-[2-(5-Ethyl-2-pyridinyl)ethoxy]phenyl]methylidene)-1,3-thiazolane-2,4-dione | 144809-28-9 | C19H18N2O3S | 详情 | 详情 |
| (VIII) | 14144 | 4-Fluorobenzonitrile | 1194-02-1 | C7H4FN | 详情 | 详情 |
| (IX) | 14145 | 4-[2-(5-Ethyl-2-pyridinyl)ethoxy]benzonitrile | C16H16N2O | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)The condensation of 2-(5-ethyl-2-pyridyl)ethanol (I) with 4-fluoronitrobenzene (II) by means of NaH in DMF gives 4-[2-(5-ethyl-2-pyridyl)ethoxy]nitrobenzene (III), which is reduced with H2 over Pd/C in methanol to yield the corresponding aniline (IV). The reaction of (IV) with NaNO2/HBr and methyl acrylate (V) in acetone/methanol affords the 2-bromopropionate derivative (VI), which is cyclized with thiourea (VII) by means of NaOAc in refluxing ethanol to provide the 2-imino-4-thiazolidinone (VIII). Finally, this compound is hydrolyzed with refluxing 2N HCl.
| 【1】 Meguro, K.; Fujita, T. (Takeda Chemical Industries, Ltd.); Thiazolidinedione derivs., their production and use. EP 0193256; ES 8705886; JP 1986267580; US 4687777 . |
| 【2】 Sohda, T.; Momose, Y.; Meguro, K.; Kawamatsu, Y.; Sugiyama, Y.; Ikeda, H.; Studies on antidiabetic agents. Synthesis and hypoglycemic activity of 5-[4-(pyridylalkoxy)benzyl]-2,4-thiazolidinediones. Arzneim-Forsch Drug Res 1990, 40, 1, 37. |
| 【3】 Prous, J.; Castaner, J.; PIOGLITAZONE HYDROCHLORIDE < Prop INNM; USAN >. Drugs Fut 1990, 15, 11, 1080. |
| 【4】 Meguro, K.; Momose, Y.; Sohda, T.; Oi, S.; Ikeda, H.; Hatanaka, C.; Studies on antidiabetic agents. X. Synthesis and biological activities of pioglitazone and related compounds. Chem Pharm Bull 1991, 39, 6, 1440-5. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 14139 | 2-(5-Ethyl-2-pyridinyl)-1-ethanol | 5223-06-3 | C9H13NO | 详情 | 详情 |
| (II) | 14153 | 4-Fluoronitrobenzene; 1-Fluoro-4-nitrobenzene | 350-46-9 | C6H4FNO2 | 详情 | 详情 |
| (III) | 62867 | 5-ethyl-2-[2-(4-nitrophenoxy)ethyl]pyridine; 2-(5-ethyl-2-pyridinyl)ethyl 4-nitrophenyl ether | C15H16N2O3 | 详情 | 详情 | |
| (IV) | 62868 | 4-[2-(5-ethyl-2-pyridinyl)ethoxy]aniline; 4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenylamine | C15H18N2O | 详情 | 详情 | |
| (V) | 14156 | methyl acrylate | 96-33-3 | C4H6O2 | 详情 | 详情 |
| (VI) | 62869 | methyl 2-bromo-3-{4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl}propanoate | C19H22BrNO3 | 详情 | 详情 | |
| (VII) | 10180 | Thiourea | 62-56-6 | CH4N2S | 详情 | 详情 |
| (VIII) | 62870 | 5-{4-[2-(5-ethyl-2-pyridinyl)ethoxy]benzyl}-2-imino-1,3-thiazolidin-4-one | C19H21N3O2S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)
| 【1】 Adiyrunan M, Guner D, Yurdakul A, et al. 2003. Ap rocess for the production of 5-[4-[2-(5-ethyl-2-pyridylethoxy) benzyl]-2,4-thiazolidinedione hydrochloride. W0 2004000810 |
| 【2】 Edward HJ. 1993. A reduction method for substituted 5-methylene-thiazoliclinediones. W0 9313095 |
| 【3】 Ulliard M, Derrien Y, Pintus T. 2002. Method for preparing compounds derived from thiazolidinedione, oxazolidinedione or hydantoin. W0 200206457 |
| 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) | 14139 | 2-(5-Ethyl-2-pyridinyl)-1-ethanol | 5223-06-3 | C9H13NO | 详情 | 详情 |
| (II) | 62866 | 2-(5-ethyl-2-pyridinyl)ethyl methanesulfonate | C10H15NO3S | 详情 | 详情 | |
| (III) | 13433 | 4-Hydroxybenzaldehyde; p-Hydroxybenzaldehyde | 123-08-0 | C7H6O2 | 详情 | 详情 |
| (IV) | 14141 | 4-[2-(5-Ethyl-2-pyridinyl)ethoxy]benzaldehyde | C16H17NO2 | 详情 | 详情 | |
| (V) | 10883 | 1,3-Thiazolane-2,4-dione; 2,4-Thiazolidinedione | 2295-31-0 | C3H3NO2S | 详情 | 详情 |
| (VI) | 14143 | 5-((E)-[4-[2-(5-Ethyl-2-pyridinyl)ethoxy]phenyl]methylidene)-1,3-thiazolane-2,4-dione | 144809-28-9 | C19H18N2O3S | 详情 | 详情 |