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【结 构 式】 
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【分子编号】19980 【品名】3,5-di(tert-butyl)-4-hydroxybenzoic acid 【CA登记号】1421-49-4 |
【 分 子 式 】C15H22O3 【 分 子 量 】250.33788 【元素组成】C 71.97% H 8.86% O 19.17% |
合成路线1
该中间体在本合成路线中的序号：(I)3,5-Di-tert-butyl-4-hydroxybenzoic acid (I) was converted to amide (III) via activation as the acyl imidazole (II) followed by treatment with aqueous ammonia. Subsequent condensation of (III) with ethyl 4-chloroacetoacetate (IV) produced oxazole (V). Basic hydrolysis of the ethyl ester of (V) yielded carboxylic acid (VI), which was reduced to alcohol (VII) with borane in THF. Treatment of (VII) with methanesulfonyl chloride and triethylamine generated mesylate (VIII). This was coupled with 4-hydroxybenzaldehyde (IX), yielding ether (X). Finally, reductive condensation of (X) with ethyl methylamine in the presence of NaBH3CN furnished the corresponding tertiary amine.
| 【1】 Heinz, L.J.; Panetta, J.A.; Phillips, M.L.; Shadle, J.K. (Eli Lilly and Company); Novel cpds. useful as neuro-protective agents. EP 0971709; WO 9815274 . |
| 【2】 Shannon, H.E.; Panetta, J.A. (Eli Lilly and Company); Method for treating pain. WO 9909980 . |
| 【3】 Shannon, H.E.; Panetta, J.A. (Eli Lilly and Company); Method for treating neuropathic pain. WO 9909979 . |
| 【4】 Heinz, L.J.; Panetta, J.A.; Phillips, M.L.; Rieck, J.A.; Rizzo, J.R.; Shadle, J.K.; Varie, D.L.; Anderson, B.A. (Eli Lilly and Company); Oxazoles, thiazoles, oxazolines, oxadiazoles and benzoxazoles useful as neuro-protective agents. EP 0908454; WO 9918091 . |
| 【5】 Panetta, J.A.; Shannon, H.E. (Eli Lilly and Company); Method for treating pain. WO 9909829 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 40588 | N-methyl-1-ethanamine; N-ethyl-N-methylamine | 624-78-2 | C3H9N | 详情 | 详情 | |
| (I) | 19980 | 3,5-di(tert-butyl)-4-hydroxybenzoic acid | 1421-49-4 | C15H22O3 | 详情 | 详情 |
| (II) | 35204 | [3,5-di(tert-butyl)-4-hydroxyphenyl](1H-imidazol-1-yl)methanone | C18H24N2O2 | 详情 | 详情 | |
| (III) | 35205 | 3,5-di(tert-butyl)-4-hydroxybenzamide | C15H23NO2 | 详情 | 详情 | |
| (IV) | 23541 | ethyl 4-chloro-3-oxobutanoate；Ethyl 4-chloro-3-oxobutanoate；Ethyl 4-chloroacetoacetate | 638-07-3 | C6H9ClO3 | 详情 | 详情 |
| (V) | 35206 | ethyl 2-[2-[3,5-di(tert-butyl)-4-hydroxyphenyl]-1,3-oxazol-4-yl]acetate | C21H29NO4 | 详情 | 详情 | |
| (VI) | 35207 | 2-[2-[3,5-di(tert-butyl)-4-hydroxyphenyl]-1,3-oxazol-4-yl]acetic acid | C19H25NO4 | 详情 | 详情 | |
| (VII) | 35208 | 2,6-di(tert-butyl)-4-[4-(2-hydroxyethyl)-1,3-oxazol-2-yl]phenol | C19H27NO3 | 详情 | 详情 | |
| (VIII) | 35209 | 2-[2-[3,5-di(tert-butyl)-4-hydroxyphenyl]-1,3-oxazol-4-yl]ethyl methanesulfonate | C20H29NO5S | 详情 | 详情 | |
| (IX) | 13433 | 4-Hydroxybenzaldehyde; p-Hydroxybenzaldehyde | 123-08-0 | C7H6O2 | 详情 | 详情 |
| (X) | 35210 | 4-(2-[2-[3,5-di(tert-butyl)-4-hydroxyphenyl]-1,3-oxazol-4-yl]ethoxy)benzaldehyde | C26H31NO4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)1) The N-acylation of DL-serine (I) with 3,5-di-tert-butyl-4-hydroxybenzoic acid by means of carbonyldiimidazole (CDI) in THF gives the acylated serine (III), which is cyclized by means of CBr4/triphenylphosphine/imidazole in acetonitrile to yields the oxazoline (IV). The dehydrogenation of (IV) with activated MnO2 in acetone affords 2-(3,5-di-tert-butyl-4-hydroxyphenyl)oxazole-4-carboxylic acid methyl ester (V), which is reduced with LiBH4 in THF/methanol giving the oxazolylmethnaol (VI). The reaction of (VI) with Br2/triphenylphosphine in acetonitrile yields the bromomethyl derivtive (VII), which is condensed with N-ethyl-N-[2-(4-hydroxyphenyl)ethyl]formamide (VIII) by means of NaH in THF to afford the formylated precursor (IX). Finally, this compound is converted into LY-382924 by reduction of the formyl group with AlH3 (LiAlH4/H2SO4) in THF and treatmnt with HCl gas in CHCl3. 2) The intermediate N-ethyl-N-[2-(4-hydroxyphenyl)ethyl]formamide (VIII) has been obtained as follows: The acylation of 2-(4-hydroxyphenyl)ethylamine (X) with acetic anhydride gives the acetamide (XI), which is reduced with LiAlH4 to the secondary amine (XII). Finally, this amine is formylated with formic acid and carbonyldiimidazole (CDI) in THF.
| 【1】 Heinz, L.J.; et al.; Synthesis and biological evaluation of a novel series of antioxidants for the treatment of global cerebral ischemia. 217th ACS Natl Meet (March 21 1999, Anaheim) 1998, Abst MEDI 130. |
| 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) | 14224 | Serine, methyl ester; methyl 2-amino-3-hydroxypropanoate | 2104-89-4 | C4H9NO3 | 详情 | 详情 |
| (II) | 19980 | 3,5-di(tert-butyl)-4-hydroxybenzoic acid | 1421-49-4 | C15H22O3 | 详情 | 详情 |
| (III) | 19981 | methyl 2-[[3,5-di(tert-butyl)-4-hydroxybenzoyl]amino]-3-hydroxypropanoate | C19H29NO5 | 详情 | 详情 | |
| (IV) | 19982 | methyl 2-[3,5-di(tert-butyl)-4-hydroxyphenyl]-4,5-dihydro-1,3-oxazole-4-carboxylate | C19H27NO4 | 详情 | 详情 | |
| (V) | 19983 | methyl 2-[3,5-di(tert-butyl)-4-hydroxyphenyl]-1,3-oxazole-4-carboxylate | C19H25NO4 | 详情 | 详情 | |
| (VI) | 19984 | 2,6-di(tert-butyl)-4-[4-(hydroxymethyl)-1,3-oxazol-2-yl]phenol | C18H25NO3 | 详情 | 详情 | |
| (VII) | 19985 | 4-[4-(bromomethyl)-1,3-oxazol-2-yl]-2,6-di(tert-butyl)phenol | C18H24BrNO2 | 详情 | 详情 | |
| (VIII) | 19986 | ethyl(4-hydroxyphenethyl)formamide | C11H15NO2 | 详情 | 详情 | |
| (IX) | 19987 | 4-([2-[3,5-di(tert-butyl)-4-hydroxyphenyl]-1,3-oxazol-4-yl]methoxy)phenethyl(ethyl)formamide | C29H38N2O4 | 详情 | 详情 | |
| (X) | 19988 | 4-(2-Aminoethyl)phenol; Tyramine | 51-67-2 | C8H11NO | 详情 | 详情 |
| (XI) | 19989 | N-(4-hydroxyphenethyl)acetamide | C10H13NO2 | 详情 | 详情 | |
| (XII) | 19990 | 4-[2-(ethylamino)ethyl]phenol | C10H15NO | 详情 | 详情 |