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【结 构 式】 
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【分子编号】14224 【品名】Serine, methyl ester; methyl 2-amino-3-hydroxypropanoate 【CA登记号】2104-89-4 |
【 分 子 式 】C4H9NO3 【 分 子 量 】119.1204 【元素组成】C 40.33% H 7.62% N 11.76% O 40.29% |
合成路线1
该中间体在本合成路线中的序号：(II)D-Cycloserine can be obtained by several different ways: 1) The esterification of DL-serine (I) with methanol gives the methyl ester (II), which is cyclized with ethyl imidobenzoate (III) yielding 2-phenyl-2-oxazoline-4-carboxylic acid methyl ester (IV). The reaction of (IV) with hydroxylamine and sodium ethoxide affords the hydroxamic acid (V), which is treated with HCl in dioxane to give 2-benzamido-3-chloropropionohydroxamic acid (VI). The cyclization of (VI) with base, followed by acidification yields 4-benzamidoisoxazolidin-3-one (VII), which by treatment with methanolic HCl is converted to 3-(aminooxy)-DL-alanine methyl ester (VIII). The cyclization of (VIII) with KOH affords DL-4-aminoisoxazolidin-3-one as a racemic mixture, which is resolved with D-tartaric acid.
| 【1】 Folkers, K.; Stammer, C.H.; Holly, F.W.; Wilson, A.N.; Synthesis of D-4-amino-3-isoxazolidone. J Am Chem Soc 1955, 77, 2, 2346-7. |
| 【2】 Schlapfer, R.; Majnoni, S.; Furst, A.; Von Plattner, P.A.; Frick, H.; Boller, A.; Kirchensteiner, H.; Hegedus, B.; Spiegelberg, H.; Synthesis of 4-amino-3-isoxazolidinone (cycloserine) and some analogs. Helv Chim Acta 1957, 40, 5, 1531-52. |
| 【3】 Prous, J.; Mealy, N.; Castaner, J.; D-Cycloserine. Drugs Fut 1994, 19, 11, 988. |
| 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) | 14223 | DL-2-Amino-3-hydroxypropionic acid; DL-Serine; (+/-)-2-Amino-3-hydroxypropionic acid; Serine | 302-84-1 | C3H7NO3 | 详情 | 详情 |
| (II) | 14224 | Serine, methyl ester; methyl 2-amino-3-hydroxypropanoate | 2104-89-4 | C4H9NO3 | 详情 | 详情 |
| (III) | 14225 | ethyl benzenecarboximidoate | C9H11NO | 详情 | 详情 | |
| (IV) | 14226 | methyl 2-phenyl-4,5-dihydro-1,3-oxazole-4-carboxylate | C11H11NO3 | 详情 | 详情 | |
| (V) | 14227 | N-Hydroxy-2-phenyl-4,5-dihydro-1,3-oxazole-4-carboxamide | C10H10N2O3 | 详情 | 详情 | |
| (VI) | 14228 | N-[1-(Chloromethyl)-2-(hydroxyamino)-2-oxoethyl]benzamide | C10H11ClN2O3 | 详情 | 详情 | |
| (VII) | 14229 | N-(3-Oxotetrahydro-4-isoxazolyl)benzamide | C10H10N2O3 | 详情 | 详情 | |
| (VIII) | 14230 | methyl 2-amino-3-(aminooxy)propanoate | C4H10N2O3 | 详情 | 详情 | |
| (IX) | 63865 | 4-amino-3-isoxazolidinone | C3H6N2O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)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 |
合成路线3
该中间体在本合成路线中的序号：(III)Synthesis of oxazole intermediate (IX): The reaction of 2,2-dichloroacetonitrile (I) with sodium methoxide in methanol gives methyl 2,2-dichloroethanimidoate (II), which is cyclized with DL-serine methyl ester (III) in methanol to yield oxazoline (IV). The reaction of (IV) with sodium methoxide in methanol affords 2-(chloromethyl)-4-methoxy-4,5-dihydrooxazole-4-carboxylic acid methyl ester (V), which is treated with Ts-OH in refluxing toluene to provide the chloromethyloxazole (VI). The reaction of (VI) with pyrrolidine (VII) in toluene gives the 2-(1-pyrrolidinylmethyl)oxazole-4-carboxylic acid methyl ester (VIII), which is hydrolyzed with K2CO3 to yield the target oxazole (IX). Alternatively, the reaction of 2-(bromomethyl)oxazole-4-carboxylic acid ethyl ester (X) with pyrrolidine (VII) gives the precursor (XI), which is hydrolyzed with K2CO3 as before to afford the target oxazole intermediate (IX).
| 【1】 Hermitage, S.A.; et al.; An efficient, practical approach to the synthesis of 2,4-disubstituted thiazoles and oxazoles: Application to the synthesis of GW475151. Org Process Res Dev 2001, 5, 1, 37. |
| 【2】 Johnson, M.R.; Shah, P.; MacDonald, S.J.F.; Harrison, L.A.; Finch, H.; Smith, R.A.; Inglis, G.G.A.; Clarke, G.D.E.; Dowle, M.D. (Glaxo Group Ltd.); Pyrrolopyrrolone derivs. as inhibitors of neutrophil elastase. WO 9912933 . |
| 【3】 Hermitage, S.A.; Cardwell, K.S. (Glaxo Group Ltd.); Process for preparing oxazole derivs.. WO 0053589 . |
| 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) | 47789 | 2,2-dichloroacetonitrile; Dichloroacetonitrile | 3018-12-0 | C2HCl2N | 详情 | 详情 |
| (II) | 47790 | methyl 2,2-dichloroethanimidoate | C3H5Cl2NO | 详情 | 详情 | |
| (III) | 14224 | Serine, methyl ester; methyl 2-amino-3-hydroxypropanoate | 2104-89-4 | C4H9NO3 | 详情 | 详情 |
| (IV) | 47791 | methyl 2-(dichloromethyl)-4,5-dihydro-1,3-oxazole-4-carboxylate | C6H7Cl2NO3 | 详情 | 详情 | |
| (V) | 47792 | methyl 2-(chloromethyl)-4-methoxy-4,5-dihydro-1,3-oxazole-4-carboxylate | C7H10ClNO4 | 详情 | 详情 | |
| (VI) | 47793 | methyl 2-(chloromethyl)-1,3-oxazole-4-carboxylate | C6H6ClNO3 | 详情 | 详情 | |
| (VII) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (VIII) | 47794 | methyl 2-(1-pyrrolidinylmethyl)-1,3-oxazole-4-carboxylate | C10H14N2O3 | 详情 | 详情 | |
| (IX) | 47795 | potassium 2-(1-pyrrolidinylmethyl)-1,3-oxazole-4-carboxylate | C9H11KN2O3 | 详情 | 详情 | |
| (X) | 47796 | ethyl 2-(bromomethyl)-1,3-oxazole-4-carboxylate | C7H8BrNO3 | 详情 | 详情 | |
| (XI) | 47797 | ethyl 2-(1-pyrrolidinylmethyl)-1,3-oxazole-4-carboxylate | C11H16N2O3 | 详情 | 详情 |