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【结 构 式】 
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【分子编号】55397 【品名】2,3-Butanedione 2-oxime; 2,3-Butanedione monoxime; 2,3-Butanedione oxime; 2,3-Butanedione-2-monoxime; Diacetyl monoxime 【CA登记号】57-71-6 |
【 分 子 式 】C4H7NO2 【 分 子 量 】101.10512 【元素组成】C 47.52% H 6.98% N 13.85% O 31.65% |
合成路线1
该中间体在本合成路线中的序号：(I)Condensation of 2,3-butanedione monooxime (I) with 2,2,-dimethyl-1,3-propanediamine (II) affords the bis-imine adduct (III). Subsequent reduction of the imine functions of (III) using NaBH4 in EtOH gives rise to a mixture of the meso-diamine (IV) and the racemic d,l-isomers (V). Separation of this mixture is achieved by either HPLC or fractional crystallization from acetonitrile and then from ethyl acetate. The target 99mtechnetium complex is prepared in situ by reduction of a solution of 99mTc-pertechnetate with stannous tartrate in the presence of the diamino dioxime ligand (V).
| 【1】 Nowotnik, D.P.; et al.; Development of a 99Tcm-labelled radiopharmaceutical for cerebral blood flow imaging. Nucl Med Commun 1985, 6, 9, 499. |
| 【2】 Nowotnik, D.P.; et al.; Separation of the stereoisomers of hexamethyl-propyleneamine oxime (HM-PAO) by high-performance liquid chromatography. J Liq Chromatogr 1995, 18, 4, 673. |
| 【3】 Nowotnik, D.P.; Canning, L.R.; Neirinckx, R.D.; Piper, I.M. (Amersham plc); Complexes of technetium-99m with propylene amine oximes. EP 0194843; JP 1986225159; US 4789736 . |
| 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) | 55397 | 2,3-Butanedione 2-oxime; 2,3-Butanedione monoxime; 2,3-Butanedione oxime; 2,3-Butanedione-2-monoxime; Diacetyl monoxime | 57-71-6 | C4H7NO2 | 详情 | 详情 |
| (II) | 56839 | 1,3-Diamino-2,2-dimethylpropane; Neopentandiamine | 7328-91-8 | C5H14N2 | 详情 | 详情 |
| (III) | 56840 | 3-[(3-{[(E)-2-(hydroxyimino)-1-methylpropylidene]amino}-2,2-dimethylpropyl)imino]-2-butanone oxime | C13H24N4O2 | 详情 | 详情 | |
| (IV) | 56841 | (3S)-3-[(3-{[(1R)-2-(hydroxyimino)-1-methylpropyl]amino}-2,2-dimethylpropyl)amino]-2-butanone oxime | C13H28N4O2 | 详情 | 详情 | |
| (V) | 56842 | (3R)-3-[(3-{[(1R)-2-(hydroxyimino)-1-methylpropyl]amino}-2,2-dimethylpropyl)amino]-2-butanone oxime | C13H28N4O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)The cyclization of 4-bromobenzaldehyde (I) with butanedione monooxime (II) by means of HCl in acetic acid gives 2-(4-bromophenyl)-4,5-dimethyloxazole N-oxide (III), which is chlorinated with POCl3 in refluxing chloroform to yield the chloromethyl derivative (IV). The reaction of (IV) with KCN and KI in hot DMF affords the cyanomethyl compound (V), which is hydrolyzed with KOH in water/2-methoxyethanol to provide the acetic acid derivative (VI). The reduction of (VI) with BH3/THF in THF gives the ethanol intermediate (VII), which is condensed with phenylboronic acid (VIII) by means of PPh3 and Pd(OAc)2 in propanol to yield the biphenyl derivative (IX). The reaction of the OH group of (IX) with tosyl anhydride in dichloromethane affords the tosylate (X), which is condensed with 2-(4-hydroxyphenoxy)-2-methylpropionic aid ethyl ester (XI) by means of Cs2CO3 in hot DMF to provide the ethyl ester precursor (XII). Finally, this compound is hydrolyzed with NaOH in methanol/water to obtain the target propionic acid.
| 【1】 Brooks, D.A.; et al.; Design and synthesis of 2-methyl-2-{4-[2-(5-methyl-2-aryloxazol-4-yl)ethoxy]phenoxy}propionic acids: A new class of dual PPARalpha/gamma agonists. J Med Chem 2001, 44, 13, 2061. |
| 【2】 Matthews, D.P.; Hay, D.A.; Ardecky, R.J.; Warshawsky, A.M.; Gossett, L.S.; Dominianni, S.J.; Rito, C.J.; Shuker, A.J.; Brooks, D.A.; Michellys, P.-Y.; Tyhonas, J.S. (Eli Lilly and Company; Ligand Pharmaceuticals, Inc.); Biaryl-oxa(thia)zole derivs. and their use as PPARs modulators. EP 1206457; US 6417212; WO 0116120 . |
| 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) | 22231 | 4-Bromobenzaldehyde | 1122-91-4 | C7H5BrO | 详情 | 详情 |
| (II) | 55397 | 2,3-Butanedione 2-oxime; 2,3-Butanedione monoxime; 2,3-Butanedione oxime; 2,3-Butanedione-2-monoxime; Diacetyl monoxime | 57-71-6 | C4H7NO2 | 详情 | 详情 |
| (III) | 55398 | 2-(4-bromophenyl)-4,5-dimethyl-1,3-oxazol-3-ium-3-olate | C11H10BrNO2 | 详情 | 详情 | |
| (IV) | 55399 | 2-(4-bromophenyl)-4-(chloromethyl)-5-methyl-1,3-oxazole | C11H9BrClNO | 详情 | 详情 | |
| (V) | 55400 | 2-[2-(4-bromophenyl)-5-methyl-1,3-oxazol-4-yl]acetonitrile | C12H9BrN2O | 详情 | 详情 | |
| (VI) | 55401 | 2-[2-(4-bromophenyl)-5-methyl-1,3-oxazol-4-yl]acetic acid | C12H10BrNO3 | 详情 | 详情 | |
| (VII) | 55402 | 2-[2-(4-bromophenyl)-5-methyl-1,3-oxazol-4-yl]-1-ethanol | C12H12BrNO2 | 详情 | 详情 | |
| (VIII) | 16593 | Phenylboronic acid；Benzeneboronic acid;Phenylboron dihydroxide | 98-80-6 | C6H7BO2 | 详情 | 详情 |
| (IX) | 55403 | 2-(2-[1,1'-biphenyl]-4-yl-5-methyl-1,3-oxazol-4-yl)-1-ethanol | C18H17NO2 | 详情 | 详情 | |
| (X) | 55404 | 2-(2-[1,1'-biphenyl]-4-yl-5-methyl-1,3-oxazol-4-yl)ethyl 4-methylbenzenesulfonate | C25H23NO4S | 详情 | 详情 | |
| (XI) | 55405 | ethyl 2-(4-hydroxyphenoxy)-2-methylpropanoate | C12H16O4 | 详情 | 详情 | |
| (XII) | 55406 | ethyl 2-{4-[2-(2-[1,1'-biphenyl]-4-yl-5-methyl-1,3-oxazol-4-yl)ethoxy]phenoxy}-2-methylpropanoate | C30H31NO5 | 详情 | 详情 |