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【结 构 式】 
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【分子编号】12690 【品名】(Hydroxyamino)methane; N-Methylhydroxylamine 【CA登记号】593-77-1 |
【 分 子 式 】CH5NO 【 分 子 量 】47.05684 【元素组成】C 25.52% H 10.71% N 29.77% O 34% |
合成路线1
该中间体在本合成路线中的序号：(IV)The condensation of 1-naphthol (I) with an excess of o-dichlorobenzene (II) at 100 C by means of anhydrous AlCl3 gives 4-(3,4-dichlorophenyl)-1-tetralone (III), which is allowed to react with N-methylhydroxylamine (IV) and NaOAc in refluxing ethanol, yielding the nitrone (V). The reduction of (V) with H2 over RaNi in methanol affords a racemic cis/trans (9:1) mixture of methylamines, which by crystallization of its hydrochloride in ethanol provides pure (racemic)-(cis)-(VI). Finally, the target (1S)-(cis)-compound is obtained by optical resolution of (VI) with (R)-(-)-mandelic acid.
| 【1】 Vukics, K.; et al.; Improved industrial synthesis of antidepressant sertraline. Org Process Res Dev 2002, 6, 1, 82. |
| 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) | 22935 | alpha-naphthol; 1-naphthol | 90-15-3 | C10H8O | 详情 | 详情 |
| (II) | 58592 | 1,2-Dichlorobenzene; chloroben; chloroden; cloroben; Dichloricide; Dichlorobenzol; dilantin db; dilatin db; dizene; dowtherm e; o-Dichlorobenzene; o-Dichlorobenzol; termitkil | 95-50-1 | C6H4Cl2 | 详情 | 详情 |
| (III) | 30583 | 4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenone; 4-(3',4'-Dichlorophenyl)-1-tetralone | 79580-19-3 | C16H12Cl2O | 详情 | 详情 |
| (IV) | 12690 | (Hydroxyamino)methane; N-Methylhydroxylamine | 593-77-1 | CH5NO | 详情 | 详情 |
| (V) | 58593 | [4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene](methyl)ammoniumolate | C17H15Cl2NO | 详情 | 详情 | |
| (VI) | 58594 | N-[(1S,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenyl]-N-methylamine; (1S,4S)-4-(3,4-dichlorophenyl)-N-methyl-1,2,3,4-tetrahydro-1-naphthalenamine | C17H17Cl2N | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)A new synthesis of tepoxalin has been described: The condensation of 4-chloroacetophenone (I) with succinic anhydride (II) by means of lithium bis(trimethylsilyl)amide in THF at -20 C gives 6-(4-chlorophenyl)-4,6-dioxohexanoic acid (III), which is cyclized with 4-methoxyphenylhydrazine (IV) by means of triethylamine in methanol at room temperature to afford 3-[5-(4-chlorophenyl)-1-(4-methoxyphenyl)pyrazol-3-yl]propanoic acid (V); finally this compound is condensed with methylhydroxylamine (VI) by means of oxalyl chloride and triethylamine at room temperature.
| 【1】 Forerokelly, Y.; Murray, W.; Wachter, M.; Barton, D.; The regioselective synthesis of tepoxalin, 3-[5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-pyrazolyl]-N-hydroxy-N-methylpropanamide and related 1,5-diarylpyrazole antiinflammatory agents. Synthesis 1991, 1, 1, 18. |
| 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) | 12685 | 4-Chloroacetophenone; 1-(4-Chlorophenyl)-1-ethanone; p-Chloroacetophenone | 99-91-2 | C8H7ClO | 详情 | 详情 |
| (II) | 11291 | Dihydro-2,5-furandione; Succinic anhydride | 108-30-5 | C4H4O3 | 详情 | 详情 |
| (III) | 12687 | 6-(4-Chlorophenyl)-4,6-dioxohexanoic acid | C12H11ClO4 | 详情 | 详情 | |
| (IV) | 12688 | 4-Hydrazinophenyl methyl ether; 1-(4-Methoxyphenyl)hydrazine | 3471-32-7 | C7H10N2O | 详情 | 详情 |
| (V) | 12689 | 3-[5-(4-Chlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]propionic acid | C19H17ClN2O3 | 详情 | 详情 | |
| (VI) | 12690 | (Hydroxyamino)methane; N-Methylhydroxylamine | 593-77-1 | CH5NO | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：A new method for the synthesis of tepoxalin has been reported: The cyclization of 6-(4-chlorophenyl)-4,6-dioxohexanoic acid (I) with refluxing acetic anhydride gives 5-[2-(4-chlorophenyl)-2-oxoethylidene]tetrahydrofuran-2-one (II), which is treated with methylhydroxylamine to afford the corresponding N-hydroxy-N-methylamide (III). Finally, this compound is cyclized with 4-methoxyphenylhydroazine (IV) by means of Na2CO3 in refluxing ethanol.
| 【1】 Murray, W.V.; Hadden, S.K.; A facile synthesis of tepoxalin, 5-(4-chlorophenyl)-N-hydroxy-1-(4-methoxyphenyl)-N-methyl-1H-pyrazole-3-propanamide. J Org Chem 1992, 57, 24, 6662. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 12690 | (Hydroxyamino)methane; N-Methylhydroxylamine | 593-77-1 | CH5NO | 详情 | 详情 | |
| (I) | 12687 | 6-(4-Chlorophenyl)-4,6-dioxohexanoic acid | C12H11ClO4 | 详情 | 详情 | |
| (II) | 12692 | 5-[(Z)-2-(4-Chlorophenyl)-2-oxoethylidene]dihydro-2-furanone | C12H9ClO3 | 详情 | 详情 | |
| (III) | 12693 | 6-(4-Chlorophenyl)-N-hydroxy-N-methyl-4,6-dioxohexanamide | C13H14ClNO4 | 详情 | 详情 | |
| (IV) | 12688 | 4-Hydrazinophenyl methyl ether; 1-(4-Methoxyphenyl)hydrazine | 3471-32-7 | C7H10N2O | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)The 2,4-dibromobutyrylchloride (I) was reacted with N-methylhydroxylamine (II) in methylene chloride with NaOH to yield 4-bromo-2-methyl-5,6-dihydro-2H-1,2-oxazin-3(4H)-one (III). The reaction of (III) and zinc with 3,5-di-tert-butyl-4-hydroxybenzaldehyde (IV) underwent Reformatsky-type reaction. Dehydration of the hydroxymethyl intermediate (V) in refluxing toluene with p-toluenesulfonic acid afforded BF-389.
| 【1】 Lee, S.J.; Frierson, M.R. III, Wong, S.; Naismith, R.W.; BF-389. Drugs Fut 1992, 17, 1, 12. |
| 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) | 20577 | 2,4-dibromobutanoyl chloride | C4H5Br2ClO | 详情 | 详情 | |
| (II) | 12690 | (Hydroxyamino)methane; N-Methylhydroxylamine | 593-77-1 | CH5NO | 详情 | 详情 |
| (III) | 14874 | 4-bromo-2-methyl-1,2-oxazinan-3-one | C5H8BrNO2 | 详情 | 详情 | |
| (IV) | 14875 | 3,5-Bis(1,1-dimethylethyl)-4-hydroxybenzaldehyde; 3,5-di(tert-butyl)-4-hydroxybenzaldehyde; 3,5-Di-tert-butyl-4-hydroxybenzaldehyde | 1620-98-0 | C15H22O2 | 详情 | 详情 |
| (V) | 14876 | 4-[[3,5-di(tert-butyl)-4-hydroxyphenyl](hydroxy)methyl]-2-methyl-1,2-oxazinan-3-one | C20H31NO4 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(II)The condensation of 4-formylbenzonitrile (I) with N-methylhyddroxylamine (II) by means of Na2CO3 in dichloromethane gives the nitrone (III), which is cyclized with isobutyl 3-butenoate (IV) by heating at 100 C to afford the cis-isoxazolidinyl acetate (V) (along with some trans isomer) that is purified by chromatography. The hydrolysis of the ester (V) with LiOH in THF/water yields the free acid (VI), which is condensed with the diamino ester (VII) by means of PyBop and Et3N in DMF giving the intermediate (VIII). The treatment of (VII) with dry HCl in methanol/chloroform to convert the CN group into amidino yields derivative (IX), which is finally hydrolyzed to the free acid with aqueous HCl.
| 【1】 Confalone, P.N.; Jin, F.; Mousa, S.A.; Platelet glycoprotein IIb/IIIa receptor antagonists derived from isoxazolidines. Bioorg Med Chem Lett 1999, 9, 1, 55. |
| 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) | 17552 | 4-formylbenzonitrile; 4-Cyanobenzaldehyde | 105-07-7 | C8H5NO | 详情 | 详情 |
| (II) | 12690 | (Hydroxyamino)methane; N-Methylhydroxylamine | 593-77-1 | CH5NO | 详情 | 详情 |
| (III) | 27637 | 4-[[methyl(oxo)-lambda(5)-azanylidene]methyl]benzonitrile | C9H8N2O | 详情 | 详情 | |
| (IV) | 27638 | isobutyl 3-butenoate | 24342-03-8 | C8H14O2 | 详情 | 详情 |
| (V) | 27639 | isobutyl 2-[(3R,5S)-3-(4-cyanophenyl)-2-methylisoxazolidinyl]acetate | C17H22N2O3 | 详情 | 详情 | |
| (VI) | 27640 | 2-[(3R,5S)-3-(4-cyanophenyl)-2-methylisoxazolidinyl]acetic acid | C13H14N2O3 | 详情 | 详情 | |
| (VII) | 25970 | methyl (2S)-3-amino-2-[(phenylsulfonyl)amino]propanoate | C10H14N2O4S | 详情 | 详情 | |
| (VIII) | 27641 | methyl (2S)-3-([2-[(3R,5S)-3-(4-cyanophenyl)-2-methylisoxazolidinyl]acetyl]amino)-2-[[(4-methyl-2-pyridinyl)sulfonyl]amino]propanoate | C23H27N5O6S | 详情 | 详情 | |
| (IX) | 27642 | methyl (2S)-3-[[2-((3R,5S)-3-[4-[amino(imino)methyl]phenyl]-2-methylisoxazolidinyl)acetyl]amino]-2-[[(3-methylphenyl)sulfonyl]amino]propanoate | C24H31N5O6S | 详情 | 详情 |