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【结 构 式】 
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【分子编号】32967 【品名】[(5R)-3-(4-bromophenyl)-4,5-dihydro-5-isoxazolyl]methanol 【CA登记号】 |
【 分 子 式 】C10H10BrNO2 【 分 子 量 】256.09894 【元素组成】C 46.9% H 3.94% Br 31.2% N 5.47% O 12.49% |
合成路线1
该中间体在本合成路线中的序号：(III)The asymmetric 1,3-dipolar cycloaddition of the nitrile oxide resulting from 4-bromo-N-hydroxybenzenecarboximidoyl chloride (I) to allyl alcohol (II) in the presence of (R,R)-diisopropyl tartrate and diethylzinc afforded the (R)-5-(hydroxymethyl)isoxazoline (III). After conversion of (III) to the mesylate (IV), treatment with ammonium hydroxide in a sealed vessel provided primary amine (V), which was then acetylated with Ac2O and pyridine to give amide (VI). Further treatment of (VI) with hexamethylditin and dichlorobis(triphenylphosphine) palladium yielded the trimethylstannyl derivative (VII). Reaction of N-Boc-4-piperidone (VIII) with lithium diisopropylamide and N-phenyl-trifluoromethanesulfonimide at low temperature furnished the corresponding vinyl triflate (IX). Subsequent coupling of (IX) with stannyl derivative (VII) in the presence of tris(dibenzylideneacetone)dipalladium and triphenylarsine gave rise to the N-Boc-tetrahydropyridylphenylisoxazole (X). The Boc group of (X) was then deprotected using trifluoroacetic acid, and the deprotected tetrahydropyridine (XI) was condensed with acetoxyacetyl chloride (XII), yielding the acetoxyacetamide (XIII). The acetate ester of (XIII) was finally hydrolyzed by means of K2CO3 in MeOH.
| 【1】 Ukaji, Y.; et al.; Enantioselective synthesis of 2-isoxazolines via asymmetric 1,3-dipolar cycloaddition of nitrile oxides to achiral allyl alcohols. Chem Lett 1993, 11, 1847. |
| 【2】 Barbachyn, M.R.; Thomas, R.C.; Cleek, G.J. (Pharmacia & Upjohn AB); Isoxazoline derivs. useful as antimicrobials. EP 0920421; US 5990136; WO 9807708 . |
| 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) | 32966 | 4-bromo-N-hydroxybenzenecarboximidoyl chloride | C7H5BrClNO | 详情 | 详情 | |
| (II) | 12234 | 2-Propen-1-ol; Allyl alcohol | 107-18-6 | C3H6O | 详情 | 详情 |
| (III) | 32967 | [(5R)-3-(4-bromophenyl)-4,5-dihydro-5-isoxazolyl]methanol | C10H10BrNO2 | 详情 | 详情 | |
| (IV) | 32968 | [(5R)-3-(4-bromophenyl)-4,5-dihydro-5-isoxazolyl]methyl methanesulfonate | C11H12BrNO4S | 详情 | 详情 | |
| (V) | 32969 | [(5R)-3-(4-bromophenyl)-4,5-dihydro-5-isoxazolyl]methylamine; [(5R)-3-(4-bromophenyl)-4,5-dihydro-5-isoxazolyl]methanamine | C10H11BrN2O | 详情 | 详情 | |
| (VI) | 32970 | N-[[(5R)-3-(4-bromophenyl)-4,5-dihydro-5-isoxazolyl]methyl]acetamide | C12H13BrN2O2 | 详情 | 详情 | |
| (VII) | 32971 | N-([(5R)-3-[4-(trimethylstannyl)phenyl]-4,5-dihydro-5-isoxazolyl]methyl)acetamide | C15H22N2O2Sn | 详情 | 详情 | |
| (VIII) | 18620 | tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone | 79099-07-3 | C10H17NO3 | 详情 | 详情 |
| (IX) | 32972 | tert-butyl 4-[[(trifluoromethyl)sulfonyl]oxy]-3,6-dihydro-1(2H)-pyridinecarboxylate | C11H16F3NO5S | 详情 | 详情 | |
| (X) | 32973 | tert-butyl 4-(4-[(5R)-5-[(acetamido)methyl]-4,5-dihydro-3-isoxazolyl]phenyl)-3,6-dihydro-1(2H)-pyridinecarboxylate | C22H29N3O4 | 详情 | 详情 | |
| (XI) | 32974 | N-([(5R)-3-[4-(1,2,3,6-tetrahydro-4-pyridinyl)phenyl]-4,5-dihydro-5-isoxazolyl]methyl)acetamide | C17H21N3O2 | 详情 | 详情 | |
| (XII) | 10456 | Acetoxiacetil chloride; 2-chloro-2-oxoethyl acetate | 13831-31-7 | C4H5ClO3 | 详情 | 详情 |
| (XIII) | 32975 | 2-[4-(4-[(5R)-5-[(acetamido)methyl]-4,5-dihydro-3-isoxazolyl]phenyl)-3,6-dihydro-1(2H)-pyridinyl]-2-oxoethyl acetate | C21H25N3O5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(III)The asymmetric 1,3-dipolar cycloaddition of the nitrile oxide resulting from 4-bromo-N-hydroxybenzenecarboximidoyl chloride (I) to allyl alcohol (II) in the presence of (R,R)-diisopropyl tartrate and diethylzinc afforded the (R)-5-(hydroxymethyl)isoxazoline (III). Treatment of 4-bromopyridine (IV) with hexamethylditin and dichlorobis(triphenylphosphine)palladium yielded 4-trimethylstannylpyridine (V). Subsequent coupling of bromophenylisoxazoline (III) with stannylpyridine (V) in the presence of tris(dibenzylideneacetone)-dipalladium and tri(2-furyl)phosphine gave rise to the pyridylphenylisoxazole (VI). After conversion of (VI) to the mesylate (VII), treatment with ammonium hydroxide in a sealed vessel provided primary amine (VIII). Finally, acetylation of (VIII) with Ac2O and pyridine furnished the title amide.
| 【1】 Ukaji, Y.; et al.; Enantioselective synthesis of 2-isoxazolines via asymmetric 1,3-dipolar cycloaddition of nitrile oxides to achiral allyl alcohols. Chem Lett 1993, 11, 1847. |
| 【2】 Barbachyn, M.R.; Thomas, R.C.; Cleek, G.J. (Pharmacia & Upjohn AB); Isoxazoline derivs. useful as antimicrobials. EP 0920421; US 5990136; WO 9807708 . |
| 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) | 32966 | 4-bromo-N-hydroxybenzenecarboximidoyl chloride | C7H5BrClNO | 详情 | 详情 | |
| (II) | 12234 | 2-Propen-1-ol; Allyl alcohol | 107-18-6 | C3H6O | 详情 | 详情 |
| (III) | 32967 | [(5R)-3-(4-bromophenyl)-4,5-dihydro-5-isoxazolyl]methanol | C10H10BrNO2 | 详情 | 详情 | |
| (IV) | 23565 | 4-bromopyridine | 1120-87-2 | C5H4BrN | 详情 | 详情 |
| (V) | 32976 | 4-(trimethylstannyl)pyridine | C8H13NSn | 详情 | 详情 | |
| (VI) | 32977 | [(5R)-3-[4-(4-pyridinyl)phenyl]-4,5-dihydro-5-isoxazolyl]methanol | C15H14N2O2 | 详情 | 详情 | |
| (VII) | 32978 | [(5R)-3-[4-(4-pyridinyl)phenyl]-4,5-dihydro-5-isoxazolyl]methyl methanesulfonate | C16H16N2O4S | 详情 | 详情 | |
| (VIII) | 32979 | [(5R)-3-[4-(4-pyridinyl)phenyl]-4,5-dihydro-5-isoxazolyl]methanamine; [(5R)-3-[4-(4-pyridinyl)phenyl]-4,5-dihydro-5-isoxazolyl]methylamine | C15H15N3O | 详情 | 详情 |