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【结 构 式】

【分子编号】32966

【品名】4-bromo-N-hydroxybenzenecarboximidoyl chloride

【CA登记号】

【 分 子 式 】C7H5BrClNO

【 分 子 量 】234.47954

【元素组成】C 35.86% H 2.15% Br 34.08% Cl 15.12% N 5.97% O 6.82%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(I)

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:(I)

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
Extended Information