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【结 构 式】

【分子编号】32407

【品名】methyl 2-(bromomethyl)acrylate

【CA登记号】

【 分 子 式 】C5H7BrO2

【 分 子 量 】179.01338

【元素组成】C 33.55% H 3.94% Br 44.64% O 17.88%

与该中间体有关的原料药合成路线共 4 条

合成路线1

该中间体在本合成路线中的序号:(I)

The condensation of 2-(bromomethyl)acrylic acid methyl ester (I) with 1H-tetrazole (II) by means of K2CO3 in DMF gives 2-(1-tetrazolylmethyl)acrylic acid methyl ester (III), which is cyclized with 3-cyanobenzaldehyde oxime (IV) by means of NaOCl yielding the oxazoline carboxylic ester (V). The hydrolysis of (V) with LiOH in THF affords the free carboxylic acid (VI), which is condensed with 2-(6-aminopyridin-3-yl)-N-tert-butybenzenesulfonamide (VII) by means of SOCl2 and triethylamine giving the carboxamide (VIII). Finally, this compound is treated with HCl and then with ammonium acetate to eliminate the tert-butyl protecting group and to hydrolyze the cyano group to the target amidino compound.

1 Alexander, R.S.; Wesler, R.R.; Ellis, C.D.; Quan, M.L.; Liauw, A.Y.; Wong, P.C.; Lam, G.; Knabb, R.M.; Wright, M.R.; Design and synthesis of isoxazoline derivatives as factor Xa inhibitors. 2(1). J Med Chem 1999, 42, 15, 2760.
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) 32407 methyl 2-(bromomethyl)acrylate C5H7BrO2 详情 详情
(II) 32408 1H-1,2,3,4-tetraazole; Tetrazole 288-94-8 CH2N4 详情 详情
(III) 32409 methyl 2-(1H-1,2,3,4-tetraazol-1-ylmethyl)acrylate C6H8N4O2 详情 详情
(IV) 23357 3-[(hydroxyimino)methyl]benzonitrile C8H6N2O 详情 详情
(V) 32410 methyl 3-(3-cyanophenyl)-5-(1H-1,2,3,4-tetraazol-1-ylmethyl)-4,5-dihydro-5-isoxazolecarboxylate C14H12N6O3 详情 详情
(VI) 32411 3-(3-cyanophenyl)-5-(1H-1,2,3,4-tetraazol-1-ylmethyl)-4,5-dihydro-5-isoxazolecarboxylic acid C13H10N6O3 详情 详情
(VII) 32412 2-(6-amino-3-pyridinyl)-N-(tert-butyl)benzenesulfonamide C15H19N3O2S 详情 详情
(VIII) 32413 N-(5-[2-[(tert-butylamino)sulfonyl]phenyl]-2-pyridinyl)-3-(3-cyanophenyl)-5-(1H-1,2,3,4-tetraazol-1-ylmethyl)-4,5-dihydro-5-isoxazolecarboxamide C28H27N9O4S 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 condensation of 2-(bromomethyl)acrylic acid methyl ester (I) with 1H-tetrazole (II) by means of K2CO3 in DMF gives 2-(1-tetrazolylmethyl)acrylic acid methyl ester (III), which is cyclized with 3-cyanobenzaldehyde oxime (IV) by means of NaOCl yielding the oxazoline carboxylic ester (V). The hydrolysis of (V) with LiOH in THF affords the free carboxylic acid (VI), which is condensed with 4'-amino-N-tert-butylbiphenyl-2-sulfonamide (VII) by means of SOCl2 and triethylamine giving the carboxamide (VIII). Finally, this compound is treated with HCl and then with ammonium acetate to eliminate the tert-butyl protecting group and to hydrolyze the cyano group to the target amidino compound.

1 Alexander, R.S.; Wesler, R.R.; Ellis, C.D.; Quan, M.L.; Liauw, A.Y.; Wong, P.C.; Lam, G.; Knabb, R.M.; Wright, M.R.; Design and synthesis of isoxazoline derivatives as factor Xa inhibitors. 2(1). J Med Chem 1999, 42, 15, 2760.
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) 32407 methyl 2-(bromomethyl)acrylate C5H7BrO2 详情 详情
(II) 32408 1H-1,2,3,4-tetraazole; Tetrazole 288-94-8 CH2N4 详情 详情
(III) 32409 methyl 2-(1H-1,2,3,4-tetraazol-1-ylmethyl)acrylate C6H8N4O2 详情 详情
(IV) 23357 3-[(hydroxyimino)methyl]benzonitrile C8H6N2O 详情 详情
(V) 32410 methyl 3-(3-cyanophenyl)-5-(1H-1,2,3,4-tetraazol-1-ylmethyl)-4,5-dihydro-5-isoxazolecarboxylate C14H12N6O3 详情 详情
(VI) 32411 3-(3-cyanophenyl)-5-(1H-1,2,3,4-tetraazol-1-ylmethyl)-4,5-dihydro-5-isoxazolecarboxylic acid C13H10N6O3 详情 详情
(VII) 23363 4'-amino-N-(tert-butyl)[1,1'-biphenyl]-2-sulfonamide C16H20N2O2S 详情 详情
(VIII) 32414 N-[2'-[(tert-butylamino)sulfonyl][1,1'-biphenyl]-4-yl]-3-(3-cyanophenyl)-5-(1H-1,2,3,4-tetraazol-1-ylmethyl)-4,5-dihydro-5-isoxazolecarboxamide C29H28N8O4S 详情 详情

合成路线3

该中间体在本合成路线中的序号:(I)

Conversion of the bromo derivative (I) into the corresponding azido compound (II) is performed by treatment with NaN3 in DMSO. Separately, aldehyde (III) is treated with hydroxylamine to provide oxime (IV), which is then condensed with derivative (II) by means of bleach in CH2Cl2 to furnish isoxazoline derivative (V). Hydrolysis of the methyl ester of (V) by means of LiOH in THF affords carboxylic acid (VI), which is treated with SOCl2 and then condensed with amine (VII) by means of Et3N to give carboxamide (VIII). Reduction of the azido moiety of (VIII) by means of P(OEt)3 in THF yields amine (IX), which is then derivatized by reaction with mesyl chloride (MeSO2Cl) to provide mesylate (X). Finally, the desired compound is obtained by treatment of (X) with TFA for tert-butyl group removal, followed by reduction of the nitro moiety with SnCl2.

1 Wong, P.C.; Ellis, C.D.; Rossi, K.A.; Wexler, R.R.; Wright, M.R.; Quan, M.L.; Lam, P.Y.; He, M.Y.; Knabb, R.M.; Liauw, A.Y.; Nonbenzamidine isoxazolin derivatives as factor Xa inhibitors. 221st ACS Natl Meet (April 1 2001, San Diego) 2001, Abst MEDI 52.
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) 32407 methyl 2-(bromomethyl)acrylate C5H7BrO2 详情 详情
(II) 50083 methyl 2-(azidomethyl)acrylate C5H7N3O2 详情 详情
(III) 50084 3-Nitro-4-chlorobenzaldehyde; 4-Chloro-3-nitrobenzaldehyde 16588-34-4 C7H4ClNO3 详情 详情
(IV) 50085 N-(4-chloro-3-nitrobenzyl)hydroxylamine; 1-chloro-4-[(hydroxyamino)methyl]-2-nitrobenzene C7H7ClN2O3 详情 详情
(V) 50086 methyl 5-(azidomethyl)-3-(4-chloro-3-nitrophenyl)-4,5-dihydro-5-isoxazolecarboxylate C12H10ClN5O5 详情 详情
(VI) 50087 5-(azidomethyl)-3-(4-chloro-3-nitrophenyl)-4,5-dihydro-5-isoxazolecarboxylic acid C11H8ClN5O5 详情 详情
(VII) 32412 2-(6-amino-3-pyridinyl)-N-(tert-butyl)benzenesulfonamide C15H19N3O2S 详情 详情
(VIII) 50088 5-(azidomethyl)-N-(5-[2-[(tert-butylamino)sulfonyl]phenyl]-2-pyridinyl)-3-(4-chloro-3-nitrophenyl)-4,5-dihydro-5-isoxazolecarboxamide C26H25ClN8O6S 详情 详情
(IX) 50089 5-(aminomethyl)-N-(5-[2-[(tert-butylamino)sulfonyl]phenyl]-2-pyridinyl)-3-(4-chloro-3-nitrophenyl)-4,5-dihydro-5-isoxazolecarboxamide C26H27ClN6O6S 详情 详情
(X) 50090 N-(5-[2-[(tert-butylamino)sulfonyl]phenyl]-2-pyridinyl)-3-(4-chloro-3-nitrophenyl)-5-[[(methylsulfonyl)amino]methyl]-4,5-dihydro-5-isoxazolecarboxamide C27H29ClN6O8S2 详情 详情

合成路线4

该中间体在本合成路线中的序号:(VI)

Mesylate (II), prepared from the (hydroxymethyl)phosphinic acid derivative (I), was condensed with the protected glucosamine (III) in the presence of NaH to produce the phosphinate adduct (IV) as a diastereomeric mixture. Selective removal of the P-acetyl ketal group of (IV) with chlorotrimethylsilane and a trace of water gave rise to the deprotected phosphinate (V). This was subjected to Arbuzov reaction with methyl (bromomethyl)acrylate (VI) under silylating conditions to afford the substituted phosphinate (VII). Concomitant double-bond hydrogenation and hydrogenolysis of the benzyl and benzylidene groups of (VII) was effected by hydrogenation over Pd/C. The resulting product (VIII) was then peracetylated with acetic anhydride/pyridine to give the triacetate (IX). Treatment of (IX) with aminoethanol in THF selectively removed the anomeric acetate to produce (X) as a complex diastereomeric mixture.

1 Reck, F.; et al.; Inhibitors of the bacterial cell wall biosynthesis enzyme MurC. Bioorg Med Chem Lett 2001, 11, 11, 1451.
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) 53154 ethyl 1,1-diethoxyethyl(hydroxymethyl)phosphinate n/a C9H21O5P 详情 详情
(II) 53155 [(1,1-diethoxyethyl)(ethoxy)phosphoryl]methyl methanesulfonate n/a C10H23O7PS 详情 详情
(III) 53156 N-[(2R,4aR,6S,7R,8R,8aS)-6-(benzyloxy)-8-hydroxy-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl]acetamide n/a C22H25NO6 详情 详情
(IV) 53157 ethyl {[(2R,4aR,6S,7R,8R,8aR)-7-(acetylamino)-6-(benzyloxy)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-8-yl]oxy}methyl(1,1-diethoxyethyl)phosphinate n/a C31H44NO10P 详情 详情
(V) 53158 ethyl {[(2R,4aR,6S,7R,8R,8aR)-7-(acetylamino)-6-(benzyloxy)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-8-yl]oxy}methylphosphinate n/a C25H32NO8P 详情 详情
(VI) 32407 methyl 2-(bromomethyl)acrylate C5H7BrO2 详情 详情
(VII) 53159 methyl 2-{[({[(2R,4aR,6S,7R,8R,8aR)-7-(acetylamino)-6-(benzyloxy)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-8-yl]oxy}methyl)(ethoxy)phosphoryl]methyl}acrylate n/a C30H38NO10P 详情 详情
(VIII) 53160 methyl 3-[({[(2S,3R,4R,5R,6R)-3-(acetylamino)-2,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-4-yl]oxy}methyl)(ethoxy)phosphoryl]-2-methylpropanoate n/a C16H30NO10P 详情 详情
(IX) 53161 methyl 3-[[({(2R,3R,4R,5R,6R)-3-(acetylamino)-2,5-bis(acetyloxy)-6-[(acetyloxy)methyl]tetrahydro-2H-pyran-4-yl}oxy)methyl](ethoxy)phosphoryl]-2-methylpropanoate n/a C22H36NO13P 详情 详情
(X) 53162 methyl 3-[[({(3R,4R,5R,6R)-3-(acetylamino)-5-(acetyloxy)-6-[(acetyloxy)methyl]-2-hydroxytetrahydro-2H-pyran-4-yl}oxy)methyl](ethoxy)phosphoryl]-2-methylpropanoate n/a C20H34NO12P 详情 详情
Extended Information