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【结 构 式】 
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【分子编号】23357 【品名】3-[(hydroxyimino)methyl]benzonitrile 【CA登记号】 |
【 分 子 式 】C8H6N2O 【 分 子 量 】146.14852 【元素组成】C 65.75% H 4.14% N 19.17% O 10.95% |
合成路线1
该中间体在本合成路线中的序号：(IV)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：(IV)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)3-Cyanobenzaldehyde oxime (I) was treated with N-chlorosuccinimide to afford hydroxyiminoyl chloride (II). Subsequent cycloaddition of the intermediate nitrile oxide, generated in situ from (II) and Et3N, with methyl methoxyacrylate (III) produced isoxazole (IV). Then, basic hydrolysis of the ester group, followed by treatment with SOCl2 provided acid chloride (V). Aminobiphenyl (VIII) was obtained by Suzuki coupling of 4-bromoaniline (VI) with boronic acid (VII) using a palladium catalyst. Condensation of (VIII) with acid chloride (V) in the presence of Et3N then gave amide (IX). Alternatively, amide (IX) was obtained by AlMe3-catalyzed condensation of ester (IV) with amine (VIII). Treatment of nitrile (IX) with HCl in MeOH-CHCl3 generated the corresponding iminoester (X) with concomitant cleavage of the N-tert-butyl group. Finally, reaction of this iminoester with methanolic ammonium carbonate afforded the target amidine.
| 【1】 Wexler, R.R.; Bostrom, L.L.; Pinto, D.J.; Wrong, P.C.; Pruitt, J.R.; Knabb, R.M.; Estrella, M.J.; Quan, M.L.; Isoxazolines and isoxazoles as factor Xa inhibitor. 216th ACS Natl Meet (Aug. 23-27, Boston) 1998, Abst MEDI 077. |
| 【2】 Quan, M.L.; Pinto, D.J.P.; Fevig, J.M.; Pruitt, J.R. (DuPont Pharmaceuticals Co.); Oxygen or sulfur containing heteroaromatics as fac. WO 9828282 . |
| 【3】 Pinto, D.J.P.; Pruitt, J.R.; Fevig, J.M.; Quan, M.L. (DuPont Pharmaceuticals Co.); Phenyl-isoxazoles as factor Xa inhibitors. US 6187797 . |
| 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) | 23357 | 3-[(hydroxyimino)methyl]benzonitrile | C8H6N2O | 详情 | 详情 | |
| (II) | 23358 | 3-cyano-N-hydroxybenzenecarboximidoyl chloride | C8H5ClN2O | 详情 | 详情 | |
| (IV) | 23360 | methyl 3-(3-cyanophenyl)-4-isoxazolecarboxylate | C12H8N2O3 | 详情 | 详情 | |
| (V) | 23361 | 3-(3-cyanophenyl)-4-isoxazolecarbonyl chloride | C11H5ClN2O2 | 详情 | 详情 | |
| (VII) | 23363 | 4'-amino-N-(tert-butyl)[1,1'-biphenyl]-2-sulfonamide | C16H20N2O2S | 详情 | 详情 | |
| (VIII) | 23364 | 3-(3-cyanophenyl)-4-isoxazolecarbonyl chloride | C11H5ClN2O2 | 详情 | 详情 | |
| (IX) | 23365 | N-[2'-[(tert-butylamino)sulfonyl][1,1'-biphenyl]-4-yl]-3-(3-cyanophenyl)-4-isoxazolecarboxamide | C27H24N4O4S | 详情 | 详情 | |
| (X) | 23366 | methyl 3-[4-([[2'-(aminosulfonyl)[1,1'-biphenyl]-4-yl]amino]carbonyl)-3-isoxazolyl]benzenecarboximidoate | C24H20N4O5S | 详情 | 详情 | |
| (XII) | 22700 | methyl (E)-3-methoxy-2-propenoate | 34846-90-7 | C5H8O3 | 详情 | 详情 |
| (XVI) | 22531 | 4-Bromoaniline; 4-Bromophenylamine | 106-40-1 | C6H6BrN | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)3-Cyanobenzaldehyde (I) was converted to oxime (II) by reaction with hydroxylamine in pyridine. The intermediate nitrile oxide, generated from chlorination and further elimination of HCl, underwent a [2+3] cycloaddition with itaconic acid monomethyl ester (III) to produce the isoxazoline (IV). The carboxylate group of (IV) was then activated as the corresponding acid chloride (V) upon treatment with SOCl2. Boronic acid (VII) was prepared from N-tert-butyl benzenesulfonamide (VI) by lithiation with n-butyllithium, followed by reaction with triisopropyl borate and quenching with HCl. Subsequent Suzuki coupling of (VII) with 2-amino-5-bromopyrimidine (VIII) using Pd(PPh3)4 and Na2CO3 afforded the 2-amino-4-arylpyrimidine (IX). Condensation of amine (IX) with acid chloride (V) in the presence of Et3N gave amide (X). The N-tert-butyl group of (X) was then deprotected by means of trifluoroacetic acid to yield (XI) as the trifluoroacetate salt. The cyano group of (XI) was converted to imidate (XII) with HCl and MeOH. This was finally reacted with ammonium acetate in MeOH to furnish the title amidine.
| 【1】 Quan, M.L.; Liauw, A.Y.; Ellis, C.D.; et al.; Design and synthesis of isoxazoline derivatives as factor Xa inhibitors. 1. J Med Chem 1999, 42, 15, 2752. |
| 【2】 Quan, M.L.; Wityak, J.; Galemmo, R.A. Jr.; Stouten, P.F.W.; Pruitt, J.R. (DuPont Pharmaceuticals Co.); Isoxazoline, isothiazoline and pyrazoline factor Xa inhibitors. EP 0874629; US 5939418; WO 9723212 . |
| 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) | 13245 | 3-Formylbenzonitrile; 3-Cyanobenzaldehyde | 24964-64-5 | C8H5NO | 详情 | 详情 |
| (II) | 23357 | 3-[(hydroxyimino)methyl]benzonitrile | C8H6N2O | 详情 | 详情 | |
| (III) | 34820 | 2-(2-methoxy-2-oxoethyl)acrylic acid | 7338-27-4 | C6H8O4 | 详情 | 详情 |
| (IV) | 26630 | 3-(3-cyanophenyl)-5-(2-methoxy-2-oxoethyl)-4,5-dihydro-5-isoxazolecarboxylic acid | C14H12N2O5 | 详情 | 详情 | |
| (V) | 34821 | methyl 2-[5-(chlorocarbonyl)-3-(3-cyanophenyl)-4,5-dihydro-5-isoxazolyl]acetate | C14H11ClN2O4 | 详情 | 详情 | |
| (VI) | 26626 | N-(tert-butyl)benzenesulfonamide | C10H15NO2S | 详情 | 详情 | |
| (VII) | 26627 | 2-[(tert-butylamino)sulfonyl]phenylboronic acid | C10H16BNO4S | 详情 | 详情 | |
| (VIII) | 34822 | 5-bromo-2-pyrimidinamine; 5-bromo-2-pyrimidinylamine | 7752-82-1 | C4H4BrN3 | 详情 | 详情 |
| (IX) | 34823 | 2-(2-amino-5-pyrimidinyl)-N-(tert-butyl)benzenesulfonamide | C14H18N4O2S | 详情 | 详情 | |
| (X) | 34824 | methyl 2-[5-[[(5-[2-[(tert-butylamino)sulfonyl]phenyl]-2-pyrimidinyl)amino]carbonyl]-3-(3-cyanophenyl)-4,5-dihydro-5-isoxazolyl]acetate | C28H28N6O6S | 详情 | 详情 | |
| (XI) | 34825 | methyl 2-[5-[([5-[2-(aminosulfonyl)phenyl]-2-pyrimidinyl]amino)carbonyl]-3-(3-cyanophenyl)-4,5-dihydro-5-isoxazolyl]acetate | C24H20N6O6S | 详情 | 详情 | |
| (XII) | 34826 | methyl 2-(5-[([5-[2-(aminosulfonyl)phenyl]-2-pyrimidinyl]amino)carbonyl]-3-[3-[imino(methoxy)methyl]phenyl]-4,5-dihydro-5-isoxazolyl)acetate | C25H24N6O7S | 详情 | 详情 |