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【结 构 式】 
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【分子编号】23363 【品名】4'-amino-N-(tert-butyl)[1,1'-biphenyl]-2-sulfonamide 【CA登记号】 |
【 分 子 式 】C16H20N2O2S 【 分 子 量 】304.41308 【元素组成】C 63.13% H 6.62% N 9.2% O 10.51% S 10.53% |
合成路线1
该中间体在本合成路线中的序号：(VII)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2
该中间体在本合成路线中的序号：(VII)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3
该中间体在本合成路线中的序号：(IV)The cyclization of the chlorooxime (I) with formylacetic methyl ester (II) by means of diazomethane and TEA gives the 3-(3-cyanophenyl)isoxazole-4-carboxylic acid methyl ester (III), which is condensed with 4'-amino-N-tert-butylbiphenyl-2-sulfonamide (IV) by means of AlMe3 to yield the corresponding amide (V). The methanolysis of the cyano group of (V) with HCl and methanol affords the iminoester (VI), which is finally converted into the target amidine by reaction with ammonium carbonate.
| 【1】 Bostrom, L.L.; Knabb, R.M.; Wong, P.C.; Pinto, D.J.; Estrella, M.J.; Wexler, R.R.; Pruitt, J.R.; Wright, M.R.; Isoxazolines and isoxazoles as factor Xa inhibitors. Bioorg Med Chem Lett 2000, 10, 8, 685. |
| 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) | 23358 | 3-cyano-N-hydroxybenzenecarboximidoyl chloride | C8H5ClN2O | 详情 | 详情 | |
| (II) | 51426 | methyl 3-oxopropanoate | C4H6O3 | 详情 | 详情 | |
| (III) | 23360 | methyl 3-(3-cyanophenyl)-4-isoxazolecarboxylate | C12H8N2O3 | 详情 | 详情 | |
| (IV) | 23363 | 4'-amino-N-(tert-butyl)[1,1'-biphenyl]-2-sulfonamide | C16H20N2O2S | 详情 | 详情 | |
| (V) | 23365 | N-[2'-[(tert-butylamino)sulfonyl][1,1'-biphenyl]-4-yl]-3-(3-cyanophenyl)-4-isoxazolecarboxamide | C27H24N4O4S | 详情 | 详情 | |
| (VI) | 23366 | methyl 3-[4-([[2'-(aminosulfonyl)[1,1'-biphenyl]-4-yl]amino]carbonyl)-3-isoxazolyl]benzenecarboximidoate | C24H20N4O5S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VII)The cyclization of 3-bromophenylhydrazine (I) with 2-(trichloroacetyl)-3-methoxycrotonic acid (II) in refluxing ethanol gives, after chromatographic separation, 1-(3-bromophenyl)-3-methylpyrazole-5-carboxylic acid ethyl ester (III), which by reaction with CuCN in refluxing N-methylpyrrolidone is converted into the 3-cyanophenyl analogue (IV). The hydrolysis of (IV) with LiOH in THF/water affords the corresponding carboxylic acid (V), which by reaction with oxalyl chloride in dichloromethane gives the acyl chloride (VI). The condensation of (VI) with 4'-amino-N-tert-butylbiphenyl-2-sulfonamide (VII) by means of TEA in dichloromethane provides the corresponding amide (VIII), which is finally treated first with HCl in methanol, and then with ammonium carbonate in the same solvent.
| 【1】 Orwat, M.J.; Cacciola, J.; Han, Q.; Fevig, J.M.; Pinto, D.J.P.; Rossi, K.A.; Pruitt, J.R.; Quan, M.L. (DuPont Pharmaceuticals Co.); Nitrogen containing heteroaromatics as factor Xa inhibitors. EP 0946508; WO 9828269 . |
| 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) | 37812 | 1-(3-bromophenyl)hydrazine | 27246-81-7 | C6H7BrN2 | 详情 | 详情 |
| (II) | 37813 | (Z)-4-methoxy-2-(2,2,2-trichloroacetyl)-3-pentenoic acid | C8H9Cl3O4 | 详情 | 详情 | |
| (III) | 37814 | ethyl 1-(3-bromophenyl)-3-methyl-1H-pyrazole-5-carboxylate | C13H13BrN2O2 | 详情 | 详情 | |
| (IV) | 37815 | ethyl 1-(3-cyanophenyl)-3-methyl-1H-pyrazole-5-carboxylate | C14H13N3O2 | 详情 | 详情 | |
| (V) | 37816 | 1-(3-cyanophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid | C12H9N3O2 | 详情 | 详情 | |
| (VI) | 37817 | 1-(3-cyanophenyl)-3-methyl-1H-pyrazole-5-carbonyl chloride | C12H8ClN3O | 详情 | 详情 | |
| (VII) | 23363 | 4'-amino-N-(tert-butyl)[1,1'-biphenyl]-2-sulfonamide | C16H20N2O2S | 详情 | 详情 | |
| (VIII) | 37818 | N-[2'-[(tert-butylamino)sulfonyl][1,1'-biphenyl]-4-yl]-1-(3-cyanophenyl)-3-methyl-1H-pyrazole-5-carboxamide | C28H27N5O3S | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VIII)The reaction of 3-formylbenzonitrile (I) with methyl 2-bromoacetate (II) by means of activated Zn in hot THF gives 3-(3-cyanophenyl)-3-hydroxypropionic acid methyl ester (III), which is oxidized with activated MnO2 in hot dichloromethane yielding the oxoester (IV). The bromination of (IV) with NBS in CCl4 affords the alpha bromo derivative (V), which is cyclized with thioacetamide (VI) in hot THF affording 4-(3-cyanophenyl)-2-methylthiazole-5-carboxylic acid methyl ester (VII). The condensation of (VII) with 4'-amino-N-tert-butylbiphenyl-2-sulfonamide (VIII) by means of trimethylaluminum in toluene/dichloromethane gives the corresponding amide (IX), which is treated with hot TFA to eliminate the ter-butyl protecting group yielding intermediate (X). Finally, the cyano group of (X) is treated first with anhydrous HCl in methanol, and finally with ammonium carbonate in the same solvent to obtain the target amidine.
| 【1】 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 . |
| 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) | 12309 | methyl 2-bromoacetate; methyl bromoacetate | 96-32-2 | C3H5BrO2 | 详情 | 详情 |
| (III) | 28346 | methyl 3-(3-cyanophenyl)-3-hydroxypropanoate | C11H11NO3 | 详情 | 详情 | |
| (IV) | 28347 | methyl 3-(3-cyanophenyl)-3-oxopropanoate | C11H9NO3 | 详情 | 详情 | |
| (V) | 28348 | methyl 2-bromo-3-(3-cyanophenyl)-3-oxopropanoate | C11H8BrNO3 | 详情 | 详情 | |
| (VI) | 19170 | ethanethioamide | 62-55-5 | C2H5NS | 详情 | 详情 |
| (VII) | 28349 | methyl 4-(3-cyanophenyl)-2-methyl-1,3-thiazole-5-carboxylate | C13H10N2O2S | 详情 | 详情 | |
| (VIII) | 23363 | 4'-amino-N-(tert-butyl)[1,1'-biphenyl]-2-sulfonamide | C16H20N2O2S | 详情 | 详情 | |
| (IX) | 28350 | N-[2'-[(tert-butylamino)sulfonyl][1,1'-biphenyl]-4-yl]-4-(3-cyanophenyl)-2-methyl-1,3-thiazole-5-carboxamide | C28H26N4O3S2 | 详情 | 详情 | |
| (X) | 28351 | N-[2'-(aminosulfonyl)[1,1'-biphenyl]-4-yl]-4-(3-cyanophenyl)-2-methyl-1,3-thiazole-5-carboxamide | C24H18N4O3S2 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(V)The reaction of N-tert-butylbenzenesulfonamide (I) with triisopropyl borate by means of BuLi in THF gives the boronic acid (II), which is condensed with 4-bromonitrobenzene (III) by means of palladium tetrakis(triphenylphosphine) to yield the N-tert-butyl-4'-nitrobiphenyl-2-sulfonamide (IV). The reduction of (IV) with H2 over Pd/C in methanol affords the biphenylamine (V), which is acylated with 3-(3-cyanophenyl)-5-(methoxycarbonylmethyl)-4,5-dihydroisoxazole-5-carboxylic acid (VI), by means of SOCl2 in acetonitrile affording the corresponding amide (VII). The reaction of (VII) with trifluoroacetic acid eliminates the tert-butyl protecting group providing intermediate (VIII). Finally, the cyano group of (VIII) is converted into amidino by reaction with HCl in chloroform/methanol and reaction of the intermediate imidate with ammonium acetate. Alternatively, biphenylamine (V) can also be obtained as follows: The reaction of 4-bromoaniline (IX) with tert-butoxycarbonyl anhydride in THF gives the corresponding carbamate (X), which is condensed with the boronic acid (II) by means of palladium tetrakis triphenylphosphine and deprotected with trifluoroacetic acid to afford the target intermediate (V).
| 【1】 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) | 26626 | N-(tert-butyl)benzenesulfonamide | C10H15NO2S | 详情 | 详情 | |
| (II) | 26627 | 2-[(tert-butylamino)sulfonyl]phenylboronic acid | C10H16BNO4S | 详情 | 详情 | |
| (III) | 26628 | 1-bromo-4-nitrobenzene | 99-99-0 | C6H4BrNO2 | 详情 | 详情 |
| (IV) | 26629 | N-(tert-butyl)-4'-nitro[1,1'-biphenyl]-2-sulfonamide | C16H18N2O4S | 详情 | 详情 | |
| (V) | 23363 | 4'-amino-N-(tert-butyl)[1,1'-biphenyl]-2-sulfonamide | C16H20N2O2S | 详情 | 详情 | |
| (VI) | 26630 | 3-(3-cyanophenyl)-5-(2-methoxy-2-oxoethyl)-4,5-dihydro-5-isoxazolecarboxylic acid | C14H12N2O5 | 详情 | 详情 | |
| (VII) | 26631 | methyl 2-[5-[([2'-[(tert-butylamino)sulfonyl][1,1'-biphenyl]-4-yl]amino)carbonyl]-3-(3-cyanophenyl)-4,5-dihydro-5-isoxazolyl]acetate | C30H30N4O6S | 详情 | 详情 | |
| (VIII) | 26632 | methyl 2-[5-([[2'-(aminosulfonyl)[1,1'-biphenyl]-4-yl]amino]carbonyl)-3-(3-cyanophenyl)-4,5-dihydro-5-isoxazolyl]acetate | C26H22N4O6S | 详情 | 详情 | |
| (IX) | 22531 | 4-Bromoaniline; 4-Bromophenylamine | 106-40-1 | C6H6BrN | 详情 | 详情 |
| (X) | 26633 | tert-butyl 4-bromophenylcarbamate | C11H14BrNO2 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(V)7-Aminoisoquinoline (I) was diazotized and then reduced with SnCl2 to afford the tin double salt of hydrazino isoquinoline (II), which was subsequently condensed with ethyl 2,4-dioxopentanoate oxime (III) yielding isoquinolinyl pyrazole (IV) as the major regioisomer. Displacement of the methyl ester group with biphenyl amine (V) in the presence of Me3Al furnished amide (VI). Introduction of the 1-amino moiety was accomplished via formation of the N-oxide (VII), followed by rearrangement with tosyl chloride and further displacement with ethanolamine. Finally, deprotection of the N-tert-butyl group with trifluoroacetic acid gave rise to the title compound.
| 【1】 Quan, M.L.; Clark, C.G.; Lam, P.Y.; Pinto, D.J.-P.; Han, Q.; Fevig, J.M.; Li, R.; Pruitt, J.R.; Dominguez, C. (DuPont Pharmaceuticals Co.); Novel guanidine mimics as factor Xa inhibitors. EP 0991638; WO 9857951 . |
| 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) | 39253 | 7-isoquinolinamine; 7-isoquinolinylamine | 23707-37-1 | C9H8N2 | 详情 | 详情 |
| (II) | 39254 | 7-hydrazinoisoquinoline | C9H9N3 | 详情 | 详情 | |
| (III) | 39255 | ethyl 2-(hydroxyimino)-4-oxopentanoate | C7H11NO4 | 详情 | 详情 | |
| (IV) | 39256 | methyl 1-(7-isoquinolinyl)-3-methyl-1H-pyrazole-5-carboxylate | C15H13N3O2 | 详情 | 详情 | |
| (V) | 23363 | 4'-amino-N-(tert-butyl)[1,1'-biphenyl]-2-sulfonamide | C16H20N2O2S | 详情 | 详情 | |
| (VI) | 39257 | N-[2'-[(tert-butylamino)sulfonyl][1,1'-biphenyl]-4-yl]-1-(7-isoquinolinyl)-3-methyl-1H-pyrazole-5-carboxamide | C30H29N5O3S | 详情 | 详情 | |
| (VII) | 39258 | 7-[5-[([2'-[(tert-butylamino)sulfonyl][1,1'-biphenyl]-4-yl]amino)carbonyl]-3-methyl-1H-pyrazol-1-yl]-2-isoquinoliniumolate | C30H29N5O4S | 详情 | 详情 | |
| (VIII) | 39259 | 1-(1-amino-7-isoquinolinyl)-N-[2'-[(tert-butylamino)sulfonyl][1,1'-biphenyl]-4-yl]-3-methyl-1H-pyrazole-5-carboxamide | C30H30N6O3S | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(IV)The intermediate biphenylamine (IV) was prepared by Suzuki coupling of N-Boc-4-bromoaniline (I) with 2-(N-tert-butylaminosulfonyl)phenylboronic acid (II), followed by deprotection of the Boc group.
| 【1】 Galemmo, R.A. Jr.; Fevig, J.; Lam, P.Y.; et al.; New functional groups for interaction with the S1 pocket of factor Xa: The discovery of 1-(4-methoxyphenyl)pyrazole inhibitors. 220th ACS Natl Meet (Aug 20 2000, Washington DC) 2000, Abst MEDI 290. |
| 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) | 26633 | tert-butyl 4-bromophenylcarbamate | C11H14BrNO2 | 详情 | 详情 | |
| (II) | 26627 | 2-[(tert-butylamino)sulfonyl]phenylboronic acid | C10H16BNO4S | 详情 | 详情 | |
| (III) | 44128 | 4-[(tert-butoxycarbonyl)amino]-2'-[(tert-butylamino)sulfonyl]-1,1'-biphenyl; tert-butyl 2'-[(tert-butylamino)sulfonyl][1,1'-biphenyl]-4-ylcarbamate | C21H28N2O4S | 详情 | 详情 | |
| (IV) | 23363 | 4'-amino-N-(tert-butyl)[1,1'-biphenyl]-2-sulfonamide | C16H20N2O2S | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(IV)Ethyl 2,4-dioxopentanoate (V) was converted into the O-methyloxime (VI) and subsequently cyclized with 4-methoxyphenylhydrazine (VII) to furnish pyrazole (VIII) (1,2). Optionally, ester (VIII) was hydrolyzed and then converted to acid chloride (IX) by treatment with oxalyl chloride (1). Biphenylamine (IV) was coupled with ester (VIII) in the presence of trimethylaluminium (2) or, alternatively, with acid chloride (IX) (1) to give amide (X). The N-tert-butyl group of (X) was finally removed by refluxing in trifluoroacetic acid.
| 【1】 Galemmo, R.A. Jr.; Fevig, J.; Lam, P.Y.; et al.; New functional groups for interaction with the S1 pocket of factor Xa: The discovery of 1-(4-methoxyphenyl)pyrazole inhibitors. 220th ACS Natl Meet (Aug 20 2000, Washington DC) 2000, Abst MEDI 290. |
| 【2】 Dominguez, C.; Fevig, J.M.; Galemmo, R.A. Jr.; Pinto, D.J.P.; Pruitt, J.R.; lma, P.; Quan, M.L.; Han, Q. (DuPont Pharmaceuticals Co.); Inhibitors of factor Xa with a neutral P1 specificity group. US 5998424; WO 9857937 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 23363 | 4'-amino-N-(tert-butyl)[1,1'-biphenyl]-2-sulfonamide | C16H20N2O2S | 详情 | 详情 | |
| (V) | 42500 | ethyl 2,4-dioxopentanoate | 615-79-2 | C7H10O4 | 详情 | 详情 |
| (VI) | 44129 | ethyl 2-(methoxyimino)-4-oxopentanoate | C8H13NO4 | 详情 | 详情 | |
| (VII) | 12688 | 4-Hydrazinophenyl methyl ether; 1-(4-Methoxyphenyl)hydrazine | 3471-32-7 | C7H10N2O | 详情 | 详情 |
| (VIII) | 44130 | ethyl 1-(4-methoxyphenyl)-3-methyl-1H-pyrazole-5-carboxylate | C14H16N2O3 | 详情 | 详情 | |
| (IX) | 44131 | 1-(4-methoxyphenyl)-3-methyl-1H-pyrazole-5-carbonyl chloride | C12H11ClN2O2 | 详情 | 详情 | |
| (X) | 44132 | N-[2'-[(tert-butylamino)sulfonyl][1,1'-biphenyl]-4-yl]-1-(4-methoxyphenyl)-3-methyl-1H-pyrazole-5-carboxamide | C28H30N4O4S | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(XIV)Addition of triisopropyl borate to the ortho-lithiated derivative of N-tert-butyl benzenesulfonamide (XI), followed by acid aqueous work-up, gives rise to the boronic acid (XII). Subsequent Suzuki coupling between (XII) and 4-bromoaniline (XIII) affords the biphenyl sulfonamide (XIV). Then, trimethylaluminum-catalyzed condensation of the pyrazole ester (X) with the biphenyl amine (XIV) generates amide (XV). The N-tert-butyl protecting group of (XV) is finally cleaved with trifluoroacetic acid to furnish the title compound.
| 【1】 Jia, Z.J.; et al.; Design, synthesis and biological activity of novel non-amidine factor Xa inhibitors: Part 1: Structure-activity relationships of the substituted 1-(2-naphthyl)-1H-pyrazole-5-carboxylamides. Bioorg Med Chem Lett 2002, 12, 12, 1651. |
| 【2】 Wang, L.; Zhu, B.-Y.; Li, W.; Zhang, P.; Huang, W.; Song, Y.; Goldman, E.; Zuckett, J.; Scarborough, R. (Millennium Pharmaceuticals, Inc.); Benzamides and related inhibitors of factor Xa. EP 1216228; EP 1216231; WO 0119788; WO 0119798 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 57034 | ethyl 1-(3-fluoro-2-naphthyl)-3-methyl-1H-pyrazole-5-carboxylate | C17H15FN2O2 | 详情 | 详情 | |
| (XI) | 26626 | N-(tert-butyl)benzenesulfonamide | C10H15NO2S | 详情 | 详情 | |
| (XII) | 26627 | 2-[(tert-butylamino)sulfonyl]phenylboronic acid | C10H16BNO4S | 详情 | 详情 | |
| (XIII) | 22531 | 4-Bromoaniline; 4-Bromophenylamine | 106-40-1 | C6H6BrN | 详情 | 详情 |
| (XIV) | 23363 | 4'-amino-N-(tert-butyl)[1,1'-biphenyl]-2-sulfonamide | C16H20N2O2S | 详情 | 详情 | |
| (XV) | 57035 | N-{2'-[(tert-butylamino)sulfonyl][1,1'-biphenyl]-4-yl}-1-(3-fluoro-2-naphthyl)-3-methyl-1H-pyrazole-5-carboxamide | C31H29FN4O3S | 详情 | 详情 |