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【结 构 式】 
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【分子编号】32624 【品名】2-Nitrobenzenesulfonyl chloride 【CA登记号】1694-92-4 |
【 分 子 式 】C6H4ClNO4S 【 分 子 量 】221.6208 【元素组成】C 32.52% H 1.82% Cl 16% N 6.32% O 28.88% S 14.47% |
合成路线1
该中间体在本合成路线中的序号：(II)The reaction of 2-amino-3-(N-methylcarbamoyl)propionic acid (I) with 2-nitrophenylsulfonylchloride (II) by means of K2CO3 in THF gives 2-(2-nitrophenylsulfonylamino)-3-(N-methylcarbamoyl)propionic acid (III), which is esterified with N-hydroxysuccinimide (IV) by means of dicyclohexylcarbodiimide in THF yielding the corresponding N-succinimido ester (V). The condensation of (V) with amoxicillin [6-[alpha-amino-alpha-(4-hydroxyphenyl)acetylamino]penicillanic acid] (VI) by means of triethylamine in THF-CHCl3 affords 6-[alpha[2-(2-nitrophenylsulfonylamino)-3-N-methylcarbamoylpropionamido]-alpha-(4-hydroxyphenyl)acetamido]penicillanic acid (VII). Finally, the sulfonic group is eliminated by treatment with thiobenzamide (A) in ethanol-THF.
| 【1】 Kawazu, M.; et al. (Tanabe Seiyaku Co., Ltd.); Penicillins and processes for preparing the same. DE 2638067; FR 2323384; NL 7610151; US 4053609 . |
| 【2】 Castaner, J.; Blancafort, P.; Serradell, M.N.; TA-058. Drugs Fut 1980, 5, 3, 151. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 32629 | Thiobenzamide; Benzenecarbothioamide | 2227-79-4 | C7H7NS | 详情 | 详情 |
| (I) | 32623 | (2R)-2-amino-3-(N-methylcarbamoyl)propionic acid; (2R)-2-amino-4-(methylamino)-4-oxobutyric acid | C5H10N2O3 | 详情 | 详情 | |
| (II) | 32624 | 2-Nitrobenzenesulfonyl chloride | 1694-92-4 | C6H4ClNO4S | 详情 | 详情 |
| (III) | 32625 | (2R)-2-(2-nitrophenylsulfonylamino)-3-(N-methylcarbamoyl)propionic acid; (2R)-4-(methylamino)-2-[[(2-nitrophenyl)sulfonyl]amino]-4-oxobutyric acid | C11H13N3O7S | 详情 | 详情 | |
| (IV) | 10264 | 1-Hydroxydihydro-1H-pyrrole-2,5-dione; N-Hydroxysuccinimide; 1-Hydroxy-2,5-pyrrolidinedione | 6066-82-6 | C4H5NO3 | 详情 | 详情 |
| (V) | 32626 | (3R)-4-[(2,5-dioxo-1-pyrrolidinyl)oxy]-N-methyl-3-[[(2-nitrophenyl)sulfonyl]amino]-4-oxobutanamide | C15H16N4O9S | 详情 | 详情 | |
| (VI) | 32627 | 6-[alpha-amino-alpha-(4-hydroxyphenyl)acetamido]penicillanic acid; Amoxicillin; (2S,5R,6R)-6-[[(2R)-2-amino-2-(4-hydroxyphenyl)ethanoyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid | 26787-78-0 | C16H19N3O5S | 详情 | 详情 |
| (VII) | 32628 | (2S,5R,6R)-6-([(2R)-2-(4-hydroxyphenyl)-2-[((2R)-4-(methylamino)-2-[[(2-nitrophenyl)sulfonyl]amino]-4-oxobutanoyl)amino]ethanoyl]amino)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid; 6-[alpha[2-(2-nitrophenylsulfonylamino)-3-N-methylcarbamoylpropionamido]-alpha-(4-hydroxyphenyl)acetamido]penicillanic acid | C27H30N6O11S2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)The reaction of 2-azabicyclo[2,2,1]-5-hepten-3-one (I) with 2-nitrophenylsulfonyl chloride (II) by means of BuLi in THF gives the sulfonamide (III), which is condensed with the chloropurine (IV) by means of Pd[P(OPr)3]4 in THF or NMP to yield the adduct (V). The N-protection of the formamide group of (V) with Boc2O and NaH in THF affords compound (VI), which is reduced and deprotected with NaBH4 in methanol to provide the N-Boc protected chloropurine (VII). Finally, this compound is treated with hot HOAc to furnish the target chloropurine (VIII) (see schemes 14673102a intermediate (VIII), 14673103a intermediate (VIII), 14673104a intermediate (IX), 14673107a intermediate (XII), 14673111a intermediate (IX) and 14673113a intermediate (XIII)).
| 【1】 katagiri, N.; et al.; Efficient synthesis of carbovir and its congener via pi-allylpalladium complex formation by ring strain-assisted C-N bond cleavage. J Org Chem 1997, 62, 6, 1580. |
| 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) | 55527 | 2-azabicyclo[2.2.1]hept-5-en-3-one | C6H7NO | 详情 | 详情 | |
| (II) | 32624 | 2-Nitrobenzenesulfonyl chloride | 1694-92-4 | C6H4ClNO4S | 详情 | 详情 |
| (III) | 55522 | 2-[(2-nitrophenyl)sulfonyl]-2-azabicyclo[2.2.1]hept-5-en-3-one | C12H10N2O5S | 详情 | 详情 | |
| (IV) | 55523 | 6-chloro-9H-purin-2-ylformamide | C6H4ClN5O | 详情 | 详情 | |
| (V) | 55524 | N-({(1S,4R)-4-[6-chloro-2-(formylamino)-9H-purin-9-yl]-2-cyclopenten-1-yl}carbonyl)-2-nitrobenzenesulfonamide | C18H14ClN7O6S | 详情 | 详情 | |
| (VI) | 55525 | tert-butyl 6-chloro-9-[(1R,4S)-4-({[(2-nitrophenyl)sulfonyl]amino}carbonyl)-2-cyclopenten-1-yl]-9H-purin-2-yl(formyl)carbamate | C23H22ClN7O8S | 详情 | 详情 | |
| (VII) | 55526 | tert-butyl 6-chloro-9-[(1R,4S)-4-(hydroxymethyl)-2-cyclopenten-1-yl]-9H-purin-2-ylcarbamate | C16H20ClN5O3 | 详情 | 详情 | |
| (VIII) | 17650 | [(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]methanol | C11H12ClN5O | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)The acylation of 1,7-heptanediamine (I) with 2-nitrobenzenesulfonyl chloride (II) by means of TEA in dichloromethane gives the bis sulfamide (III), which is submitted to macrocyclization with the dimesylate (IV) by means of Cs2CO3 in hot DMF, yielding the protected 1,4,7-triazacyclotetradecane (V). The cleavage of the phosphoryl group of (IV) with HBr in acetic acid affords the secondary amine (VI), which is alkylated with he benzyl chloride (VII) by means of K2CO3 in refluxing acetonitrile, providing the adduct (VIII). This compound is deprotected with K2CO3 in DMF and treated with HCl or HBr to furnish the corresponding target salts.
| 【2】 Bogucki, D.E.; Boehringer, E.M.; Wang, Z.; Bridger, G.J.; Schols, D.; Skerlj, R.T. (AnorMED Inc.); Antiviral macrocyclic cpds.. EP 1095031; WO 0002870 . |
| 【1】 De Clercq, E.; HEnson, G.; Schols, D.; Witvrouw, M.; Macfarland, R.T.; Bridger, G.J.; Skerli, R.T.; Yasuda, N.; An orally bioavailable CXCR4 antagonist for inhibition of HIV replication. 40th Intersci Conf Antimicrob Agents Chemother (Sept 17 2000, Toronto) 2000, Abst F-1845. |
| 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) | 12941 | 7-Aminoheptylamine; 1,7-Diaminoheptane; 1,7-Heptanediamine | 646-19-5 | C7H18N2 | 详情 | 详情 |
| (II) | 32624 | 2-Nitrobenzenesulfonyl chloride | 1694-92-4 | C6H4ClNO4S | 详情 | 详情 |
| (III) | 46248 | 2-nitro-N-(7-[[(2-nitrophenyl)sulfonyl]amino]heptyl)benzenesulfonamide | C19H24N4O8S2 | 详情 | 详情 | |
| (IV) | 34634 | 2-((diethoxyphosphoryl)[2-[(methylsulfonyl)oxy]ethyl]amino)ethyl methanesulfonate | C10H24NO9PS2 | 详情 | 详情 | |
| (V) | 46249 | diethyl 1,7-bis[(2-nitrophenyl)sulfonyl]-1,4,7-triazacyclotetradecan-4-ylphosphonate | C27H40N5O11PS2 | 详情 | 详情 | |
| (VI) | 46250 | 1,7-bis[(2-nitrophenyl)sulfonyl]-1,4,7-triazacyclotetradecane | C23H31N5O8S2 | 详情 | 详情 | |
| (VII) | 46251 | N-[4-(chloromethyl)benzyl]-2-nitro-N-(2-pyridinylmethyl)benzenesulfonamide | C20H18ClN3O4S | 详情 | 详情 | |
| (VIII) | 46252 | N-[4-([1,7-bis[(2-nitrophenyl)sulfonyl]-1,4,7-triazacyclotetradecan-4-yl]methyl)benzyl]-2-nitro-N-(2-pyridinylmethyl)benzenesulfonamide | C43H48N8O12S3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)The intermediate benzyl chloride (VII) is obtained as follows: The reduction of 4-(bromomethyl)benzoic acid methyl ester (IX) with DIBAL in dichloromethane gives 4-(bromomethyl)benzyl alcohol (X), which is condensed with sulfamide (XI) (obtained by sulfonation of 2-(aminomethyl)pyridine (XII) with sulfonyl chloride (II) and TEA), by means of K2CO3 in dichloromethane, yielding the disubstituted sulfamide (XIII). Finally, the hydroxymethyl group of (XIII) is treated with MsCl and TEA in refluxing dichloromethane to afford the target benzyl chloride (VII).
| 【1】 Bogucki, D.E.; Boehringer, E.M.; Wang, Z.; Bridger, G.J.; Schols, D.; Skerlj, R.T. (AnorMED Inc.); Antiviral macrocyclic cpds.. EP 1095031; WO 0002870 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 32624 | 2-Nitrobenzenesulfonyl chloride | 1694-92-4 | C6H4ClNO4S | 详情 | 详情 |
| (VII) | 46251 | N-[4-(chloromethyl)benzyl]-2-nitro-N-(2-pyridinylmethyl)benzenesulfonamide | C20H18ClN3O4S | 详情 | 详情 | |
| (IX) | 14565 | methyl 4-(bromomethyl)benzoate | 2417-72-3 | C9H9BrO2 | 详情 | 详情 |
| (X) | 46253 | [4-(bromomethyl)phenyl]methanol | C8H9BrO | 详情 | 详情 | |
| (XI) | 46254 | 2-nitro-N-(2-pyridinylmethyl)benzenesulfonamide | C12H11N3O4S | 详情 | 详情 | |
| (XII) | 13582 | 2-Pyridinylmethanamine; 2-Pyridinylmethylamine; 2-(Aminomethyl)pyridine | 3731-51-9 | C6H8N2 | 详情 | 详情 |
| (XIII) | 46255 | N-[4-(hydroxymethyl)benzyl]-2-nitro-N-(2-pyridinylmethyl)benzenesulfonamide | C20H19N3O5S | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(V)The condensation of ArgoGel-OH resin (I) with N-(Fmoc)-glycine (II) by means of DIC and DMAP gives the resin-bound Fmoc-glycine (III), which is deprotected with piperidine to yield the resin-bound glycine (IV). The reaction of (IV) with 2-nitrophenylsulfonyl chloride (V) affords the sulfonamide (VI), which is alkylated with 2-cyclopentylethanol (VII) by means of DIAD and PPh3 to provide the N-alkylated sulfonamide (VIII). The reaction of (VIII) with Ph-SH, DBU and pyridine gives the N-alkylated resin-bound glycine (IX), which is condensed with 1-(chlorocarbonyl)-L-proline tert-butyl ester (X) to yield the resin-bound dipeptide tert-butyl ester (XI). Hydrolysis of the ester group of (XI) with TFA affords the free resin-bound dipeptide (XII), which is condensed with 4,5-dimethylthiazole-2-amine (XIII) by means of PyBOP and DMAP to provide the corresponding prolinamide (XIV). Finally, this compound is treated with hydroxylamine in order to cleave the title compound from the resin by formation of the desired hydroxamic acid.
| 【1】 Lewis, J.G.; Wu, C.; Jacobs, J.; et al.; Iterative parallel synthesis-derived N-alkyl urea hydroxamic acids: A new class of peptide deformylase inhibitors. 41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001, Chicago) 2001, Abst F-358. |
| 【2】 Patel, D.V.; Jacobs, J.W.; Lewis, J.; Ni, Z.-J. (Versicor, Inc.); Novel urea cpds., compsns. and methods of use and preparation. WO 0144178 . |
| 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) | 11295 | Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol | 107-21-1 | C2H6O2 | 详情 | 详情 |
| (II) | 42131 | 2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]acetic acid | 29022-11-5 | C17H15NO4 | 详情 | 详情 |
| (III) | 54030 | 2-hydroxyethyl 2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}acetate | C19H19NO5 | 详情 | 详情 | |
| (IV) | 54031 | 2-hydroxyethyl 2-aminoacetate | C4H9NO3 | 详情 | 详情 | |
| (V) | 32624 | 2-Nitrobenzenesulfonyl chloride | 1694-92-4 | C6H4ClNO4S | 详情 | 详情 |
| (VI) | 54032 | 2-hydroxyethyl 2-{[(2-nitrophenyl)sulfonyl]amino}acetate | C10H12N2O7S | 详情 | 详情 | |
| (VII) | 54033 | 2-Cyclopentylethanol; 2-Hydroxyethylcyclopentane; alpha-Methylcyclopentanemethanol; Cyclopentylmethylcarbinol | 766-00-7 | C7H14O | 详情 | 详情 |
| (VIII) | 54034 | 2-hydroxyethyl 2-{(2-cyclopentylethyl)[(2-nitrophenyl)sulfonyl]amino}acetate | C17H24N2O7S | 详情 | 详情 | |
| (IX) | 54035 | 2-hydroxyethyl 2-[(2-cyclopentylethyl)amino]acetate | C11H21NO3 | 详情 | 详情 | |
| (X) | 54036 | tert-butyl (2S)-1-(chlorocarbonyl)-2-pyrrolidinecarboxylate | C10H16ClNO3 | 详情 | 详情 | |
| (XI) | 54037 | tert-butyl (2S)-1-({(2-cyclopentylethyl)[2-(2-hydroxyethoxy)-2-oxoethyl]amino}carbonyl)-2-pyrrolidinecarboxylate | C21H36N2O6 | 详情 | 详情 | |
| (XII) | 54038 | (2S)-1-({(2-cyclopentylethyl)[2-(2-hydroxyethoxy)-2-oxoethyl]amino}carbonyl)-2-pyrrolidinecarboxylic acid | C17H28N2O6 | 详情 | 详情 | |
| (XIII) | 54039 | 4,5-dimethyl-1,3-thiazol-2-ylamine; 4,5-dimethyl-1,3-thiazol-2-amine | C5H8N2S | 详情 | 详情 | |
| (XIV) | 54040 | 2-hydroxyethyl 2-{(2-cyclopentylethyl)[((2S)-2-{[(4,5-dimethyl-1,3-thiazol-2-yl)amino]carbonyl}pyrrolidinyl)carbonyl]amino}acetate | C22H34N4O5S | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(IX)The reaction of 3(R)-(tert-butoxycarbonylamino)-5-hexenoic acid (I) first with KI and I2, and then with NaN3 gives 6-azido-3(R)-(tert-butoxycarbonylamino)hexano-5-lactone (II), which is hydrolyzed with LiOH and protected with Tbdms-Cl to yield 6-azido-3(R)-(tert-butoxycarbonylamino)-5-(tert-butyldimethylsilyloxy)hexanoic acid (III). The reaction of acid (III) with pentafluorophenyl trifluoroacetate affords the corresponding activated ester as a mixture of diastereomers (IV) + (V). After separation, the desired diastereomer (IV) is condensed with 2-(1-methylhydrazino)acetic acid tert-butyl ester (VI) to provide the corresponding hydrazide (VII), which is reduced at the azido group by means of PPh3 in THF/water to give the amino compound (VIII). The condensation of (VIII) with 2-nitrophenylsulfonyl chloride (IX) by means of collidine in dichloromethane yields the sulfonamide (X), which is methylated with MeI and Cs2CO3 in DMF to afford the N-methylsulfonamide (XI). Finally, this compound is deprotected by reaction first with PhSH and K2CO3 and then with 4M HCl to provide the target hydrazide.
| 【1】 Raju, B.; Mortell, K.; O'Dowd, H.; et al.; N- and C-terminal modifications of negamycin. 42nd Intersci Conf Antimicrob Agents Chemother (Sept 27 2002, San Diego) 2002, Abst F-1685. |
| 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) | 61916 | N-[((5S)-3-{4-[6-(methylsulfanyl)-3-pyridazinyl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide | C17H18N4O3S | 详情 | 详情 | |
| (II) | 61923 | tert-butyl (4R)-2-(azidomethyl)-6-oxotetrahydro-2H-pyran-4-ylcarbamate | C11H18N4O4 | 详情 | 详情 | |
| (III) | 61924 | (3R)-6-azido-3-[(tert-butoxycarbonyl)amino]-5-{[tert-butyl(dimethyl)silyl]oxy}hexanoic acid | C17H34N4O5Si | 详情 | 详情 | |
| (IV) | 61926 | 2,3,4,5,6-pentafluorophenyl (3R,5R)-6-azido-3-[(tert-butoxycarbonyl)amino]-5-{[tert-butyl(dimethyl)silyl]oxy}hexanoate | C23H33F5N4O5Si | 详情 | 详情 | |
| (V) | 61925 | 2,3,4,5,6-pentafluorophenyl (3R,5S)-6-azido-3-[(tert-butoxycarbonyl)amino]-5-{[tert-butyl(dimethyl)silyl]oxy}hexanoate | C23H33F5N4O5Si | 详情 | 详情 | |
| (VI) | 61909 | tert-butyl 2-(1-methylhydrazino)acetate | C7H16N2O2 | 详情 | 详情 | |
| (VII) | 61927 | tert-butyl 2-[2-((3R,5R)-6-azido-3-[(tert-butoxycarbonyl)amino]-5-{[tert-butyl(dimethyl)silyl]oxy}hexanoyl)-1-methylhydrazino]acetate | C24H48N6O6Si | 详情 | 详情 | |
| (VIII) | 61928 | tert-butyl 2-[2-((3R,5R)-6-amino-3-[(tert-butoxycarbonyl)amino]-5-{[tert-butyl(dimethyl)silyl]oxy}hexanoyl)-1-methylhydrazino]acetate | C24H50N4O6Si | 详情 | 详情 | |
| (IX) | 32624 | 2-Nitrobenzenesulfonyl chloride | 1694-92-4 | C6H4ClNO4S | 详情 | 详情 |
| (X) | 61929 | tert-butyl 2-[2-((3R,5R)-3-[(tert-butoxycarbonyl)amino]-5-{[tert-butyl(dimethyl)silyl]oxy}-6-{[(2-nitrophenyl)sulfonyl]amino}hexanoyl)-1-methylhydrazino]acetate | C30H53N5O10SSi | 详情 | 详情 | |
| (XI) | 61930 | tert-butyl 2-[2-((3R,5R)-3-[(tert-butoxycarbonyl)amino]-5-{[tert-butyl(dimethyl)silyl]oxy}-6-{methyl[(2-nitrophenyl)sulfonyl]amino}hexanoyl)-1-methylhydrazino]acetate | C31H55N5O10SSi | 详情 | 详情 |