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【结 构 式】 
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【分子编号】14640 【品名】O-benzylhydroxylamine; 1-[(aminooxy)methyl]benzene 【CA登记号】622-33-3 |
【 分 子 式 】C7H9NO 【 分 子 量 】123.1546 【元素组成】C 68.27% H 7.37% N 11.37% O 12.99% |
合成路线1
该中间体在本合成路线中的序号：(VII)The condensation of 3-(4-fluorophenoxy)propionic acid (I) with 4-piperidone (II) by means of pivaloyl chloride and TEA in refluxing toluene gives the amide (III), which is submitted to oxidation with diacetoxyiodobenzene and KOH in methanol, yielding the hydroxy-dimethoxyketal (IV). The methylation of the OH group of (IV) with Me-I and Ag2O in DMF affords the corresponding methoxy compound (V), which is hydrolyzed with HOAc to provide the methoxypiperidone (VI). The reaction of (VI) with O-benzylhydroxylamine (VII) and pyridine in refluxing toluene gives the oxime (VIII), which is diastereoselectively reduced with BH3 in THF, yielding the cis-isomer (IX). Finally, this amine is condensed with 4-amino-5-chloro-2-methoxybenzoic acid (X) by means of ethyl chloroformate, TEA and HOBt in DMF to afford the target amide.
| 【1】 Cossy, J.; et al.; A short synthesis of cisapride: A gastrointestinal stimulant derived from cis-4-amino-3-methoxypiperidine. Tetrahedron Lett 2001, 42, 33, 5713. |
| 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) | 39121 | 3-(4-fluorophenoxy)propionic acid | 2967-70-6 | C9H9FO3 | 详情 | 详情 |
| (II) | 27115 | 4-piperidinone | 40064-34-4 | C5H9NO | 详情 | 详情 |
| (III) | 49549 | 1-[3-(4-fluorophenoxy)propanoyl]-4-piperidinone | C14H16FNO3 | 详情 | 详情 | |
| (IV) | 49550 | 3-(4-fluorophenoxy)-1-(3-hydroxy-4,4-dimethoxy-1-piperidinyl)-1-propanone | C16H22FNO5 | 详情 | 详情 | |
| (V) | 49551 | 3-(4-fluorophenoxy)-1-(3,4,4-trimethoxy-1-piperidinyl)-1-propanone | C17H24FNO5 | 详情 | 详情 | |
| (VI) | 49552 | C15H18FNO4 | 详情 | 详情 | ||
| (VII) | 14640 | O-benzylhydroxylamine; 1-[(aminooxy)methyl]benzene | 622-33-3 | C7H9NO | 详情 | 详情 |
| (VIII) | 49553 | 1-[3-(4-fluorophenoxy)propanoyl]-3-methoxy-4-piperidinone O-benzyloxime | C22H25FN2O4 | 详情 | 详情 | |
| (IX) | 49554 | (3S,4R)-1-[3-(4-fluorophenoxy)propyl]-3-methoxy-4-piperidinamine; (3S,4R)-1-[3-(4-fluorophenoxy)propyl]-3-methoxypiperidinylamine | C15H23FN2O2 | 详情 | 详情 | |
| (X) | 12419 | 4-Amino-5-chloro-2-methoxybenzoic acid | 7206-70-4 | C8H8ClNO3 | 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 N-tert-butoxycarbonylthreonin (I) with O-benzylhydroxylamine (II) by means of N-hydroxybenzotriazole acid dicyclohexylcarbodiimide in THF gives N-tert-butoxycarbonyl-N-benzyloxythreoninamide (III), which is cyclized by means of triphenylphosphine and diethyl azodicarboxylate in THF yielding N-benzyloxy-3-(tert-butoxycarbonylamino)-4-methylazetidin-2-one (IV). The hydrogenolysis of (IV) with H2 over Pd/C in ethanol affords 3-(tert-butoxycarbonylamino)-4-methyl-N-hydroxyazetidin-2-one (V), which is reduced with TiCl3 in ethanol - aqueous ammnonium acetate giving 3-(tert-butoxycarbonylamino)-4-methylazetidin-2-one (VI). The hydrolysis of (VI) with trifluoroacetic acid in CH2Cl2 anisole, followed by reaction with benzyl chloroformate in acetone yields 3-(benzyloxycarbonylamino)-4-methylazetidin-2-one (VII). The sulfonation of (VII) with SO3 in DMF, and treatment of the resulting product with tetrabutylammonium sulfate in CH2Cl2 affords 3-(benzyloxycarbonylamino)-4-methyl-2-oxoazetidin-1-sulfonic acid tetrabutylammonium salt (VIII), which is debenzylated by hydrogenolysis with H2 over Pd/C in DMF giving 3-amino-4-methyl-2-oxoazetidin-1-sulfonic acid tetrabutylammonium salt (IX). The condensation of (IX) with alpha-[[(1-diphenylmethoxycarbonyl)-1-methylethoxy]imino]-(2-amino-4-thiazolyl)acetic acid (X), by means of N-hydroxybenzotriazole or N-hydroxysuccinimide and dicyclohexylcarbodiimide in acetone yields 3-[[(2-amino-4-thiazolyl)[[1-(diphenylmethoxycarbonyl]-1-methylethoxy]imino]acetyl]amino]-4-methyl-2-oxoazetidine-1-sulfonic acid (XI), which is finally hydrolyzed with trifluoroacetic acid.
| 【1】 Fox, R.; Denzel, T.W.; Singh, J.; et al.; Regioselective activation of aminothiazole(iminoxyacetic acid)acetic acid: An efficient synthesis of the monobactam aztreonam. Org Process Res Dev 2002, 6, 6, 863. |
| 【2】 Sykes, R.B.; Parker, W.L.; Cimarusti, C.M.; Koster, W.H.; Slusarchyk, W.A.; Fritz, A.W.; Floyd, D.M. (Bristol-Myers Squibb Co.); beta-Lactam antibiotics containing sulphonic groups. BE 0887428; DE 3104145; GB 2071650; JP 56125362 . |
| 【3】 Castaner, J.; Blancafort, P.; Serradell, M.N.; Aztreonam. Drugs Fut 1983, 8, 4, 295. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10101 | Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene | 501-53-1 | C8H7ClO2 | 详情 | 详情 | |
| (I) | 30642 | (2S,3S)-2-[(tert-butoxycarbonyl)amino]-3-hydroxybutyric acid | 2592-18-9 | C9H17NO5 | 详情 | 详情 |
| (II) | 14640 | O-benzylhydroxylamine; 1-[(aminooxy)methyl]benzene | 622-33-3 | C7H9NO | 详情 | 详情 |
| (III) | 30643 | tert-butyl (1S,2S)-1-[[(benzyloxy)amino]carbonyl]-2-hydroxypropylcarbamate | C16H24N2O5 | 详情 | 详情 | |
| (IV) | 30644 | tert-butyl (2S,3S)-1-(benzyloxy)-2-methyl-4-oxoazetidinylcarbamate | C16H22N2O4 | 详情 | 详情 | |
| (V) | 30645 | tert-butyl (2S,3S)-1-hydroxy-2-methyl-4-oxoazetidinylcarbamate | C9H16N2O4 | 详情 | 详情 | |
| (VI) | 30646 | tert-butyl (2S,3S)-2-methyl-4-oxoazetidinylcarbamate | C9H16N2O3 | 详情 | 详情 | |
| (VII) | 30647 | benzyl (2S,3S)-2-methyl-4-oxoazetidinylcarbamate | C12H14N2O3 | 详情 | 详情 | |
| (VIII) | 30648 | N,N,N-tributyl-1-butanaminium (2S,3S)-3-[[(benzyloxy)carbonyl]amino]-2-methyl-4-oxo-1-azetidinesulfonate | C28H49N3O6S | 详情 | 详情 | |
| (IX) | 30649 | N,N,N-tributyl-1-butanaminium (2S,3S)-3-amino-2-methyl-4-oxo-1-azetidinesulfonate | C20H43N3O4S | 详情 | 详情 | |
| (X) | 30650 | 2-(2-amino-1,3-thiazol-4-yl)-2-[[2-(benzhydryloxy)-1,1-dimethyl-2-oxoethoxy]imino]acetic acid | C22H21N3O5S | 详情 | 详情 | |
| (XI) | 30651 | (2S,3S)-3-[(2-(2-amino-1,3-thiazol-4-yl)-2-[[2-(benzhydryloxy)-1,1-dimethyl-2-oxoethoxy]imino]acetyl)amino]-2-methyl-4-oxo-1-azetidinesulfonic acid | C26H27N5O8S2 | 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 esterification of N-(tert-butoxycarbonyl)-D-glutamic acid 5-O-benzyl ester (I) with phenol by means of DCC and pyridine in ethyl acetate gives the mixed ester (II), which is treated with H2 over Pd/C in methanol to yield the N-(tert-butoxycarbonyl)-D-glutamic acid 1-O-phenyl ester (III). The cyclization of (III) with O-benzylhydroxylamine (IV) by means of EDC, HOBT and TEA in dichloromethane affords N-[1-(benzyloxy)-2,6-dioxopiperidin-3(R)-yl]carbamic acid tert-butyl ester (V), which is treated with HCl gas in dichloromethane to provide 3(R)-amino-1-(benzyloxy)piperidine-2,6-dione (VI). The reaction of (VI) with phthalic anhydride (VII) by means of TEA in THF gives the phthalimido derivative (VIII), which is debenzylated with H2 over Pd/C in methanol to yield 1-hydroxy-3-(R)-(phthalimido)piperidine-2,6-dione (IX). Finally, the OH group of (IX) is eliminated by reaction with phenacyl bromide (X) and TEA in acetonitrile to afford the phenacyl ether (XI), which is submitted to a nucleophilic cleavage by means of DMAP as the base to obtain the target (R)-thalidomide.
| 【1】 Robin, S.; et al.; A convenient asymmetric synthesis of thalidomide. Tetrahedron Asymmetry 1995, 6, 6, 1249. |
| 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) | 57869 | (2R)-5-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]-5-oxopentanoic acid | C17H23NO6 | 详情 | 详情 | |
| (II) | 57862 | 5-benzyl 1-phenyl (2R)-2-[(tert-butoxycarbonyl)amino]pentanedioate | C23H27NO6 | 详情 | 详情 | |
| (III) | 57863 | (4R)-4-[(tert-butoxycarbonyl)amino]-5-oxo-5-phenoxypentanoic acid | C16H21NO6 | 详情 | 详情 | |
| (IV) | 14640 | O-benzylhydroxylamine; 1-[(aminooxy)methyl]benzene | 622-33-3 | C7H9NO | 详情 | 详情 |
| (V) | 57864 | tert-butyl (3R)-1-(benzyloxy)-2,6-dioxopiperidinylcarbamate | C17H22N2O5 | 详情 | 详情 | |
| (VI) | 57865 | (3R)-3-amino-1-(benzyloxy)-2,6-piperidinedione | C12H14N2O3 | 详情 | 详情 | |
| (VII) | 11900 | 2-Benzofuran-1,3-dione;1,2-Benzenedicarboxylic Anhydride;1,2-BENZENE DICARBOXYLIC ACID ANHYDRIDE;1,2-BENZENEDICARBONIC ACID, ANHYDRIDE;1,3-DIOXOPHTHALAN;1,3-ISOBENZOFURANDIONE;o-phthalic anhydride; Phthalic anhydride | 85-44-9 | C8H4O3 | 详情 | 详情 |
| (VIII) | 57866 | 2-[(3R)-1-(benzyloxy)-2,6-dioxopiperidinyl]-1H-isoindole-1,3(2H)-dione | C20H16N2O5 | 详情 | 详情 | |
| (IX) | 57867 | 2-[(3R)-1-hydroxy-2,6-dioxopiperidinyl]-1H-isoindole-1,3(2H)-dione | C13H10N2O5 | 详情 | 详情 | |
| (X) | 10315 | 2-Bromo-1-phenyl-ethanone; 2-Bromo-1-phenyl-1-ethanone | 70-11-1 | C8H7BrO | 详情 | 详情 |
| (XI) | 57868 | 2-[(3R)-2,6-dioxo-1-(2-oxo-2-phenylethoxy)piperidinyl]-1H-isoindole-1,3(2H)-dione | C21H16N2O6 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(IV)The esterification of N-(tert-butoxycarbonyl)-L-glutamic acid 5-O-benzyl ester (I) with phenol by means of DCC and pyridine in ethyl acetate gives the mixed ester (II), which is treated with H2 over Pd/C in methanol to yield the N-(tert-butoxycarbonyl)-L-glutamic acid 1-O-phenyl ester (III). The cyclization of (III) with O-benzylhydroxylamine (IV) by means of EDC, HOBT and TEA in dichloromethane affords N-[1-(benzyloxy)-2,6-dioxopiperidin-3(S)-yl]carbamic acid tert-butyl ester (V), which is treated with HCl gas in dichloromethane to provide 3(S)-amino-1-(benzyloxy)piperidine-2,6-dione (VI). The reaction of (VI) with phthalic anhydride (VII) by means of TEA in THF gives the phthalimido derivative (VIII), which is debenzylated with H2 over Pd/C in methanol to yield 1-hydroxy-3-(S)-(phthalimido)piperidine-2,6-dione (IX). Finally the OH group of (IX) is eliminated by reaction with phenacyl bromide (X) and TEA in acetonitrile to afford the phenacyl ether (XI), which is submitted to a nucleophilic cleavage by means of DMAP as the base to obtain the target (S)-thalidomide. Alternatively, the phthalimido derivative (VIII) can also be obtained by reaction of 2(S)-(phthalimido)glutaric anhydride (XII) with O-benzylhydroxylamine (IV) by means of DCC and pyridine in dichloromethane.
| 【1】 Robin, S.; et al.; A convenient asymmetric synthesis of thalidomide. Tetrahedron Asymmetry 1995, 6, 6, 1249. |
| 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) | 25141 | (2S)-5-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]-5-oxopentanoic acid | 13574-13-5 | C17H23NO6 | 详情 | 详情 |
| (II) | 57870 | 5-benzyl 1-phenyl (2S)-2-[(tert-butoxycarbonyl)amino]pentanedioate | C23H27NO6 | 详情 | 详情 | |
| (III) | 57871 | (4S)-4-[(tert-butoxycarbonyl)amino]-5-oxo-5-phenoxypentanoic acid | C16H21NO6 | 详情 | 详情 | |
| (IV) | 14640 | O-benzylhydroxylamine; 1-[(aminooxy)methyl]benzene | 622-33-3 | C7H9NO | 详情 | 详情 |
| (V) | 57872 | tert-butyl (3S)-1-(benzyloxy)-2,6-dioxopiperidinylcarbamate | C17H22N2O5 | 详情 | 详情 | |
| (VI) | 57873 | (3S)-3-amino-1-(benzyloxy)-2,6-piperidinedione | C12H14N2O3 | 详情 | 详情 | |
| (VII) | 11900 | 2-Benzofuran-1,3-dione;1,2-Benzenedicarboxylic Anhydride;1,2-BENZENE DICARBOXYLIC ACID ANHYDRIDE;1,2-BENZENEDICARBONIC ACID, ANHYDRIDE;1,3-DIOXOPHTHALAN;1,3-ISOBENZOFURANDIONE;o-phthalic anhydride; Phthalic anhydride | 85-44-9 | C8H4O3 | 详情 | 详情 |
| (VIII) | 57874 | 2-[(3S)-1-(benzyloxy)-2,6-dioxopiperidinyl]-1H-isoindole-1,3(2H)-dione | C20H16N2O5 | 详情 | 详情 | |
| (IX) | 57875 | 2-[(3S)-1-hydroxy-2,6-dioxopiperidinyl]-1H-isoindole-1,3(2H)-dione | C13H10N2O5 | 详情 | 详情 | |
| (X) | 10315 | 2-Bromo-1-phenyl-ethanone; 2-Bromo-1-phenyl-1-ethanone | 70-11-1 | C8H7BrO | 详情 | 详情 |
| (XI) | 57876 | 2-[(3S)-2,6-dioxo-1-(2-oxo-2-phenylethoxy)piperidinyl]-1H-isoindole-1,3(2H)-dione | C21H16N2O6 | 详情 | 详情 | |
| (XII) | 57877 | 2-[(3S)-2,6-dioxotetrahydro-2H-pyran-3-yl]-1H-isoindole-1,3(2H)-dione | C13H9NO5 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(II)The reaction of N-(tert-butoxycarbonyl)-3-hydroxyvaline (I) with O-benzylhydroxylamine (II) by means of hydroxybenzotriazole (HBT) and dicyclohexylcarbodiimide (DCC) in THF gives the corresponding benzyloxyamide (III), which is treated with the pyridine.SO3 complex (IV) in pyridine to yield N-(tert-butoxycarbonyl)-3-(sulfooxy)-N2-(benzyloxy)valinamide (V). The cyclization of (V) by means of K2CO3 in ethyl acetate - water affords 1-(benzyloxy)-3-(tert-butoxycarbonylamino)-4,4-dimethylazetidin-2-one (VI), which is debenzylated by hydrogenation with H2 over Pd/C in methanol to give the N-hydroxyazetidine (VII). The reaction of (VII) with the sulfonating complex (IV) affords the 1-azetidinyl sulfuric ester (VIII), which is deprotected by reaction with trifluoroacetic acid in anisole - dichloromethane yielding 3-amino-4,4-dimethyl-2-oxoazetidinyl-1-sulfate (IX). The condensation of (IX) with 2-(2-aminothiazol-4-yl)-2(Z)-(diphenylmethoxycarbonylmethoxyimino)acetic acid (X) by means of diphenyl chlorophosphate (PCP) and triethylamine in DMF gives the diphenylmethyl ester (XI) of the final product, which is finally deprotected by hydrolysis with trifluoroacetic acid and anisole.
| 【1】 Slusarchyk, W.A.; Dejneka, T.; Kostes, W.H. (Bristol-Myers Squibb Co.); Preparation of 4,4-dialkyl-2-azetidinones. AU 8652460; BE 090411; DE 3602347; ES 8706112; ES 8800897; FR 2576596; GB 2170201; US 4638061 . |
| 【2】 Gurney, J.D.; Prous, J.; Castaner, J.; TIGEMONAM < Rec INN >. Drugs Fut 1989, 14, 10, 966. |
| 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) | 21366 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-hydroxy-3-methylbutyric acid | C10H19NO5 | 详情 | 详情 | |
| (II) | 14640 | O-benzylhydroxylamine; 1-[(aminooxy)methyl]benzene | 622-33-3 | C7H9NO | 详情 | 详情 |
| (III) | 21368 | tert-butyl (1S)-1-[[(benzyloxy)amino]carbonyl]-2-hydroxy-2-methylpropylcarbamate | C17H26N2O5 | 详情 | 详情 | |
| (V) | 21369 | (5S)-9,9-dimethyl-5-[1-methyl-1-(sulfoperoxy)ethyl]-4,7-dioxo-1-phenyl-2,8-dioxa-3,6-diazadecane | C17H26N2O9S | 详情 | 详情 | |
| (VI) | 21370 | tert-butyl (3S)-1-(benzyloxy)-2,2-dimethyl-4-oxoazetidinylcarbamate | C17H24N2O4 | 详情 | 详情 | |
| (VII) | 21371 | tert-butyl (3S)-1-hydroxy-2,2-dimethyl-4-oxoazetidinylcarbamate | C10H18N2O4 | 详情 | 详情 | |
| (VIII) | 21372 | tert-butyl (3S)-2,2-dimethyl-4-oxo-1-(sulfoperoxy)azetidinylcarbamate | C10H18N2O8S | 详情 | 详情 | |
| (IX) | 21373 | (3S)-3-amino-4,4-dimethyl-1-(sulfoperoxy)-2-azetidinone | C5H10N2O6S | 详情 | 详情 | |
| (X) | 21374 | 2-(2-amino-1,3-thiazol-4-yl)-2-[[2-(benzhydryloxy)-2-oxoethoxy]imino]acetic acid | C20H17N3O5S | 详情 | 详情 | |
| (XI) | 21375 | benzhydryl 2-[[((Z)-1-(2-amino-1,3-thiazol-4-yl)-2-[[(3S)-2,2-dimethyl-4-oxo-1-(sulfoperoxy)azetidinyl]amino]-2-oxoethylidene)amino]oxy]acetate | C25H25N5O10S2 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(VII)This compound can be obtained by two related ways: The reaction of cyclopentanone (I) with ethyl cyanoacetate (II) by means of HOAc/NH4OAc gives the cyclopentylidene derivative (III), which by reaction with KCN yields 1-(cyanomethyl)cyclopentanecarbonitrile (IV). The hydrolysis of (IV) with HCl affords the dicarboxylic acid (V), which by reaction with Ac2O affords the corresponding cyclic anhydride (VI). Finally, the reaction of (VI) with O-benzyl hydroxylamine hydrochloride and NaHCO3 provides the target compound. Alternatively, the cyclic anhydride (VI) is treated with hydroxylamine hydrochloride and Na2CO3 to gives the N-hydroxyimide (VIII), which is converted into its sodium salt (IX) by means of NaOEt in EtOH, and finally alkylated with benzyl chloride (X) to provide the target compound.
| 【1】 Scott, K.R.; Nicholson, J.M.; Edafiogho, I.O.; Farrar, V.A.; Hinko, C.N.; Moore, J.A.; Imidooxy anticonvulsants: Structural analogs with special emphasis on N-(benzyloxy)-2-azaspiro[4,4]nonane-1,3-dione. Drugs Fut 1992, 17, 5, 395. |
| 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) | 15113 | cyclopentanone | 120-92-3 | C5H8O | 详情 | 详情 |
| (II) | 11877 | Cyanoacetic acid ethyl ester; Ethyl 2-cyanoacetate; Ethyl cyanoacetate; Ethyl isocyanacetate | 105-56-6 | C5H7NO2 | 详情 | 详情 |
| (III) | 43191 | ethyl 2-cyano-2-cyclopentylideneacetate | 5407-83-0 | C10H13NO2 | 详情 | 详情 |
| (IV) | 43192 | 1-(cyanomethyl)cyclopentanecarbonitrile | C8H10N2 | 详情 | 详情 | |
| (V) | 43193 | 1-(carboxymethyl)cyclopentanecarboxylic acid | C8H12O4 | 详情 | 详情 | |
| (VI) | 27158 | 2-oxaspiro[4.4]nonane-1,3-dione | C8H10O3 | 详情 | 详情 | |
| (VII) | 14640 | O-benzylhydroxylamine; 1-[(aminooxy)methyl]benzene | 622-33-3 | C7H9NO | 详情 | 详情 |
| (VIII) | 43194 | 2-hydroxy-2-azaspiro[4.4]nonane-1,3-dione | C8H11NO3 | 详情 | 详情 | |
| (IX) | 43195 | sodium 1,3-dioxo-2-azaspiro[4.4]nonan-2-olate | C8H10NNaO3 | 详情 | 详情 | |
| (X) | 19171 | 1-(Chloromethyl)benzene; Benzyl chloride | 100-44-7 | C7H7Cl | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(II)This compound is prepared as follows: Optical active (-)-epoxide (I) is reacted with O-benzylhydroxylamine (II) to give (+)-trans-4-benzyloxyamino-3-ol (III), which, without further purification, is converted with acetyl chloride/pyridine into the final product, Y-27152.
| 【1】 Yamanaka, T.; Seki, T.; Nakajima, T.; Yaoka, O. (Welfide Corporation); Benzopyran compound and its pharmaceutical use. EP 0339562; JP 1990223574; US 5021432; US 5143936 . |
| 【2】 Yamanaka, T.; Nakajima, T.; Y-27152. Drugs Fut 1992, 17, 11, 999. |
| 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) | 14639 | (1aS,7bS)-2,2-dimethyl-1a,7b-dihydro-2H-oxireno[2,3-c]chromene-6-carbonitrile | C12H11NO2 | 详情 | 详情 | |
| (II) | 14640 | O-benzylhydroxylamine; 1-[(aminooxy)methyl]benzene | 622-33-3 | C7H9NO | 详情 | 详情 |
| (III) | 14641 | (3S,4R)-4-[(benzyloxy)amino]-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromene-6-carbonitrile | C19H20N2O3 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(I)Sequential introduction of two tert-butoxycarbonyl groups into O-benzyl hydroxylamine (I) afforded the di-Boc-protected hydroxylamine (II). The O-benzyl group was then removed by hydrogenolysis over Pd/C yielding intermediate (III).
| 【1】 Koster, W.H.; Sundeen, J.E.; Straub, H.; Ermann, P.H.; Treuner, U. (Bristol-Myers Squibb Co.); Heteroaroyl derivs. of monocyclic beta-lactam antibiotics. EP 0484881; JP 1992283579 . |
合成路线9
该中间体在本合成路线中的序号：(XI)Treatment of butanedioate derivative (I) with methallyl iodide (II) and LDA in THF affords alkene (III), which is then reduced by hydrogenation over Pd/C and subjected to saponification by means of KOH in dioxane to yield succinic acid (IV). Protection of (IV) with 2,2-dimethoxypropane (V) and p-TsOH in DMF provides derivative (VI), which is then coupled with pentafluorophenol (VII) by using EDC in CH2Cl2 to furnish activated ester (VIII). Displacement of the pentafluorophenol moiety of (VIII) by treatment with L-tert-leucine methylamide (IX) in DMF gives methylamide derivative (X), which is deprotected with THF and HCl and condensed with O-benzylhydroxylamine (XI) by means of EDC to afford derivative (XII). Finally, (XII) is debenzylated by hydrogenation over Pd/C in EtOH to give the target compound.
| 【1】 Davenport, R.J.; Watson, R.J.; An improved synthesis of the broad spectrum matrix metalloprotease inhibitor marimastat. Tetrahedron Lett 2000, 41, 41, 7983. |
| 【2】 Dickens, J.P.; Crimmin, M.J.; Beckett, R.P. (British Biotech plc); Natural amino acid derivs. as metalloproteinase inhibitors. EP 0651738; EP 0651739; GB 2268933; GB 2268934; JP 1995509460; JP 1998204081; WO 9402446; WO 9402447 . |
| 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) | 43782 | diisopropyl (2S)-2-hydroxybutanedioate | C10H18O5 | 详情 | 详情 | |
| (II) | 43783 | 3-iodo-2-methyl-1-propene | C4H7I | 详情 | 详情 | |
| (III) | 43784 | diisopropyl (2S,3R)-2-hydroxy-3-(2-methyl-2-propenyl)butanedioate | C14H24O5 | 详情 | 详情 | |
| (IV) | 43785 | (2S,3R)-2-hydroxy-3-isobutylbutanedioic acid | C8H14O5 | 详情 | 详情 | |
| (V) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (VI) | 43786 | (2R)-2-[(4S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]-4-methylpentanoic acid | C11H18O5 | 详情 | 详情 | |
| (VII) | 22662 | 2,3,4,5,6-pentafluorophenol | 771-61-9 | C6HF5O | 详情 | 详情 |
| (VIII) | 43787 | 2,3,4,5,6-pentafluorophenyl (2R)-2-[(4S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]-4-methylpentanoate | C17H17F5O5 | 详情 | 详情 | |
| (IX) | 18843 | (2S)-2-amino-N,3,3-trimethylbutanamide | 89226-12-0 | C7H16N2O | 详情 | 详情 |
| (X) | 43788 | (2R)-N-[(1S)-2,2-dimethyl-1-[(methylamino)carbonyl]propyl]-2-[(4S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]-4-methylpentanamide | C18H32N2O5 | 详情 | 详情 | |
| (XI) | 14640 | O-benzylhydroxylamine; 1-[(aminooxy)methyl]benzene | 622-33-3 | C7H9NO | 详情 | 详情 |
| (XII) | 43789 | (2S,3R)-N(1)-(benzyloxy)-N(4)-[(1S)-2,2-dimethyl-1-[(methylamino)carbonyl]propyl]-2-hydroxy-3-isobutylbutanediamide | C22H35N3O5 | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(VIII)2. The reaction of the diacid monoester (IV) with oxalyl chloride in benzene gives the corresponding acyl chloride (V), which is treated with aniline (II) and pyridine in THF, yielding the monoester monoamide (VI). The hydrolysis of the ester group of (VI) with OH in refluxing methanol affords the monoamide carboxylic acid (VII), which is condensed with O-benzylhydroxylamine (VIII) by means of DCC in pyridine to provide the protected hydroxamic acid (IX). Finally, this compound is debenzylated with H2 over Pd/C in methanol to furnish the target hydroxamic acid with yields of 35-65%. 3. A mixture of diacid dichloride (I), aniline (II) and O-benzylhydroxylamine (VIII) in pyridine gives, after chromatographic purification, the protected hydroxamic acid (IX), which is debenzylated as before to provide the target hydroxamic acid with yields of 20-35%. 4. The reaction of acid dichloride (I) with aniline (II) and O-(trimethylsilyl)hydroxylamine (X) by means of TEA in chloroform gives the trimethylsilyl protected compound (XI), which is desilylated with NH4Cl in hot methanol to afford the target hydroxamic acid with yields of 20-33%.
| 【1】 Breslow, R.; Rifkind, R.A.; Jursic, B. (Columbia University; Sloan-Kettering Institute); Novel potent inducers of terminal differentiation and methods of use thereof. WO 9307148 . |
| 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) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (IV) | 53943 | Ethyl hydrogen suberate; Monoethyl suberate; Suberic acid monoethyl ester | 14113-01-0 | C10H18O4 | 详情 | 详情 |
| (V) | 53944 | ethyl 8-chloro-8-oxooctanoate | C10H17ClO3 | 详情 | 详情 | |
| (VI) | 53945 | ethyl 8-anilino-8-oxooctanoate | C16H23NO3 | 详情 | 详情 | |
| (VII) | 53946 | 8-anilino-8-oxooctanoic acid | C14H19NO3 | 详情 | 详情 | |
| (VIII) | 14640 | O-benzylhydroxylamine; 1-[(aminooxy)methyl]benzene | 622-33-3 | C7H9NO | 详情 | 详情 |
| (IX) | 53947 | N~1~-(benzyloxy)-N~8~-phenyloctanediamide | C21H26N2O3 | 详情 | 详情 | |
| (X) | 26091 | O-(trimethylsilyl)hydroxylamine; (aminooxy)(trimethyl)silane | 22737-36-6 | C3H11NOSi | 详情 | 详情 |
| (XI) | 53948 | N~1~-phenyl-N~8~-[(trimethylsilyl)oxy]octanediamide | C17H28N2O3Si | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(XIII)The reaction of N-Boc-L-serine (I) with 2-fluoronitrobenzene (II) by means of NaH in DMF gives N-Boc-O-(2-nitrophenyl)-L-serine (III), which is reduced with H2 over Pd/C in methanol yielding the 2-aminophenyl derivative (IV). The cyclization of (IV) by means of EDAC in DMF affords the benzoxazepinone (V), which is condensed with benzyl 2-bromoacetate (VI) by means of LHMDS in THF providing the benzoxazepinone acetic ester (VII). The deprotection of the carbamate group of (VII) with HCl in dioxane affords (VIII) with a free amino group that is condensed with 2-benzyl-3-[N-(benzyloxy)-N-formylamino]propionic acid (IX) by means of EDAC in dichloromethane giving the corresponding amide (X). The deprotection of the benzyl groups of (X) with H2 over Pd/C in methanol yields the expected mixture of diastereomers that is resolved by preparative HPLC to afford the target compound.
| 【1】 Asaad, M.M.; Robl, J.A.; Simpkins, L.M.; N-Formyl hydroxylamine containing dipeptides: Generation of a new class of vasopeptidase inhibitors. Bioorg Med Chem Lett 2000, 10, 3, 257. |
| 【2】 Robl, J.A. (Bristol-Myers Squibb Co.); N-Formyl hydroxylamine containing cpds. useful as ACE inhibitors and/or NEP inhibitors. WO 9738705 . |
| 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) | 20126 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-hydroxypropionic acid | C8H15NO5 | 详情 | 详情 | |
| (II) | 13463 | o-Fluoronitrobenzene; 1-fluoro-2-nitrobenzene | 1493-27-2 | C6H4FNO2 | 详情 | 详情 |
| (III) | 37271 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-(2-nitrophenoxy)propionic acid | C14H18N2O7 | 详情 | 详情 | |
| (IV) | 37272 | (2S)-3-(2-aminophenoxy)-2-[(tert-butoxycarbonyl)amino]propionic acid | C14H20N2O5 | 详情 | 详情 | |
| (V) | 37273 | tert-butyl (3S)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-ylcarbamate | C14H18N2O4 | 详情 | 详情 | |
| (VI) | 12869 | benzyl 2-bromoacetate | 5437-45-6 | C9H9BrO2 | 详情 | 详情 |
| (VII) | 37274 | benzyl 2-[(3S)-3-[(tert-butoxycarbonyl)amino]-4-oxo-3,4-dihydro-1,5-benzoxazepin-5(2H)-yl]acetate | C23H26N2O6 | 详情 | 详情 | |
| (VIII) | 37275 | benzyl 2-[(3S)-3-amino-4-oxo-3,4-dihydro-1,5-benzoxazepin-5(2H)-yl]acetate | C18H18N2O4 | 详情 | 详情 | |
| (IX) | 37276 | 2-benzyl-N-(benzyloxy)-N-formyl-beta-alanine | C18H19NO4 | 详情 | 详情 | |
| (X) | 37278 | benzyl 2-[(3S)-3-([2-benzyl-3-[(benzyloxy)(formyl)amino]propanoyl]amino)-4-oxo-3,4-dihydro-1,5-benzoxazepin-5(2H)-yl]acetate | C36H35N3O7 | 详情 | 详情 | |
| (XI) | 37280 | 2-benzylmalonic acid | 616-75-1 | C10H10O4 | 详情 | 详情 |
| (XII) | 37279 | 2-benzylacrylic acid | C10H10O2 | 详情 | 详情 | |
| (XIII) | 14640 | O-benzylhydroxylamine; 1-[(aminooxy)methyl]benzene | 622-33-3 | C7H9NO | 详情 | 详情 |
| (XIV) | 37277 | 2-benzyl-N-(benzyloxy)-beta-alanine | C17H19NO3 | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：(XIII)The reaction of N-Boc-L-serine (I) with 2-fluoronitrobenzene (II) by means of NaH in DMF gives N-Boc-O-(2-nitrophenyl)-L-serine (III), which is reduced with H2 over Pd/C in methanol yielding the 2-aminophenyl derivative (IV). The cyclization of (IV) by means of EDAC in DMF affords the benzoxazepinone (V), which is condensed with benzyl 2-bromoacetate (VI) by means of LHMDS in THF providing the benzoxazepinone acetic ester (VII). The deprotection of the carbamate group of (VII) with HCl in dioxane affords (VIII) with a free amino group that is condensed with 2-benzyl-3-[N-(benzyloxy)-N-formylamino]propionic acid (IX) by means of EDAC in dichloromethane giving the corresponding amide (X). The deprotection of the benzyl groups of (X) with H2 over Pd/C in methanol yields the expected mixture of diastereomers that is resolved by preparative HPLC to afford the target compound. The intermediate 2-benzyl-3-[N-(benzyloxy)-N-formylamino]propionic acid (IX) has been obtained as follows: The reaction of benzylmalonic acid (XI) with aqueous formaldehyde and dimethylamine gives 2-benzyl-2-propenoic acid (XII), which is condensed with O-benzylhydroxylamine (XIII) in refluxing ethanol yielding 2-benzyl-3-(benzyloxyamino)propionic acid (XIV). Finally, this compound is N-formylated with formic acid/acetic anhydride to afford the desired intermediate (IX).
| 【1】 Asaad, M.M.; Robl, J.A.; Simpkins, L.M.; N-Formyl hydroxylamine containing dipeptides: Generation of a new class of vasopeptidase inhibitors. Bioorg Med Chem Lett 2000, 10, 3, 257. |
| 【2】 Robl, J.A. (Bristol-Myers Squibb Co.); N-Formyl hydroxylamine containing cpds. useful as ACE inhibitors and/or NEP inhibitors. WO 9738705 . |
| 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) | 20126 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-hydroxypropionic acid | C8H15NO5 | 详情 | 详情 | |
| (II) | 13463 | o-Fluoronitrobenzene; 1-fluoro-2-nitrobenzene | 1493-27-2 | C6H4FNO2 | 详情 | 详情 |
| (III) | 37271 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-(2-nitrophenoxy)propionic acid | C14H18N2O7 | 详情 | 详情 | |
| (IV) | 37272 | (2S)-3-(2-aminophenoxy)-2-[(tert-butoxycarbonyl)amino]propionic acid | C14H20N2O5 | 详情 | 详情 | |
| (V) | 37273 | tert-butyl (3S)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-ylcarbamate | C14H18N2O4 | 详情 | 详情 | |
| (VI) | 12869 | benzyl 2-bromoacetate | 5437-45-6 | C9H9BrO2 | 详情 | 详情 |
| (VII) | 37274 | benzyl 2-[(3S)-3-[(tert-butoxycarbonyl)amino]-4-oxo-3,4-dihydro-1,5-benzoxazepin-5(2H)-yl]acetate | C23H26N2O6 | 详情 | 详情 | |
| (VIII) | 37275 | benzyl 2-[(3S)-3-amino-4-oxo-3,4-dihydro-1,5-benzoxazepin-5(2H)-yl]acetate | C18H18N2O4 | 详情 | 详情 | |
| (IX) | 37276 | 2-benzyl-N-(benzyloxy)-N-formyl-beta-alanine | C18H19NO4 | 详情 | 详情 | |
| (X) | 37278 | benzyl 2-[(3S)-3-([2-benzyl-3-[(benzyloxy)(formyl)amino]propanoyl]amino)-4-oxo-3,4-dihydro-1,5-benzoxazepin-5(2H)-yl]acetate | C36H35N3O7 | 详情 | 详情 | |
| (XI) | 37280 | 2-benzylmalonic acid | 616-75-1 | C10H10O4 | 详情 | 详情 |
| (XII) | 37279 | 2-benzylacrylic acid | C10H10O2 | 详情 | 详情 | |
| (XIII) | 14640 | O-benzylhydroxylamine; 1-[(aminooxy)methyl]benzene | 622-33-3 | C7H9NO | 详情 | 详情 |
| (XIV) | 37277 | 2-benzyl-N-(benzyloxy)-beta-alanine | C17H19NO3 | 详情 | 详情 |
合成路线13
该中间体在本合成路线中的序号：(XXI)The intermediate 2(R)-benzyl-3-(benzyloxyamino)propionic acid (XV) has been obtained as follows: The reaction of benzylmalonic acid (XIX) with aqueous formaldehyde and dimethylamine gives 2-benzyl-2-propenoic acid (XX), which is condensed with O-benzylhydroxylamine (XXI) in refluxing ethanol yielding racemic 2-benzyl-3-(benzyloxyamino)propionic acid (XXII). Finally, this compound is submitted to optical resolution with (1R,2S)(-)-ephedrine in acetonitrile to afford the chiral target intermediate (XV).
| 【1】 Asaad, M.M.; Robl, J.A.; Simpkins, L.M.; N-Formyl hydroxylamine containing dipeptides: Generation of a new class of vasopeptidase inhibitors. Bioorg Med Chem Lett 2000, 10, 3, 257. |
| 【2】 Robl, J.A. (Bristol-Myers Squibb Co.); N-Formyl hydroxylamine containing cpds. useful as ACE inhibitors and/or NEP inhibitors. WO 9738705 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XV) | 37283 | (2R)-2-benzyl-3-[(benzyloxy)amino]propionic acid | C17H19NO3 | 详情 | 详情 | |
| (XIX) | 37280 | 2-benzylmalonic acid | 616-75-1 | C10H10O4 | 详情 | 详情 |
| (XX) | 37279 | 2-benzylacrylic acid | C10H10O2 | 详情 | 详情 | |
| (XXI) | 14640 | O-benzylhydroxylamine; 1-[(aminooxy)methyl]benzene | 622-33-3 | C7H9NO | 详情 | 详情 |
| (XXII) | 37277 | 2-benzyl-N-(benzyloxy)-beta-alanine | C17H19NO3 | 详情 | 详情 |
合成路线14
该中间体在本合成路线中的序号：(XVII)The intermediate 2(R)-benzyl-3-(benzyloxyamino)propionic acid (XI) has been obtained as follows: The reaction of benzylmalonic acid (XV) with aqueous formaldehyde and dimethylamine gives 2-benzyl-2-propenoic acid (XVI), which is condensed with O-benzylhydroxylamine (XVII) in refluxing ethanol yielding racemic 2-benzyl-3-(benzyloxyamino)propionic acid (XVIII). Finally, this compound is submitted to optical resolution with (1R,2S)(-)-ephedrine in acetonitrile to afford the chiral target intermediate (XI).
| 【1】 Asaad, M.M.; Robl, J.A.; Simpkins, L.M.; N-Formyl hydroxylamine containing dipeptides: Generation of a new class of vasopeptidase inhibitors. Bioorg Med Chem Lett 2000, 10, 3, 257. |
| 【2】 Robl, J.A. (Bristol-Myers Squibb Co.); N-Formyl hydroxylamine containing cpds. useful as ACE inhibitors and/or NEP inhibitors. WO 9738705 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XI) | 37283 | (2R)-2-benzyl-3-[(benzyloxy)amino]propionic acid | C17H19NO3 | 详情 | 详情 | |
| (XV) | 37280 | 2-benzylmalonic acid | 616-75-1 | C10H10O4 | 详情 | 详情 |
| (XVI) | 37279 | 2-benzylacrylic acid | C10H10O2 | 详情 | 详情 | |
| (XVII) | 14640 | O-benzylhydroxylamine; 1-[(aminooxy)methyl]benzene | 622-33-3 | C7H9NO | 详情 | 详情 |
| (XVIII) | 37277 | 2-benzyl-N-(benzyloxy)-beta-alanine | C17H19NO3 | 详情 | 详情 |
合成路线15
该中间体在本合成路线中的序号：(XIV)The intermediate 2(R)-benzyl-3-(benzyloxyamino)propionic acid (IX) has been obtained as follows: The reaction of benzylmalonic acid (XII) with aqueous formaldehyde and dimethylamine gives 2-benzyl-2-propenoic acid (XIII), which is condensed with O-benzylhydroxylamine (XIV) in refluxing ethanol yielding racemic 2-benzyl-3-(benzyloxyamino)propionic acid (XV). Finally, this compound is submitted to optical resolution with (1R,2S)(-)-ephedrine in acetonitrile to afford the chiral target intermediate (IX).
| 【1】 Asaad, M.M.; Robl, J.A.; Simpkins, L.M.; N-Formyl hydroxylamine containing dipeptides: Generation of a new class of vasopeptidase inhibitors. Bioorg Med Chem Lett 2000, 10, 3, 257. |
| 【2】 Robl, J.A. (Bristol-Myers Squibb Co.); N-Formyl hydroxylamine containing cpds. useful as ACE inhibitors and/or NEP inhibitors. WO 9738705 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IX) | 37283 | (2R)-2-benzyl-3-[(benzyloxy)amino]propionic acid | C17H19NO3 | 详情 | 详情 | |
| (XII) | 37280 | 2-benzylmalonic acid | 616-75-1 | C10H10O4 | 详情 | 详情 |
| (XIII) | 37279 | 2-benzylacrylic acid | C10H10O2 | 详情 | 详情 | |
| (XIV) | 14640 | O-benzylhydroxylamine; 1-[(aminooxy)methyl]benzene | 622-33-3 | C7H9NO | 详情 | 详情 |
| (XV) | 37277 | 2-benzyl-N-(benzyloxy)-beta-alanine | C17H19NO3 | 详情 | 详情 |
合成路线16
该中间体在本合成路线中的序号：(I)The reaction of 14C-labeled acetone (I) with O-benzylhydroxylamine (II) and pyridine in refluxing ethanol gives the corresponding oxime (III), which is methylated with MeLi and BF3.Et2O in toluene to yield labeled N-tert-butyl-O-benzylhydroxylamine (IV). The deprotection of (IV) by hydrogenation with H2 over Pd/C in methanol affords N-tert-butylhydroxylamine (V), which is finally condensed with benzaldehyde 2,4-disulfonic acid sodium salt (VI) in HOAc/water to give rise to the target imine oxide.
| 【1】 Johansson, R.; Werner, R.; Syntheses of two [14C]-labeled disodium 4-[(N-tert-butylimino)methyl]benzene-1,3-disulfonate N-oxides. J Label Compd Radiopharm 2000, 43, 13, 1265. |
| 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) | 14640 | O-benzylhydroxylamine; 1-[(aminooxy)methyl]benzene | 622-33-3 | C7H9NO | 详情 | 详情 |
| (II) | 23199 | 2-Propanone; Acetone; beta-ketopropane; chevron acetone;propan-2-one； Dimethyl formaldehyde; Dimethyl ketone; dimethylketal; Ketone propane; Methyl ketone; Propanone; Pyroacetic acid; Pyroacetic ether | 67-64-1 | C3H6O | 详情 | 详情 |
| (II) | 53313 | acetone | 67-64-1 | C3H6O | 详情 | 详情 |
| (III) | 53314 | acetone O-benzyloxime | n/a | C10H13NO | 详情 | 详情 |
| (III) | 53315 | acetone O-benzyloxime | n/a | C10H13NO | 详情 | 详情 |
| (IV) | 53316 | 1-{[(tert-butylamino)oxy]methyl}benzene; O-benzyl-N-(tert-butyl)hydroxylamine | n/a | C11H17NO | 详情 | 详情 |
| (IV) | 53317 | O-benzyl-N-(tert-butyl)hydroxylamine; 1-{[(tert-butylamino)oxy]methyl}benzene | n/a | C11H17NO | 详情 | 详情 |
| (V) | 35455 | N-(tert-butyl)hydroxylamine; 2-(hydroxyamino)-2-methylpropane | C4H11NO | 详情 | 详情 | |
| (V) | 53318 | 2-(hydroxyamino)-2-methylpropane; N-(tert-butyl)hydroxylamine | 16649-50-6 | C4H11NO | 详情 | 详情 |
| (VI) | 37311 | Benzaldehyde-2,4-disulfonic acid disodium; disodium 4-formyl-1,3-benzenedisulfonate | 33513-44-9 | C7H4Na2O7S2 | 详情 | 详情 |
合成路线17
该中间体在本合成路线中的序号：(IV)The reaction of benzohydroxamic acid (I) with benzyl bromide (II) by means of NaOH on ethanol gives the corresponding benzyl ester (III), which is treated with HCl yielding O-benzylhydroxylamine (IV). The reaction of (IV) with dicyaniamide (V) in ethanol affords the biguanide (VI), which is cyclized with cyclopentanone (VII) and HCl giving 1-benzyloxy-2,2-dimethyl-1,2-dihydro-1,3,5-triazine-4,6-diamine (VIII). The debenzylation of (VIII) with H2 over PtO2 in ethanol yields 1-hydroxy-2,2-dimethyl-1,2-dihydro-1,3,5-triazine-4,6-diamine (IX), which is finally condensed with 1,6-dibromohexane (X) by means of NaOH in methanol.
| 【1】 Zhang, X.P.; Shen, J.; Xin, Z.M.; Qiu, Q.P.; Zhou, W.C.; Synthesis and antiprotozoal activities of some new triazine derivatives including a new antitrypanosomal agent: SIPI-1029. Acta Pharm Sin 1996, 31, 11, 823. |
| 【2】 Zhou, W.; Zhang, X.; Trybizine Hydrochloride. Drugs Fut 1999, 24, 10, 1084. |
| 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) | 24777 | N-hydroxybenzamide | 495-18-1 | C7H7NO2 | 详情 | 详情 |
| (II) | 12912 | 1-(Bromomethyl)benzene; Alpha-bromotoluene | 100-39-0 | C7H7Br | 详情 | 详情 |
| (III) | 24779 | N-(benzyloxy)benzamide | C14H13NO2 | 详情 | 详情 | |
| (IV) | 14640 | O-benzylhydroxylamine; 1-[(aminooxy)methyl]benzene | 622-33-3 | C7H9NO | 详情 | 详情 |
| (V) | 23611 | N-cyanoguanidine | 461-58-5 | C2H4N4 | 详情 | 详情 |
| (VI) | 24782 | 1-[([[[[amino(imino)methyl]amino](imino)methyl]amino]oxy)methyl]benzene | C9H13N5O | 详情 | 详情 | |
| (VII) | 15113 | cyclopentanone | 120-92-3 | C5H8O | 详情 | 详情 |
| (VIII) | 24784 | 10-(benzyloxy)-6,8,10-triazaspiro[4.5]deca-6,8-diene-7,9-diamine | C14H19N5O | 详情 | 详情 | |
| (IX) | 24785 | 7,9-diamino-6,8,10-triazaspiro[4.5]deca-7,9-dien-6-ol | C7H13N5O | 详情 | 详情 | |
| (X) | 24786 | 1,6-dibromohexane | 629-03-8 | C6H12Br2 | 详情 | 详情 |
合成路线18
该中间体在本合成路线中的序号：(VII)The esterification of D-leucine (I) with benzyl alcohol and HCl gives the corresponding ester (II), which is N-benzylated by reductocondensation with benzaldehyde and sodium cyanoborohydride yielding N-benzyl-D-leucine benzyl ester (III). The condensation of (III) with methyl phenyl phosphinyl chloride (IV) by means of N-methylmorpholine in dichloromethane affords the phosphinylamino derivative (V), which is treated with H2 over Pd/C in methanol to give N-benzyl-N-[methyl(phenyl)phosphinyl]-D-leucine (VI). The condensation of (VI) with O-benzylhydroxylamine (VII) by means of 1-[3-(dimethylamino) propyl]-3-ethylcarbodiimide (DEC) and HOBT in DMF yields the N-benzyl hydroxamic acid (VIII) as a diastereomeric mixture that is separated by flash chromatography providing the diastereomer (IX). Finally, this compound is deprotected by hydrogenation with H2 over Pd/C in methanol.
| 【1】 Elst, L.V.; et al.; A multinuclear MR study of Gd-EOB-DTPA: Comprehensive preclinical characterization of an organ specific MRI contrast agent. Magn Reson Med 1997, 38, 4, 604. |
| 【2】 Taiwo, Y.O.; Pikul, S.; De, B.; McDow-Dunham, K.L. (The Procter & Gamble Co.); Phosphinic acid amides as matrix metalloprotease inhibitors. US 5830915; WO 9808853 . |
| 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) | 16010 | D-leucine | 328-38-1 | C6H13NO2 | 详情 | 详情 |
| (II) | 28648 | benzyl (2R)-2-amino-4-methylpentanoate | C13H19NO2 | 详情 | 详情 | |
| (III) | 28643 | benzyl (2R)-2-(benzylamino)-4-methylpentanoate | C20H25NO2 | 详情 | 详情 | |
| (IV) | 28644 | methyl(phenyl)phosphinic chloride | 5761-97-7 | C7H8ClOP | 详情 | 详情 |
| (V) | 28645 | benzyl (2R)-2-[benzyl[methyl(phenyl)phosphoryl]amino]-4-methylpentanoate | C27H32NO3P | 详情 | 详情 | |
| (VI) | 28646 | (2R)-2-[benzyl[methyl(phenyl)phosphoryl]amino]-4-methylpentanoic acid | C20H26NO3P | 详情 | 详情 | |
| (VII) | 14640 | O-benzylhydroxylamine; 1-[(aminooxy)methyl]benzene | 622-33-3 | C7H9NO | 详情 | 详情 |
| (VIII) | 28647 | (2R)-2-[benzyl[methyl(phenyl)phosphoryl]amino]-N-(benzyloxy)-4-methylpentanamide | C27H33N2O3P | 详情 | 详情 | |
| (IX) | 28649 | (2R)-2-[benzyl[methyl(phenyl)phosphoryl]amino]-N-(benzyloxy)-4-methylpentanamide | C27H33N2O3P | 详情 | 详情 |
合成路线19
该中间体在本合成路线中的序号：Simultaneous deprotection of the benzyl ester and the N-carbobenzoxy group of (XIII) by hydrogenolysis over Pd/C gave amino acid (XIV), which was cyclized by means of benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP) and diisopropyl ethylamine (DIEA), yielding macrocycle (XV). Cleavage of the tert-butyl ester of (XV) with trifluoroacetic acid produced carboxylic acid (XVI), and this was converted to the O-benzyl hydroxamate (XVII) by coupling with O-benzyl hydroxylamine. Further hydrolysis of the methyl ester group of (XVII) to acid (XVIII) was followed by coupling with glycine morpholide (XIX) affording diamide (XX). The O-benzyl group of (XX) was finally removed by hydrogenation in the presence of Pd/C.
| 【1】 Xue, C.-B.; Cherney, R.J.; DeCicco, C.P.; Degrado, W.F.; He, X.; Hodge, C.N.; Jacobson, I.C.; Magolda, R.L.; Arner, E.C.; Duan, J.; Nelson, D.J. (DuPont Pharmaceuticals Co.); Novel macrocyclic cpds. as metalloprotease inhibitors. EP 0863885; JP 2000502050; WO 9718207 . |
| 【2】 Nelson, D.; Magolda, R.L.; Jacobson, I.C.; He, X.; Arner, E.; Cherney, R.J.; Duan, J.; Xue, C.-B.; Decicco, C.P.; Degrado, W.F. (DuPont Pharmaceuticals Co.); Novel macrocyclic cpds. as metalloprotease inhibitors. EP 0981521; WO 9851665 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 14640 | O-benzylhydroxylamine; 1-[(aminooxy)methyl]benzene | 622-33-3 | C7H9NO | 详情 | 详情 | |
| (XIII) | 35088 | 17-benzyl 16-(tert-butyl) 5-methyl (5S,16S,17R)-19-methyl-3,11-dioxo-1-phenyl-2,12-dioxa-4,10-diazaicosane-5,16,17-tricarboxylate | C38H54N2O10 | 详情 | 详情 | |
| (XIV) | 35089 | (2R,3S)-6-[([[(5S)-5-amino-6-methoxy-6-oxohexyl]amino]carbonyl)oxy]-3-(tert-butoxycarbonyl)-2-isobutylhexanoic acid | C23H42N2O8 | 详情 | 详情 | |
| (XV) | 35090 | 12-(tert-butyl) 8-methyl (8S,11R,12S)-11-isobutyl-2,10-dioxo-1-oxa-3,9-diazacyclopentadecane-8,12-dicarboxylate | C23H40N2O7 | 详情 | 详情 | |
| (XVI) | 35091 | (8S,11R,12S)-11-isobutyl-8-(methoxycarbonyl)-2,10-dioxo-1-oxa-3,9-diazacyclopentadecane-12-carboxylic acid | C19H32N2O7 | 详情 | 详情 | |
| (XVII) | 35092 | methyl (8S,11R,12S)-12-[[(benzyloxy)amino]carbonyl]-11-isobutyl-2,10-dioxo-1-oxa-3,9-diazacyclopentadecane-8-carboxylate | C26H39N3O7 | 详情 | 详情 | |
| (XVIII) | 35093 | (8S,11R,12S)-12-[[(benzyloxy)amino]carbonyl]-11-isobutyl-2,10-dioxo-1-oxa-3,9-diazacyclopentadecane-8-carboxylic acid | C25H37N3O7 | 详情 | 详情 | |
| (XIX) | 35094 | 2-amino-1-(4-morpholinyl)-1-ethanone | C6H12N2O2 | 详情 | 详情 | |
| (XX) | 35095 | (8S,11R,12S)-N(12)-(benzyloxy)-11-isobutyl-N(8)-[2-(4-morpholinyl)-2-oxoethyl]-2,10-dioxo-1-oxa-3,9-diazacyclopentadecane-8,12-dicarboxamide | C31H47N5O8 | 详情 | 详情 |
合成路线20
该中间体在本合成路线中的序号：(I)The title compound was originally isolated from the fermentation broths of Streptomyces rubellomurinus. The chemical synthesis of this compound was further described. Treatment of O-benzyl hydroxylamine (I) with TsCl in pyridine afforded N-(benzyloxy)-p-toluenesulfonamide (II). A closely related procedure used O-(p-methoxy-benzyl)hydroxylamine. Diethyl (3-bromopropyl)phosphonate (V) was obtained by alkylation of the sodium salt of diethyl phosphonate (III) with 1,3-dibromopropane (IV). Related procedures used dibutyl phosphonate or 1-bromo-3-chloropropane instead of (III) or (IV). The condensation of protected hydroxylamine (II) with bromide (V) in the presence of NaH furnished adduct (VI). Alternatively, intermediate (VI) was prepared by first alkylation of N-(benzyloxy)-p-toluenesulfonamide (II) with 1,3-dibromopropane (IV) to give (VII), and then condensation of bromide (VII) with the sodium salt of diethyl phosphonate (III). Hydrolysis of (VI) with HCl in HOAc gave rise to 3-(N-hydroxyamino)propylphosphonic acid (VIII). This was finally acetylated with Ac2O in NaOH.
| 【1】 Takashi, K.; et al.; Studies on phosphonic acid antibiotics. I. Structure and synthesis 3-(N-acetyl-N-hydroxyamino) propylphosphonic acid (FR-900098) and its N-formyl analog (FR-31564). Tetrahedron Lett 1980, 21, 1, 95. |
| 【2】 Iguchi, E.; et al.; Studies on new phosphonic acid antibiotics II. Taxonomic studies on producing organisms of the phosphonic acid and related compounds. J Antibiot 1980, 33, 1, 18. |
| 【3】 Takeno, H.; Hemmi, K.; Hashimoto, M.; Kamiya, T. (Fujisawa Pharmaceutical Co., Ltd.); Hydroxyaminohydrocarbonphosphonic acids. DE 2733658; US 4182758; US 4206156 . |
| 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) | 14640 | O-benzylhydroxylamine; 1-[(aminooxy)methyl]benzene | 622-33-3 | C7H9NO | 详情 | 详情 |
| (II) | 39517 | N-(benzyloxy)-4-methylbenzenesulfonamide | C14H15NO3S | 详情 | 详情 | |
| (III) | 12714 | diethyl phosphonate; diethyl phosphite | 762-04-9 | C4H11O3P | 详情 | 详情 |
| (IV) | 12581 | 1,3-Dibromopropane | 109-64-8 | C3H6Br2 | 详情 | 详情 |
| (V) | 39080 | diethyl 3-bromopropylphosphonate | C7H16BrO3P | 详情 | 详情 | |
| (VI) | 39104 | diethyl 3-[(benzyloxy)[(4-methylphenyl)sulfonyl]amino]propylphosphonate | C21H30NO6PS | 详情 | 详情 | |
| (VII) | 39517 | N-(benzyloxy)-4-methylbenzenesulfonamide | C14H15NO3S | 详情 | 详情 | |
| (VIII) | 39088 | 3-(hydroxyamino)propylphosphonic acid | C3H10NO4P | 详情 | 详情 |
合成路线21
该中间体在本合成路线中的序号：Condensation of 4-nitrophthalic anhydride (I) with O-benzyl hydroxylamine in refluxing toluene produced phthalimide (II). Catalytic transfer hydrogenation employing cyclohexene in the presence of Pd/C yielded 4-amino-N-hydroxyphthalimide (III), which was condensed with ethanesulfonyl chloride to give sulfonate (IV). Finally, acylation with acid chloride (V) furnished the title compound.
| 【1】 Kerrigan, J.E.; et al.; 6-Acylamino-2-[(alkylsulfonyl)oxy]-1H-isoindole-1,3-dione mechanism-based inhibitors of human leukocyte elastase. Bioorg Med Chem Lett 2000, 10, 1, 27. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 14640 | O-benzylhydroxylamine; 1-[(aminooxy)methyl]benzene | 622-33-3 | C7H9NO | 详情 | 详情 | |
| (I) | 31028 | 5-nitro-2-benzofuran-1,3-dione | 5466-84-2 | C8H3NO5 | 详情 | 详情 |
| (II) | 38147 | 2-(benzyloxy)-5-nitro-1H-isoindole-1,3(2H)-dione | C15H10N2O5 | 详情 | 详情 | |
| (III) | 38148 | 5-amino-2-hydroxy-1H-isoindole-1,3(2H)-dione | C8H6N2O3 | 详情 | 详情 | |
| (IV) | 38149 | 5-amino-2-[(ethylsulfonyl)oxy]-1H-isoindole-1,3(2H)-dione | C10H10N2O5S | 详情 | 详情 | |
| (V) | 20650 | methyl 5-chloro-5-oxopentanoate; methyl-4-chloroformylbutyrate | 1501-26-4 | C6H9ClO3 | 详情 | 详情 |
合成路线22
该中间体在本合成路线中的序号：(IV)Claisen reaction between ethyl caproate (I) and ethyl formate (II) in the presence of NaOEt affords formyl derivative (III), which is then condensed with O-benzyl hydroxylamine hydrochloride (IV) by means of NaOAc in EtOH/H2O to yield derivative (V). Hydrolysis of the ethyl ester moiety of (V) by treatment with aqueous NaOH in MeOH provides carboxylic acid (VI), which is coupled to tert-leucine N,N-dimethylamide (VII) by means of EDC and HOAt to furnish compound (VIII). Reduction of the oxime moiety of (VIII) with NaCNBH3 in HOAc affords a mixture of diastereoisomers from which (R)-(IX) is separated by flash chromatography. Finally, treatment of (R)-(IX) with N-formyl-benzotriazole (HCOBt) in THF provides formamide (X), whose benzyl group is then removed by hydrogenation over Pd/C in MeOH.
| 【1】 Spavold, Z.M.; Launchbury, S.; Clements, J.M.; Hunter, M.G.; Davies, S.J.; Pratt, L.M.; Beckett, R.P.; Whittaker, M. (British Biotech Pharmaceuticals Ltd.); Antibacterial agents. WO 9939704 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIIIa) | 45887 | (2R)-2-[[(benzyloxy)imino]methyl]-N-[(1S)-1-[(dimethylamino)carbonyl]-2,2-dimethylpropyl]hexanamide | C22H35N3O3 | 详情 | 详情 | |
| (VIIIb) | 45890 | (2S)-2-[[(benzyloxy)imino]methyl]-N-[(1S)-1-[(dimethylamino)carbonyl]-2,2-dimethylpropyl]hexanamide | C22H35N3O3 | 详情 | 详情 | |
| (I) | 51702 | Ethyl caproate; Ethyl n-Caproate; Caproic acid ethyl ester; n-Caproic acid ethylester; Capronic Ether; Isoamyl acetate; Hexanoic acid ethyl ester; Ethyl hexanoate | 123-66-0 | C8H16O2 | 详情 | 详情 |
| (II) | 16602 | ethyl formate | 109-94-4 | C3H6O2 | 详情 | 详情 |
| (III) | 45886 | (2S)-2-amino-N,N,3,3-tetramethylbutanamide | C8H18N2O | 详情 | 详情 | |
| (IV) | 14640 | O-benzylhydroxylamine; 1-[(aminooxy)methyl]benzene | 622-33-3 | C7H9NO | 详情 | 详情 |
| (V) | 45884 | ethyl 2-[[(benzyloxy)imino]methyl]hexanoate | C16H23NO3 | 详情 | 详情 | |
| (VI) | 45885 | 2-[[(benzyloxy)imino]methyl]hexanoic acid | C14H19NO3 | 详情 | 详情 | |
| (VII) | 45886 | (2S)-2-amino-N,N,3,3-tetramethylbutanamide | C8H18N2O | 详情 | 详情 | |
| (IX) | 45888 | (2R)-2-[[(benzyloxy)amino]methyl]-N-[(1S)-1-[(dimethylamino)carbonyl]-2,2-dimethylpropyl]hexanamide | C22H37N3O3 | 详情 | 详情 | |
| (X) | 45889 | (2R)-2-[[(benzyloxy)(formyl)amino]methyl]-N-[(1S)-1-[(dimethylamino)carbonyl]-2,2-dimethylpropyl]hexanamide | C23H37N3O4 | 详情 | 详情 |
合成路线23
该中间体在本合成路线中的序号：(XVII)Alternatively, compound (R)-(IX) can be obtained as follows: treatment of butylmalonic acid (XI) with formaldehyde (XII) in ethanol in the presence of piperidine provides 2-butyl acrylic acid (XIII), which is converted into oxazolidinone derivative (XVI) by first reaction with pivaloyl chloride (XIV) and Et3N in THF followed by treatment with derivative (XV) and BuLi in THF. Oxazolidinone (XVI) is then enantioselectively condensed with O-benzylhydroxylamine (XVII) and treated with p-TsOH to afford a single diastereoisomer (XVIII), which is then hydrolyzed with LiOH in THF to yield (XIX). Finally, hexanoic acid (XIX) is coupled to tert-Leucine-N,N-dimethylamide (VII) by means of EDC and HOBt in DMF.
| 【1】 Spavold, Z.M.; Launchbury, S.; Clements, J.M.; Hunter, M.G.; Davies, S.J.; Pratt, L.M.; Beckett, R.P.; Whittaker, M. (British Biotech Pharmaceuticals Ltd.); Antibacterial agents. WO 9939704 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VII) | 45886 | (2S)-2-amino-N,N,3,3-tetramethylbutanamide | C8H18N2O | 详情 | 详情 | |
| (IX) | 45888 | (2R)-2-[[(benzyloxy)amino]methyl]-N-[(1S)-1-[(dimethylamino)carbonyl]-2,2-dimethylpropyl]hexanamide | C22H37N3O3 | 详情 | 详情 | |
| (XI) | 45891 | 2-butylmalonic acid | 534-59-8 | C7H12O4 | 详情 | 详情 |
| (XII) | 22075 | Formaldehyde; Paraformaldehyde | 1118-66-7 | CH2O | 详情 | 详情 |
| (XIII) | 45892 | 2-[(ethylsulfanyl)methyl]acrylic acid | C6H10O2S | 详情 | 详情 | |
| (XIV) | 13597 | 2,2-Dimethylpropanoyl chloride; Pivaloyl chloride | 3282-30-2 | C5H9ClO | 详情 | 详情 |
| (XV) | 45893 | (4S)-4-benzyl-5,5-dimethyl-1,3-oxazolidin-2-one | C12H15NO2 | 详情 | 详情 | |
| (XVI) | 45894 | (4S)-4-benzyl-3-[2-[(ethylsulfanyl)methyl]acryloyl]-5,5-dimethyl-1,3-oxazolidin-2-one | C18H23NO3S | 详情 | 详情 | |
| (XVII) | 14640 | O-benzylhydroxylamine; 1-[(aminooxy)methyl]benzene | 622-33-3 | C7H9NO | 详情 | 详情 |
| (XVIII) | 45895 | (4S)-4-benzyl-3-[(2R)-3-[(benzyloxy)amino]-2-[(ethylsulfanyl)methyl]propanoyl]-5,5-dimethyl-1,3-oxazolidin-2-one | C25H32N2O4S | 详情 | 详情 | |
| (XIX) | 45897 | 3-[4-[2-(benzyloxy)ethoxy]phenyl]-2-ethoxypropanamide | C20H25NO4 | 详情 | 详情 |
合成路线24
该中间体在本合成路线中的序号：(V)The reaction of 2-butylmalonic acid (I) with piperidine and formaldehyde in refluxing ethanol gives 2-methylenehexanoic acid (II), which is condensed with the chiral auxiliary oxazolidine lithium salt (III) by means of pivaloyl chloride and TEA to yield the oxazolidide (IV). The addition of O-benzylhydroxylamine (V) to (IV) by means of Ts-OH proceeds with great stereospecificity, affording tosylate (VI), which is submitted to cleavage of the chiral auxiliary with LiOH in aqueous THF to provide the carboxylic acid (VII). The formylation of the benzylhydroxylamine group of (VII) with HCOO-Ac in THF gives the formamide (VIII), which is condensed with L-tert-leucine dimethylamide (IX) by means of HOAt and EDC in DMF to yield the pseudo dipeptide (X). Finally, this compound is debenzylated by hydrogenation with H2 over Pd/C in ethanol.
| 【1】 Pratt, L.M.; et al.; Asymmetric synthesis of BB-3497 - A potent peptide deformylase inhibitor. Bioorg Med Chem Lett 2001, 11, 19, 2585. |
| 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) | 45891 | 2-butylmalonic acid | 534-59-8 | C7H12O4 | 详情 | 详情 |
| (II) | 51559 | 2-butylacrylic acid | C7H12O2 | 详情 | 详情 | |
| (III) | 51560 | [(4S)-4-benzyl-5,5-dimethyl-2-oxo-1,3-oxazolidin-3-yl]lithium | C12H14LiNO2 | 详情 | 详情 | |
| (IV) | 51561 | (4S)-4-benzyl-3-(2-butylacryloyl)-5,5-dimethyl-1,3-oxazolidin-2-one | C19H25NO3 | 详情 | 详情 | |
| (V) | 14640 | O-benzylhydroxylamine; 1-[(aminooxy)methyl]benzene | 622-33-3 | C7H9NO | 详情 | 详情 |
| (VI) | 51562 | (2R)-2-[[(4S)-4-benzyl-5,5-dimethyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl]-N-(benzyloxy)-1-hexanaminium 4-methylbenzenesulfonate | C33H42N2O7S | 详情 | 详情 | |
| (VII) | 51563 | (2R)-2-[[(benzyloxy)amino]methyl]hexanoic acid | C14H21NO3 | 详情 | 详情 | |
| (VIII) | 51564 | (2R)-2-[[(benzyloxy)(formyl)amino]methyl]hexanoic acid | C15H21NO4 | 详情 | 详情 | |
| (IX) | 45886 | (2S)-2-amino-N,N,3,3-tetramethylbutanamide | C8H18N2O | 详情 | 详情 | |
| (X) | 45889 | (2R)-2-[[(benzyloxy)(formyl)amino]methyl]-N-[(1S)-1-[(dimethylamino)carbonyl]-2,2-dimethylpropyl]hexanamide | C23H37N3O4 | 详情 | 详情 |