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【结 构 式】 
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【分子编号】27058 【品名】tert-butyl (1S)-1-formyl-3-methylbutylcarbamate 【CA登记号】 |
【 分 子 式 】C11H21NO3 【 分 子 量 】215.29268 【元素组成】C 61.37% H 9.83% N 6.51% O 22.29% |
合成路线1
该中间体在本合成路线中的序号：(I)The condensation of tert-butoxycarbonyl-L-leucinal (I) with 1-benzylimidazole (II) by means of BuLi in THF gives 1-benzyl-2-[2(S)-(tert-butoxycarbonylamino)-1-hydroxy-4-methylpentyl]imidazole (III), which is hydrolyzed with HCl in dioxane yielding 2-(2(S)-amino)-1-hydroxy-4-methylpentyl]-2-benzylimidazole (IV). The condensation of (IV) with tert-butoxycarbonyl-L-leucine (V) by means of dicyclohexylcarbodiimide (DCC) and hydroxybenzotriazole (HOBT) in TFA/dichloromethane affords the protected seudo-dipeptide (VI), which is debenzylated with H2 over Pd/C giving the expected seudo-peptide (VII): Finally, this compound is oxidizad with the Dess-Martin oxidant.
| 【1】 Tao, M.; et al.; Inhibition of calpain by peptidyl heterocycles. Bioorg Med Chem Lett 1996, 6, 24, 3009. |
| 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) | 27058 | tert-butyl (1S)-1-formyl-3-methylbutylcarbamate | C11H21NO3 | 详情 | 详情 | |
| (II) | 27059 | 1-benzyl-1H-imidazole | 4238-71-5 | C10H10N2 | 详情 | 详情 |
| (III) | 27060 | tert-butyl (1S)-1-[(1-benzyl-1H-imidazol-2-yl)(hydroxy)methyl]-3-methylbutylcarbamate | C21H31N3O3 | 详情 | 详情 | |
| (IV) | 27061 | (2S)-2-amino-1-(1-benzyl-1H-imidazol-2-yl)-4-methyl-1-pentanol | C16H23N3O | 详情 | 详情 | |
| (V) | 23663 | (2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid；N-Boc-L-leucine | C11H21NO4 | 详情 | 详情 | |
| (VI) | 27062 | tert-butyl (1S)-1-[([(1S)-1-[(1-benzyl-1H-imidazol-2-yl)(hydroxy)methyl]-3-methylbutyl]amino)carbonyl]-3-methylbutylcarbamate | C27H42N4O4 | 详情 | 详情 | |
| (VII) | 27063 | tert-butyl (1S)-1-[([(1S)-1-[hydroxy(1H-imidazol-2-yl)methyl]-3-methylbutyl]amino)carbonyl]-3-methylbutylcarbamate | C20H36N4O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VII)Synthesis of the second synthon: L-Leucinol (V) was converted into the protected derivative (VI) by treatment with tert-butoxycarbonyl anhydride in methylene chloride. Oxidation of compound (VI) with NaOCl and TEMPO in the presence of sodium bromide yielded the aldehyde (VII). This aldehyde (VII), when treated with sodium bisulfite overnight at -5 to 0 C, produced the sodium bisulfite salt derivative (VIII), which was treated with KCN to obtain the nitrile derivative (IX). This nitrile derivative (IX) was heated under reflux with concentrated HCl, and after several crystallizations, afforded the desired amino acid (2R,3S)-3-amino-2-hydroxy-5-methylhexanoic acid (X). Amino acid (X) was dissolved in a mixture of water/dioxane and then treated with tert-butoxycarbonyl anhydride in the presence of TEA to yield the Boc derivative (XI), which was converted into the mixture of methyl esters (XII) in a conventional manner. Compound (XII) was heated with 2,4-dimethoxybenzaldehyde dimethyl acetal in THF in the presence of pyridinium p-toluensulfonate as catalyst to obtain the acetal (XIII). When hydrolyzed with potassium carbonate in aqueous methanol, acetal (XIII) yielded (4S,5R)-3-(tert-butoxycarbonyl)-2-(2,4-dimethoxyphenyl)-4-isobutyloxazolidine-5-carboxylic acid (XIV).
| 【1】 Laccabue, D.; Pratesi, G.; BAY 59-8862. Drugs Fut 2001, 26, 6, 533. |
| 【2】 Ojima, I.; Bombardelli, E. (Affymax Technologies, NV; State University of New York, Albany); Anti-tumor cpds., pharmaceutical compsns., methods for preparation thereof and for treatment. US 5705508 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 47545 | 1-(dimethoxymethyl)-2,4-dimethoxybenzene; 2-(dimethoxymethyl)-5-methoxyphenyl methyl ether | C11H16O4 | 详情 | 详情 | ||
| (V) | 18171 | L-(+)-leucinol; (S)-2-amino-4-methyl-1-pentanol; (2S)-2-amino-4-methyl-1-pentanol | 7533-40-6 | C6H15NO | 详情 | 详情 |
| (VI) | 47540 | BOC-Leucinol; tert-butyl (1S)-1-(hydroxymethyl)-3-methylbutylcarbamate | 82010-31-9 | C11H23NO3 | 详情 | 详情 |
| (VII) | 27058 | tert-butyl (1S)-1-formyl-3-methylbutylcarbamate | C11H21NO3 | 详情 | 详情 | |
| (VIII) | 47541 | sodium (2S)-2-[(tert-butoxycarbonyl)amino]-4-methyl-1-sulfo-1-pentanolate | C11H22NNaO6S | 详情 | 详情 | |
| (IX) | 47542 | tert-butyl (1S)-1-[cyano(hydroxy)methyl]-3-methylbutylcarbamate | C12H22N2O3 | 详情 | 详情 | |
| (X) | 47543 | (2R,3S)-3-amino-2-hydroxy-5-methylhexanoic acid | C7H15NO3 | 详情 | 详情 | |
| (XI) | 47547 | (2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-5-methylhexanoic acid | C12H23NO5 | 详情 | 详情 | |
| (XII) | 47544 | methyl (2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-5-methylhexanoate | C13H25NO5 | 详情 | 详情 | |
| (XIII) | 47546 | 3-(tert-butyl) 5-methyl (4S,5R)-2-(2,4-dimethoxyphenyl)-4-isobutyl-1,3-oxazolidine-3,5-dicarboxylate | C22H33NO7 | 详情 | 详情 | |
| (XIV) | 47538 | (4S,5R)-3-(tert-butoxycarbonyl)-2-(2,4-dimethoxyphenyl)-4-isobutyl-1,3-oxazolidine-5-carboxylic acid | C21H31NO7 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(III)The reaction of N-(tert-butoxycarbonyl)-L-leucine (I) with N,O-dimethylhydroxylamine and HBTU in DMF gives the corresponding methoxyamide (II), which is reduced with LiAlH4 in ethyl ether yielding the aldehyde (III). The reductocondensation of (III) with the piperidine (IV) by means of sodium triacetoxyborohydride in dichloromethane affords the protected adduct (V), which is finally deprotected with TFA in dichloromethane. The intermediate piperidine (IV) has been obtained as follows: The reductocondensation of the piperidinone (VI) with 4-(benzyloxy)aniline (VII) by means of sodium triacetoxyborohydride in dichloromethane gives the secondary amine (VIII), which is alkylated with 3-methyl-2-butenyl bromide (IX) and DIPEA in THF yielding the protected piperidine (IX). Finally, this compound is deprotected with TFA in dichloromethane to afford the target intermediate (IV).
| 【1】 Siebers, K.M.; Hu, L.-Y.; Rafferty, M.F.; et al.; Neuronal N-type calcium channel blocker: Structure-activity relationship of a series of (S)-2-amino-1(4-[(4-benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amino]-piperidin-1-yl)-4-methyl-pentan-1-one analogs. 219th ACS Natl Meet (March 26 2000, San Francisco) 2000, Abst MEDI 259. |
| 【2】 Rafferty, M.F.; Ryder, T.R.; Hu, L.-Y. (Pfizer Inc.); Aniline derivs. as calcium channel blockers. WO 9907689 . |
| 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) | 23663 | (2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid；N-Boc-L-leucine | C11H21NO4 | 详情 | 详情 | |
| (II) | 40395 | tert-butyl (1S)-1-[[methoxy(methyl)amino]carbonyl]-3-methylbutylcarbamate | C13H26N2O4 | 详情 | 详情 | |
| (III) | 27058 | tert-butyl (1S)-1-formyl-3-methylbutylcarbamate | C11H21NO3 | 详情 | 详情 | |
| (IV) | 38232 | N-[4-(benzyloxy)phenyl]-N-(3-methyl-2-butenyl)-N-(4-piperidinyl)amine; N-[4-(benzyloxy)phenyl]-N-(3-methyl-2-butenyl)-4-piperidinamine | C23H30N2O | 详情 | 详情 | |
| (V) | 40394 | tert-butyl (1S)-1-([4-[4-(benzyloxy)(3-methyl-2-butenyl)anilino]-1-piperidinyl]methyl)-3-methylbutylcarbamate | C34H51N3O3 | 详情 | 详情 | |
| (VI) | 18620 | tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone | 79099-07-3 | C10H17NO3 | 详情 | 详情 |
| (VII) | 22460 | 4-(benzyloxy)aniline; 4-(benzyloxy)phenylamine | C13H13NO | 详情 | 详情 | |
| (VIII) | 38230 | tert-butyl 4-[4-(benzyloxy)anilino]-1-piperidinecarboxylate | C23H30N2O3 | 详情 | 详情 | |
| (IX) | 12989 | 4-Bromo-2-methyl-2-butene; 1-Bromo-3-methyl-2-butene | 870-63-3 | C5H9Br | 详情 | 详情 |
| (X) | 38231 | tert-butyl 4-[4-(benzyloxy)(3-methyl-2-butenyl)anilino]-1-piperidinecarboxylate | C28H38N2O3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(III)Boc-Leucine (I) was converted to Weinreb amide (II) by activation with isobutyl chloroformate and N-methylpiperidine, followed by treatment of the resulting mixed anhydride with N,O-dimethylhydroxylamine. Reduction of (II) with LiAlH4 provided the aldehyde (III), which was condensed with the lithium anion of ethyl propiolate (IV) to furnish the acetylenic alcohol (Va-b) as an inseparable mixture of diastereomers. Catalytic hydrogenation of the triple bond of (Va-b) over Pd/BaSO4, followed by acid-catalyzed lactonization of the resulting hydroxy ester provided the diastereomeric mixture of gamma-lactones (VIa-b). After separation by column chromatography, alkylation of the desired isomer employing iodomethane and lithium hexamethyldisilazide at -78 C provided the desired alpha-methyl lactone (VII), along with a small amount of the corresponding epimer. Lactone (VII) hydrolysis using LiOH gave hydroxy acid (VIII), which was further protected as the silyl ether (IX) with tert-butyldimethylsilyl chloride and imidazole. The Boc protecting group of (IX) was selectively removed by treatment with trifluoroacetic acid in CH2Cl2 at 0 C, and the resulting amine (X) was treated with Fmoc-succinimide to provide the Fmoc-protected intermediate (XI).
| 【1】 Lin, X.; Shin, D.; Downs, D.; Tang, J.; Koelsch, G.; Ghosh, A.K.; Ermolieff, J.; Design of potent inhibitors for human brain memapsin 2 (beta-secretase). J Am Chem Soc 2000, 122, 14, 3522. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (Va) | 40625 | ethyl (4R,5S)-5-[(tert-butoxycarbonyl)amino]-4-hydroxy-7-methyl-2-octynoate | C16H27NO5 | 详情 | 详情 | |
| (Vb) | 40626 | ethyl (4S,5S)-5-[(tert-butoxycarbonyl)amino]-4-hydroxy-7-methyl-2-octynoate | C16H27NO5 | 详情 | 详情 | |
| (VIa) | 40627 | tert-butyl (1S)-3-methyl-1-[(2R)-5-oxotetrahydro-2-furanyl]butylcarbamate | C14H25NO4 | 详情 | 详情 | |
| (VIb) | 40628 | tert-butyl (1S)-3-methyl-1-[(2S)-5-oxotetrahydro-2-furanyl]butylcarbamate | C14H25NO4 | 详情 | 详情 | |
| (I) | 23663 | (2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid；N-Boc-L-leucine | C11H21NO4 | 详情 | 详情 | |
| (II) | 40395 | tert-butyl (1S)-1-[[methoxy(methyl)amino]carbonyl]-3-methylbutylcarbamate | C13H26N2O4 | 详情 | 详情 | |
| (III) | 27058 | tert-butyl (1S)-1-formyl-3-methylbutylcarbamate | C11H21NO3 | 详情 | 详情 | |
| (IV) | 35333 | ethyl propiolate | 623-47-2 | C5H6O2 | 详情 | 详情 |
| (VII) | 40629 | tert-butyl (1S)-3-methyl-1-[(2S,4R)-4-methyl-5-oxotetrahydro-2-furanyl]butylcarbamate | C15H27NO4 | 详情 | 详情 | |
| (VIII) | 40630 | (2R,4S,5S)-5-[(tert-butoxycarbonyl)amino]-4-hydroxy-2,7-dimethyloctanoic acid | C15H29NO5 | 详情 | 详情 | |
| (IX) | 40631 | (2R,4S,5S)-5-[(tert-butoxycarbonyl)amino]-4-[[tert-butyl(dimethyl)silyl]oxy]-2,7-dimethyloctanoic acid | C21H43NO5Si | 详情 | 详情 | |
| (X) | 40632 | (2R,4S,5S)-5-amino-4-[[tert-butyl(dimethyl)silyl]oxy]-2,7-dimethyloctanoic acid | C16H35NO3Si | 详情 | 详情 | |
| (XI) | 40633 | (2R,4S,5S)-4-[[tert-butyl(dimethyl)silyl]oxy]-5-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-2,7-dimethyloctanoic acid | C31H45NO5Si | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(III)Boc-Leucine (I) was converted to Weinreb amide (II) by activation with isobutyl chloroformate and N-methylpiperidine, followed by treatment of the resulting mixed anhydride with N,O-dimethylhydroxylamine. Reduction of (II) with LiAlH4 provided the aldehyde (III), which was condensed with the lithium anion of ethyl propiolate (IV) to furnish the acetylenic alcohol (Va-b) as an inseparable mixture of diastereomers. Catalytic hydrogenation of the triple bond of (Va-b) over Pd/BaSO4, followed by acid-catalyzed lactonization of the resulting hydroxy ester provided the diastereomeric mixture of gamma-lactones (VIa-b). After separation by column chromatography, alkylation of the desired isomer employing iodomethane and lithium hexamethyldisilazide at -78 C provided the desired alpha-methyl lactone (VII), along with a small amount of the corresponding epimer. Lactone (VII) hydrolysis using LiOH gave hydroxy acid (VIII), which was further protected as the silyl ether (IX) with tert-butyldimethylsilyl chloride and imidazole. The Boc protecting group of (IX) was selectively removed by treatment with trifluoroacetic acid in CH2Cl2 at 0 C, and the resulting amine (X) was treated with Fmoc-succinimide to provide the Fmoc-protected intermediate (XI).
| 【1】 Lin, X.; Shin, D.; Downs, D.; Tang, J.; Koelsch, G.; Ghosh, A.K.; Ermolieff, J.; Design of potent inhibitors for human brain memapsin 2 (beta-secretase). J Am Chem Soc 2000, 122, 14, 3522. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (Va) | 40625 | ethyl (4R,5S)-5-[(tert-butoxycarbonyl)amino]-4-hydroxy-7-methyl-2-octynoate | C16H27NO5 | 详情 | 详情 | |
| (Vb) | 40626 | ethyl (4S,5S)-5-[(tert-butoxycarbonyl)amino]-4-hydroxy-7-methyl-2-octynoate | C16H27NO5 | 详情 | 详情 | |
| (VIa) | 40627 | tert-butyl (1S)-3-methyl-1-[(2R)-5-oxotetrahydro-2-furanyl]butylcarbamate | C14H25NO4 | 详情 | 详情 | |
| (VIb) | 40628 | tert-butyl (1S)-3-methyl-1-[(2S)-5-oxotetrahydro-2-furanyl]butylcarbamate | C14H25NO4 | 详情 | 详情 | |
| (I) | 23663 | (2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid；N-Boc-L-leucine | C11H21NO4 | 详情 | 详情 | |
| (II) | 40395 | tert-butyl (1S)-1-[[methoxy(methyl)amino]carbonyl]-3-methylbutylcarbamate | C13H26N2O4 | 详情 | 详情 | |
| (III) | 27058 | tert-butyl (1S)-1-formyl-3-methylbutylcarbamate | C11H21NO3 | 详情 | 详情 | |
| (IV) | 35333 | ethyl propiolate | 623-47-2 | C5H6O2 | 详情 | 详情 |
| (VII) | 40629 | tert-butyl (1S)-3-methyl-1-[(2S,4R)-4-methyl-5-oxotetrahydro-2-furanyl]butylcarbamate | C15H27NO4 | 详情 | 详情 | |
| (VIII) | 40630 | (2R,4S,5S)-5-[(tert-butoxycarbonyl)amino]-4-hydroxy-2,7-dimethyloctanoic acid | C15H29NO5 | 详情 | 详情 | |
| (IX) | 40631 | (2R,4S,5S)-5-[(tert-butoxycarbonyl)amino]-4-[[tert-butyl(dimethyl)silyl]oxy]-2,7-dimethyloctanoic acid | C21H43NO5Si | 详情 | 详情 | |
| (X) | 40632 | (2R,4S,5S)-5-amino-4-[[tert-butyl(dimethyl)silyl]oxy]-2,7-dimethyloctanoic acid | C16H35NO3Si | 详情 | 详情 | |
| (XI) | 40633 | (2R,4S,5S)-4-[[tert-butyl(dimethyl)silyl]oxy]-5-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-2,7-dimethyloctanoic acid | C31H45NO5Si | 详情 | 详情 |