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【结 构 式】 
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【分子编号】27154 【品名】(2S)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-methylbutyric acid 【CA登记号】45170-31-8 |
【 分 子 式 】C11H21NO4 【 分 子 量 】231.29208 【元素组成】C 57.12% H 9.15% N 6.06% O 27.67% |
合成路线1
该中间体在本合成路线中的序号：(XV)The reaction of (XIII) with HCl in dioxane eliminates the carbamate protecting group giving (XIV) with a free amino group, which is condensed with N-(tert-butoxycarbonyl)-N-methyl-L-valine (XV) by means of NMM and TBTU in dichloromethane to provide the intermediate (XVI) with four amide groups. Elimination of the ter-butyl carbamate group of (XVI) with HCl in dioxane affords compound (XVII) with a reactive methylamino group, which is finally condensed with 3-cyclohexyl-2(R)-methylpropionyl chloride (XVIII) by means of NMM in dichloromethane to afford the target compound.
| 【1】 Gauthier, J.-A.; Moss, N. (Bio-Mega, Inc.; Boehringer Ingelheim GmbH); Herpes ribonucleotide reductase inhibitors. EP 0837845; JP 1999508246; US 5672586; WO 9700855 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIII) | 27152 | benzyl 1-((1S)-1-[[(2R,5S)-5-[(tert-butoxycarbonyl)amino]-2-(3,3-dimethyl-2-oxobutyl)-6,6-dimethyl-4-oxoheptanoyl]amino]-2-[[(1R)-1-ethyl-2,2-dimethylpropyl]amino]-2-oxoethyl)cyclopentanecarboxylate | C42H67N3O8 | 详情 | 详情 | |
| (XIV) | 27153 | benzyl 1-((1S)-1-[[(2R,5S)-5-amino-2-(3,3-dimethyl-2-oxobutyl)-6,6-dimethyl-4-oxoheptanoyl]amino]-2-[[(1R)-1-ethyl-2,2-dimethylpropyl]amino]-2-oxoethyl)cyclopentanecarboxylate | C37H59N3O6 | 详情 | 详情 | |
| (XV) | 27154 | (2S)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-methylbutyric acid | 45170-31-8 | C11H21NO4 | 详情 | 详情 |
| (XVI) | 27155 | benzyl 1-[(1S,4R,7S,10S)-7-(tert-butyl)-4-(3,3-dimethyl-2-oxobutyl)-1-([[(1R)-1-ethyl-2,2-dimethylpropyl]amino]carbonyl)-10-isopropyl-11,14,14-trimethyl-3,6,9,12-tetraoxo-13-oxa-2,8,11-triazapentadec-1-yl]cyclopentanecarboxylate | C48H78N4O9 | 详情 | 详情 | |
| (XVII) | 27156 | 1-((1S)-1-[((2R,5S)-2-(3,3-dimethyl-2-oxobutyl)-6,6-dimethyl-5-[[(2S)-3-methyl-2-(methylamino)butanoyl]amino]-4-oxoheptanoyl)amino]-2-[[(1R)-1-ethyl-2,2-dimethylpropyl]amino]-2-oxoethyl)cyclopentanecarboxylic acid | C36H64N4O7 | 详情 | 详情 | |
| (XVIII) | 27157 | (2R)-3-cyclohexyl-2-methylpropanoyl chloride | C10H17ClO | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I),(II)Cilengitide is synthesized using solid-phase Merrifield-type methods by sequentially adding N-Boc-N-Me-L-Val (I), N-Boc-D-Phe (III), N-Boc-4-O-t-Bu-L-Asp (V), N-Boc-Gly (VII) and Nalpha-Fmoc-Nomega-Mtr-L-Arg (IX) in a stepwise manner to a 4-hydroxymethylphenoxymethyl-polystyrene resin (Wang type resin), yielding peptide-resin intermediates (II), (IV), (VI), (VIII) and (X), respectively. Elimination of the resin from the peptide chain with a 1:1 mixture of TFA/dichloromethane results in the linear peptide (XI), which is then deprotected at the amino-terminal group by removing the Fmoc group with a 1:1 mixture of piperidine/DMF, to give peptide (XII).
| 【1】 Graul, A.; Sorbera, L.A.; Castañer, J.; Cilengitide. Drugs Fut 2000, 25, 7, 674. |
| 【2】 Jonczyk, A.; Goodman, S.; Diefenbach, B.; Sutter, A.; Holzmann, G.; Kessler, H.; Dechantsreiter, M. (Merck Patent GmbH); Cyclic adhesion inhibitors. DE 19534177; EP 0770622; JP 1997132593; US 6001961 . |
| 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),(II) | 27154 | (2S)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-methylbutyric acid | 45170-31-8 | C11H21NO4 | 详情 | 详情 |
| (X),(XI) | 37627 | (8S,14S,17R,20S)-17-benzyl-14-[2-(tert-butoxy)-2-oxoethyl]-8-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-3-imino-20-isopropyl-1-(4-methoxyphenyl)-19-methyl-9,12,15,18-tetraoxo-1,1-diphenyl-2,4,10,13,16,19-hexaazahenicosan-21-oic acid | C66H76N8O11 | 详情 | 详情 | |
| (III) | 22184 | (2R)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropionic acid | C14H19NO4 | 详情 | 详情 | |
| (IV) | 37622 | (2S)-2-[[(2R)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl](methyl)amino]-3-methylbutyric acid | C20H30N2O5 | 详情 | 详情 | |
| (V) | 37623 | (2S)-4-(tert-butoxy)-2-[(tert-butoxycarbonyl)amino]-4-oxobutyric acid | C13H23NO6 | 详情 | 详情 | |
| (VI) | 37624 | (6S,9R,12S)-9-benzyl-6-[2-(tert-butoxy)-2-oxoethyl]-12-isopropyl-2,2,11-trimethyl-4,7,10-trioxo-3-oxa-5,8,11-triazatridecan-13-oic acid | C28H43N3O8 | 详情 | 详情 | |
| (VII) | 18066 | N-alpha-t-BOC-glycine; 2-[(tert-butoxycarbonyl)amino]acetic acid | 4530-20-5 | C7H13NO4 | 详情 | 详情 |
| (VIII) | 37625 | (9S,12R,15S)-12-benzyl-9-[2-(tert-butoxy)-2-oxoethyl]-15-isopropyl-2,2,14-trimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazahexadecan-16-oic acid | C30H46N4O9 | 详情 | 详情 | |
| (IX) | 37626 | (2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-5-[(imino[[(4-methoxyphenyl)(diphenyl)methyl]amino]methyl)amino]pentanoic acid | C41H40N4O5 | 详情 | 详情 | |
| (XII) | 37628 | (8S,14S,17R,20S)-8-amino-17-benzyl-14-[2-(tert-butoxy)-2-oxoethyl]-3-imino-20-isopropyl-1-(4-methoxyphenyl)-19-methyl-9,12,15,18-tetraoxo-1,1-diphenyl-2,4,10,13,16,19-hexaazahenicosan-21-oic acid | C51H66N8O9 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XII)N-Boc-N-Methyl-L-valine (XII) was condensed with N,O-dimethylhydroxylamine by means of PyBOP as the coupling reagent. The resultant Weinreb amide (XIII) was then reduced to aldehyde (XIV) using LiAlH4. Wittig condensation of the valinal derivative (XIV) with (carbethoxyethylidene)triphenylphosphorane provided the unsaturated amino ester (XV). The N-Boc protecting group of (XV) was subsequently removed by treatment with trifluoroacetic acid, giving (XVI). Coupling of amino ester (XVI) with N-Boc-tert-leucine (XVII) was carried out via formation of the mixed anhydride of (XVII) with pivaloyl chloride. The resultant N-Boc dipeptide (XVIII) was further deprotected with trifluoroacetic acid, yielding (XIX). Coupling of dipeptide (XIX) with the N-Boc amino acid (IX) provided tripeptide (XX). The title compound was then obtained by sequential deprotection of the ethyl ester and N-Boc groups of (XX) using LiOH and trifluoroacetic acid, respectively.
| 【1】 Roberge, M.; Andersen, R.; Piers, E.; Nieman, J.; Coleman, J. (University of British Columbia); Hemiasterlin analogs. WO 9932509 . |
| 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) | 55118 | (2S)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-methyl-3-phenylbutanoic acid | C17H25NO4 | 详情 | 详情 | |
| (XII) | 27154 | (2S)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-methylbutyric acid | 45170-31-8 | C11H21NO4 | 详情 | 详情 |
| (XIII) | 55119 | tert-butyl (1S)-1-{[methoxy(methyl)amino]carbonyl}-2-methylpropyl(methyl)carbamate | C13H26N2O4 | 详情 | 详情 | |
| (XIV) | 55120 | tert-butyl (1S)-1-formyl-2-methylpropyl(methyl)carbamate | C11H21NO3 | 详情 | 详情 | |
| (XV) | 55121 | ethyl (E,4S)-4-[(tert-butoxycarbonyl)(methyl)amino]-2,5-dimethyl-2-hexenoate | C16H29NO4 | 详情 | 详情 | |
| (XVI) | 55122 | ethyl (E,4S)-2,5-dimethyl-4-(methylamino)-2-hexenoate | C11H21NO2 | 详情 | 详情 | |
| (XVII) | 22251 | (2S)-2-[(tert-butoxycarbonyl)amino]-3,3-dimethylbutyric acid;2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoic acid;N-(tert-butoxycarbonyl)-3-methyl-L-valine | 62965-35-9 | C11H21NO4 | 详情 | 详情 |
| (XVIII) | 55123 | ethyl (E,4S)-4-[{(2S)-2-[(tert-butoxycarbonyl)amino]-3,3-dimethylbutanoyl}(methyl)amino]-2,5-dimethyl-2-hexenoate | C22H40N2O5 | 详情 | 详情 | |
| (XIX) | 55124 | ethyl (E,4S)-4-[[(2S)-2-amino-3,3-dimethylbutanoyl](methyl)amino]-2,5-dimethyl-2-hexenoate | C17H32N2O3 | 详情 | 详情 | |
| (XX) | 55125 | ethyl (6S,9S,12S,13E)-9-(tert-butyl)-12-isopropyl-2,2,5,11,14-pentamethyl-6-(1-methyl-1-phenylethyl)-4,7,10-trioxo-3-oxa-5,8,11-triaza-13-pentadecen-15-oate | C34H55N3O6 | 详情 | 详情 |