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【结 构 式】 
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【分子编号】25395 【品名】(2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-hydroxyphenyl)propionic acid 【CA登记号】3978-80-1 |
【 分 子 式 】C14H19NO5 【 分 子 量 】281.3086 【元素组成】C 59.78% H 6.81% N 4.98% O 28.44% |
合成路线1
该中间体在本合成路线中的序号：(X)4-Methylvaleric acid (I) was converted to acid chloride (II) and then condensed with (S)-4-benzyl-2-oxazolidinone (III) to give (IV). Subsequent alkylation of (IV) with tert-butyl bromoacetate (V) in the presence of sodium bis(trimethylsilyl)amide produced the chiral intermediate (VI), which was hydrolyzed with lithium peroxide to yield (R)-2-isobutylsuccinic acid 4-tert-butyl ester (VII). Further alkylation of (VII) with 4-bromo-1-butene (VIII) afforded a 6:1 mixture of syn/anti isobutenyl compounds (IX), which upon isomerization with LDA in THF at -20 C, followed by quenching with MeOH, provided a 1:1.5 mixture of isomers. Condensation of N-Boc-L-tyrosine (X) with methylamine in the presence of EDC and HOBt gave amide (XI). Then, removal of the Boc protecting group with HCl in dioxan yielded tyrosinamide (XII). This was coupled to succinic acid derivative (IX) using EDC and HOBt to afford the corresponding amide (XIII) as an epimeric mixture. Hydroboration of the butenyl double bond, followed by oxidative treatment with H2O2 produced alcohol (XIV).
| 【1】 Sheppard, G.S.; Guo, Y.; Siummers, J.B.; Holms, J.H.; Steinman, D.H.; Michaelides, M.R.; Florjancic, A.S.; Xu, L.; Davidsen, S.K. (Abbott Laboratories Inc.); Macrocyclic inhibitors of matrix metalloproteinases and TNFalpha secretion. EP 1021423; WO 9830551 . |
| 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) | 25389 | 4-methylpentanoic acid | 646-07-1 | C6H12O2 | 详情 | 详情 |
| (II) | 25390 | 4-methylpentanoyl chloride | 38136-29-7 | C6H11ClO | 详情 | 详情 |
| (III) | 25351 | (4R)-4-benzyl-1,3-oxazolidin-2-one; (R)-(+)-4-benzyl-2-oxazolidinone | 102029-44-7 | C10H11NO2 | 详情 | 详情 |
| (IV) | 25391 | (4S)-4-benzyl-3-(4-methylpentanoyl)-1,3-oxazolidin-2-one | C16H21NO3 | 详情 | 详情 | |
| (V) | 17430 | 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate | 5292-43-3 | C6H11BrO2 | 详情 | 详情 |
| (VI) | 25392 | tert-butyl (3R)-3-[[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl]-5-methylhexanoate | C22H31NO5 | 详情 | 详情 | |
| (VII) | 25393 | (2R)-2-[2-(tert-butoxy)-2-oxoethyl]-4-methylpentanoic acid | C12H22O4 | 详情 | 详情 | |
| (VIII) | 11720 | 4-Bromo-1-butene | 5162-44-7 | C4H7Br | 详情 | 详情 |
| (IX) | 25394 | (2R)-3-(tert-butoxycarbonyl)-2-isobutyl-6-heptenoic acid | C16H28O4 | 详情 | 详情 | |
| (X) | 25395 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-hydroxyphenyl)propionic acid | 3978-80-1 | C14H19NO5 | 详情 | 详情 |
| (XI) | 25396 | tert-butyl (1S)-1-(4-hydroxybenzyl)-2-(methylamino)-2-oxoethylcarbamate | C15H22N2O4 | 详情 | 详情 | |
| (XII) | 25397 | (2S)-2-amino-3-(4-hydroxyphenyl)-N-methylpropanamide | C10H14N2O2 | 详情 | 详情 | |
| (XIII) | 25398 | tert-butyl 2-[(1R)-1-([[(1S)-1-(4-hydroxybenzyl)-2-(methylamino)-2-oxoethyl]amino]carbonyl)-3-methylbutyl]-5-hexenoate | C26H40N2O5 | 详情 | 详情 | |
| (XIV) | 25399 | tert-butyl (3R)-3-([[(1S)-1-(4-hydroxybenzyl)-2-(methylamino)-2-oxoethyl]amino]carbonyl)-2-(4-hydroxybutyl)-5-methylhexanoate | C26H42N2O6 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)The cyclization of methyl 4-bromo-3-oxopentanoate (I) with benzamide (II) and sodium hydrogen phosphate in refluxing ethanol gives methyl 2-(5-methyl-2-phenyloxazol-4-yl)acetate (III), which is reduced with LiAlH4 in THF to yield the ethanol derivative (IV). The reaction of (IV) with methanesulfonyl chloride and TEA in dichloromethane affords the mesylate (V), which is condensed with N-(tert-butoxycarbonyl)-L-tyrosine (VI) by means of NaOH in hot DMSO/water to provide the 4-O-substituted tyrosine (VII), which is deprotected by means of HCl in dioxane to give intermediate (VIII) with a free amino group. Finally, this compound is condensed with benzoylacetone (IX) by means of trimethyl orthoformate in refluxing methanol to afford the target N-substituted tyrosine derivative.
| 【1】 Oplinger, J.A.; Dezube, M.; Willson, T.M.; Collins, J.L. (Glaxo Group Ltd.); Substd. oxazoles and thiazoles derivs. as hPPAR gamma and hPPAR alpha activators. EP 1102757; WO 0008002 . |
| 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) | 49397 | methyl 4-bromo-3-oxopentanoate | C6H9BrO3 | 详情 | 详情 | |
| (II) | 40592 | Benzamide | 55-21-0 | C7H7NO | 详情 | 详情 |
| (III) | 41313 | methyl 2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)acetate | C13H13NO3 | 详情 | 详情 | |
| (IV) | 19874 | 2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)-1-ethanol | C12H13NO2 | 详情 | 详情 | |
| (V) | 41315 | 2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethyl methanesulfonate | C13H15NO4S | 详情 | 详情 | |
| (VI) | 25395 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-hydroxyphenyl)propionic acid | 3978-80-1 | C14H19NO5 | 详情 | 详情 |
| (VII) | 49398 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]propionic acid | C26H30N2O6 | 详情 | 详情 | |
| (VIII) | 49399 | (2S)-2-amino-3-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]propionic acid | C21H22N2O4 | 详情 | 详情 | |
| (IX) | 23829 | 1-phenyl-1,3-butanedione | 93-91-4 | C10H10O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IX)Alkylation of cyclopentane carboxylic acid ethyl ester (I) by treatment with dibromoethane (II) in the presence of BuLi in THF affords derivative (III), which is then converted into azide (IV) by first hydrolysis of ethyl ester with NaOH in dioxane, followed by reaction with NaN3 in DMF. Coupling of (IV) with protected cysteines (V) and (VI) by means of HBTU yields compound (VII), which is then subjected to simultaneous Trt removal and oxidation by means of iodine in CHCl3/MeOH to provide cystine derivative (VIII). Acid deprotection of (VIII), followed by coupling to protected tyrosine (IX) and final deprotection of the resulting compound, furnishes the desired cyclic cystine compound. Alternatively, (VII) can be first subjected to acid deprotection to allow next coupling with protected tyrosine (IX), furnishing derivative (X), which is finally oxidized with iodine in CHCl3/MeOH and further deprotected to afford the target cyclic cystine derivative.
| 【1】 Cook, C.; Kaplan, G.; Fry, D.; Tilley, J.W.; Wolitzky, B.; Hanglow, A.; Joshi, P.; Rowan, K.; Schwinge, V.; Fotouhi, N.; The design and synthesis of potent cyclic peptide VCAM-VLA-4 antagonists incorporating an achiral Asp-Pro mimetic. Bioorg Med Chem Lett 2000, 10, 11, 1171. |
| 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) | 46208 | ethyl cyclopentanecarboxylate | C8H14O2 | 详情 | 详情 | |
| (II) | 10252 | 1,2-Dibromoethane; Ethylene dibromide | 106-93-4 | C2H4Br2 | 详情 | 详情 |
| (III) | 46209 | ethyl 1-(2-bromoethyl)cyclopentanecarboxylate | C10H17BrO2 | 详情 | 详情 | |
| (IV) | 46210 | 1-(2-azidoethyl)cyclopentanecarboxylic acid | C8H13N3O2 | 详情 | 详情 | |
| (V) | 38971 | (5R)-5-benzyl-2-pyrrolidinone | C11H13NO | 详情 | 详情 | |
| (VI) | 46211 | tert-butyl (2R)-2-amino-3-(tritylsulfanyl)propanoate | C26H29NO2S | 详情 | 详情 | |
| (VII) | 46212 | tert-butyl (2R)-2-([[1-(2-[[(2R)-2-[(tert-butoxycarbonyl)amino]-3-(tritylsulfanyl)propanoyl]amino]ethyl)cyclopentyl]carbonyl]amino)-3-(tritylsulfanyl)propanoate | C61H69N3O6S2 | 详情 | 详情 | |
| (VIII) | 46213 | tert-butyl (8R,13R)-13-[(tert-butoxycarbonyl)amino]-6,14-dioxo-10,11-dithia-7,15-diazaspiro[4.12]heptadecane-8-carboxylate | C23H39N3O6S2 | 详情 | 详情 | |
| (IX) | 25395 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-hydroxyphenyl)propionic acid | 3978-80-1 | C14H19NO5 | 详情 | 详情 |
| (X) | 46214 | tert-butyl (2R)-2-[[(1-[(5R,8S)-8-(4-hydroxybenzyl)-12,12-dimethyl-4,7,10-trioxo-5-[(tritylsulfanyl)methyl]-11-oxa-3,6,9-triazatridec-1-yl]cyclopentyl)carbonyl]amino]-3-(tritylsulfanyl)propanoate | C70H78N4O8S2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(V)Coupling on N-Boc-L-valine (I) with 3-bromopropylamine (II) by means of HBTU afforded amide (III). After Boc group cleavage in (III) using trifluoroacetic acid, the resultant amine (IV) was coupled with N-Boc-L-tyrosine (V) to yield the dipeptide amide (VI). Intramolecular cyclization of (VI) to produce the macrocycle (VII) was achieved by treatment with cesium carbonate in the presence of tetrabutylammonium iodide. Subsequent acid cleavage of the Boc protecting group of (VII) furnished the intermediate amine (VIII).
| 【1】 Mak, C.C.; Le, V.-D.; Wong, C.-H.; Elder, J.H.; Lin, Y.-C.; Design, synthesis, and biological evaluation of HIV/FIV protease inhibitors incorporating a conformationally constrained macrocycle with a small P3' residue. Bioorg Med Chem Lett 2001, 11, 2, 219. |
| 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) | 19733 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid | C10H19NO4 | 详情 | 详情 | |
| (II) | 25449 | 3-bromo-1-propanamine; 3-bromopropylamine | 18370-81-5 | C3H8BrN | 详情 | 详情 |
| (III) | 47889 | tert-butyl (1S)-1-[[(3-bromopropyl)amino]carbonyl]-2-methylpropylcarbamate | C13H25BrN2O3 | 详情 | 详情 | |
| (IV) | 47890 | (2S)-2-amino-N-(3-bromopropyl)-3-methylbutanamide | C8H17BrN2O | 详情 | 详情 | |
| (V) | 25395 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-hydroxyphenyl)propionic acid | 3978-80-1 | C14H19NO5 | 详情 | 详情 |
| (VI) | 47891 | tert-butyl (1S)-2-[((1S)-1-[[(3-bromopropyl)amino]carbonyl]-2-methylpropyl)amino]-1-(4-hydroxybenzyl)-2-oxoethylcarbamate | C22H34BrN3O5 | 详情 | 详情 | |
| (VII) | 47892 | tert-butyl (8S,11S)-8-isopropyl-7,10-dioxo-2-oxa-6,9-diazabicyclo[11.2.2]heptadeca-1(15),13,16-trien-11-ylcarbamate | C22H33N3O5 | 详情 | 详情 | |
| (VIII) | 47893 | (8S,11S)-11-amino-8-isopropyl-2-oxa-6,9-diazabicyclo[11.2.2]heptadeca-1(15),13,16-triene-7,10-dione | C17H25N3O3 | 详情 | 详情 |