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【结 构 式】 
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【分子编号】17953 【品名】tert-butyl (1R)-1-formyl-2-(tritylsulfanyl)ethylcarbamate 【CA登记号】 |
【 分 子 式 】C27H29NO3S 【 分 子 量 】447.5982 【元素组成】C 72.45% H 6.53% N 3.13% O 10.72% S 7.16% |
合成路线1
该中间体在本合成路线中的序号：(VIII)The condensation of 2-bromo-4-nitrotoluene (I) with phenylboronic acid (II) by means of Pd(OAc)2 in aqueous acetone gives the biphenyl (III), which is oxidized with KMnO4 in aqueous pyridine yielding the biphenyl-2-carboxylic acid (IV). The condensation of (IV) with L-methionine methyl ester (V) by means of EDC and HOBT affords the amide (VI), which is reduced with SnCl2 to give the 5-aminobiphenyl derivative (VII). The reductocondensation of (VII) with N-(tert-butoxycarbonyl)-S-trityl-L-cysteinal (VIII) by means of NaBH3CN affords the secondary amine (IX), which is finally deprotected with HgCl2 and H2S in methanol to furnish the target ester.
| 【1】 Fossum, R.D.; Marugan, J.J.; Vogt, A.; Qian, Y.; Sebti, S.M.; Hamilton, A.D.; Probing the hydrophobic pocket of farnesyltransferase: Aromatic substitution of CAAX peptidomimetics leads to highly potent inhibitors. Bioorg Med Chem 1999, 7, 12, 3011. |
| 【2】 Sebti, S.; Hamilton, A. (University of Pittsburgh); Inhibitors of prenyl transferases. JP 1998512266; WO 9621456 . |
| 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) | 38642 | 2-bromo-1-methyl-4-nitrobenzene | 7745-93-9 | C7H6BrNO2 | 详情 | 详情 |
| (II) | 16593 | Phenylboronic acid；Benzeneboronic acid;Phenylboron dihydroxide | 98-80-6 | C6H7BO2 | 详情 | 详情 |
| (III) | 38643 | 2-methyl-5-nitro-1,1'-biphenyl | C13H11NO2 | 详情 | 详情 | |
| (IV) | 38644 | 5-nitro[1,1'-biphenyl]-2-carboxylic acid | C13H9NO4 | 详情 | 详情 | |
| (V) | 17950 | D-Methionine methyl ester; methyl (2S)-2-amino-4-(methylsulfanyl)butanoate hydrochloride | 21691-49-6 | C6H13NO2S | 详情 | 详情 |
| (VI) | 38645 | methyl (2S)-4-(methylsulfanyl)-2-[[(5-nitro[1,1'-biphenyl]-2-yl)carbonyl]amino]butanoate | C19H20N2O5S | 详情 | 详情 | |
| (VII) | 38656 | 2,2,2-trichloroethyl (3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)-1-piperidinecarboxylate | C9H14Cl3NO5 | 详情 | 详情 | |
| (VIII) | 17953 | tert-butyl (1R)-1-formyl-2-(tritylsulfanyl)ethylcarbamate | C27H29NO3S | 详情 | 详情 | |
| (IX) | 38647 | methyl (2S)-2-[[(5-[[(2R)-2-[(tert-butoxycarbonyl)amino]-3-(tritylsulfanyl)propyl]amino][1,1'-biphenyl]-2-yl)carbonyl]amino]-4-(methylsulfanyl)butanoate | C46H51N3O5S2 | 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 reductive alkylation of 3-chloroaniline (I) with L-S-trityl-N-Boc-cysteinal (II) in the presence of sodium triacetoxyborohydride produced amine (III). Chloroacetylation of (III) followed by cesium carbonate-induced cyclization of the resulting chloroacetamide (IV) furnished the protected piperazinone (V). The S-trityl group of (V) was deprotected by treatment with silver nitrate and pyridine, yielding thiol (VI), which was subsequently alkylated with ethyl iodide to give thioether (VII). Sulfur oxidation by means of magnesium monoperoxyphthalate in methanol afforded sulfone (VIII). Then, acid deprotection of the Boc protecting group of (VIII) provided the intermediate piperazinone (IX).
| 【1】 Anthony, N.J.; Ciccarone, T.M.; Gomez, R.P.; Hutchinson, J.H.; Williams, T.M.; Dinsmore, C.J.; Stokker, G.E. (Merck & Co., Inc.); Inhibitors of farnesyl-protein transferase. EP 0820445; JP 1998511098; US 5856326; WO 9630343 . |
| 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) | 25239 | 3-chloroaniline; 3-chlorophenylamine | 108-42-9 | C6H6ClN | 详情 | 详情 |
| (II) | 17953 | tert-butyl (1R)-1-formyl-2-(tritylsulfanyl)ethylcarbamate | C27H29NO3S | 详情 | 详情 | |
| (III) | 42109 | tert-butyl (1R)-2-(3-chloroanilino)-1-[(tritylsulfanyl)methyl]ethylcarbamate | C33H35ClN2O2S | 详情 | 详情 | |
| (IV) | 42110 | tert-butyl (1R)-2-[3-chloro(2-chloroacetyl)anilino]-1-[(tritylsulfanyl)methyl]ethylcarbamate | C35H36Cl2N2O3S | 详情 | 详情 | |
| (V) | 42111 | tert-butyl (2R)-4-(3-chlorophenyl)-5-oxo-2-[(tritylsulfanyl)methyl]-1-piperazinecarboxylate | C35H35ClN2O3S | 详情 | 详情 | |
| (VI) | 42112 | tert-butyl (2R)-4-(3-chlorophenyl)-5-oxo-2-(sulfanylmethyl)-1-piperazinecarboxylate | C16H21ClN2O3S | 详情 | 详情 | |
| (VII) | 42113 | tert-butyl (2R)-4-(3-chlorophenyl)-2-[(ethylsulfanyl)methyl]-5-oxo-1-piperazinecarboxylate | C18H25ClN2O3S | 详情 | 详情 | |
| (VIII) | 42114 | tert-butyl (2R)-4-(3-chlorophenyl)-2-[(ethylsulfonyl)methyl]-5-oxo-1-piperazinecarboxylate | C18H25ClN2O5S | 详情 | 详情 | |
| (IX) | 42115 | (5R)-1-(3-chlorophenyl)-5-[(ethylsulfonyl)methyl]-2-piperazinone | C13H17ClN2O3S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VII)Treatment of 3-nitro-1,8-naphthalic anhydride (I) with mercuric oxide and aqueous sodium acetate, and then with refluxing concentrated HCl provided a mixture of decarboxylation products (II) and (III). Condensation of this mixture with L-methionine methyl ester (IV) in the presence of dicyclohexylcarbodiimide and 1-hydroxybenzotriazole, followed by chromatographic separation of isomers, yielded the desired 6-nitronaphthalenecarboxamide (V). Further reduction of the nitro group with SnCl2 in ethanol gave amine (VI), which was reductively condensed with S-triphenylmethyl-N-Boc-cysteinal (VII) in the presence of sodium cyanoborohydride, acetic acid, and molecular sieves to afford (VIII). Then, hydrolysis of methyl ester with lithium hydroxide in THF-water gave acid (IX), and finally, deprotection of trityl and tert-butoxycarbonyl groups with an excess of trifluoroacetic acid in the presence of ethanedithiol provided the title compound as the trifluoroacetate salt.
| 【1】 Ito, Y.; Kato, H.; Yasuda, S.; Iwasaki, N.; Nishino, H.; Takeshita, M. (Hokuriku Seiyaku Co., Ltd.); Benzamide deriv.. EP 0640601; US 5395832; US 5500422; WO 9214705 . |
| 【2】 Baudoin, B.; Burns, C.; Commercon, A.; Guitton, J.-D. (Aventis Pharma SA); Novel farnesyl transferase inhibitors, their preparation and pharmaceutical compsns. containing same. JP 1998501259; WO 9534535 . |
| 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) | 15864 | 5-nitro-1H,3H-benzo[de]isochromene-1,3-dione; 3-Nitro-1,8-naphthalic anhydride | 3027-38-1 | C12H5NO5 | 详情 | 详情 |
| (II) | 17948 | 6-nitro-1-naphthoic acid | C11H7NO4 | 详情 | 详情 | |
| (III) | 17949 | 3-nitro-1-naphthoic acid | 4507-84-0 | C11H7NO4 | 详情 | 详情 |
| (IV) | 17950 | D-Methionine methyl ester; methyl (2S)-2-amino-4-(methylsulfanyl)butanoate hydrochloride | 21691-49-6 | C6H13NO2S | 详情 | 详情 |
| (V) | 17951 | methyl (2S)-4-(methylsulfanyl)-2-[(6-nitro-1-naphthoyl)amino]butanoate | C17H18N2O5S | 详情 | 详情 | |
| (VI) | 17952 | methyl (2S)-2-[(6-amino-1-naphthoyl)amino]-4-(methylsulfanyl)butanoate | C17H20N2O3S | 详情 | 详情 | |
| (VII) | 17953 | tert-butyl (1R)-1-formyl-2-(tritylsulfanyl)ethylcarbamate | C27H29NO3S | 详情 | 详情 | |
| (VIII) | 17954 | methyl (2S)-2-[(6-[[(2R)-2-[(tert-butoxycarbonyl)amino]-3-(tritylsulfanyl)propyl]amino]-1-naphthoyl)amino]-4-(methylsulfanyl)butanoate | C44H49N3O5S2 | 详情 | 详情 | |
| (IX) | 17955 | (2S)-2-[(6-[[(2R)-2-[(tert-butoxycarbonyl)amino]-3-(tritylsulfanyl)propyl]amino]-1-naphthoyl)amino]-4-(methylsulfanyl)butyric acid | C43H47N3O5S2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VIII)The condensation of 2-bromo-4-nitrotoluene (I) with phenylboronic acid (II) by means of Pd(OAc)2 in aqueous acetone gives the biphenyl (III), which is oxidized with KMnO4 in aqueous pyridine yielding the biphenyl-2-carboxylic acid (IV). The condensation of (IV) with L-methionine methyl ester (V) by means of EDC and HOBT affords the amide (VI), which is reduced with SnCl2 to give the 5-aminobiphenyl derivative (VII). The reductocondensation of (VII) with N-(tert-butoxycarbonyl)-S-trityl-L-cysteinal (VIII) by means of NaBH3CN affords the secondary amine (IX), which is finally deprotected and hydrolyzed first with LiOH and THF and then with TFA and Et3SiH in dichloromethane to furnish the target free acid.
| 【1】 Fossum, R.D.; Marugan, J.J.; Vogt, A.; Qian, Y.; Sebti, S.M.; Hamilton, A.D.; Probing the hydrophobic pocket of farnesyltransferase: Aromatic substitution of CAAX peptidomimetics leads to highly potent inhibitors. Bioorg Med Chem 1999, 7, 12, 3011. |
| 【2】 Sebti, S.; Hamilton, A. (University of Pittsburgh); Inhibitors of prenyl transferases. JP 1998512266; WO 9621456 . |
| 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) | 38642 | 2-bromo-1-methyl-4-nitrobenzene | 7745-93-9 | C7H6BrNO2 | 详情 | 详情 |
| (II) | 16593 | Phenylboronic acid；Benzeneboronic acid;Phenylboron dihydroxide | 98-80-6 | C6H7BO2 | 详情 | 详情 |
| (III) | 38643 | 2-methyl-5-nitro-1,1'-biphenyl | C13H11NO2 | 详情 | 详情 | |
| (IV) | 38644 | 5-nitro[1,1'-biphenyl]-2-carboxylic acid | C13H9NO4 | 详情 | 详情 | |
| (V) | 17950 | D-Methionine methyl ester; methyl (2S)-2-amino-4-(methylsulfanyl)butanoate hydrochloride | 21691-49-6 | C6H13NO2S | 详情 | 详情 |
| (VI) | 38645 | methyl (2S)-4-(methylsulfanyl)-2-[[(5-nitro[1,1'-biphenyl]-2-yl)carbonyl]amino]butanoate | C19H20N2O5S | 详情 | 详情 | |
| (VII) | 38656 | 2,2,2-trichloroethyl (3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)-1-piperidinecarboxylate | C9H14Cl3NO5 | 详情 | 详情 | |
| (VIII) | 17953 | tert-butyl (1R)-1-formyl-2-(tritylsulfanyl)ethylcarbamate | C27H29NO3S | 详情 | 详情 | |
| (IX) | 38647 | methyl (2S)-2-[[(5-[[(2R)-2-[(tert-butoxycarbonyl)amino]-3-(tritylsulfanyl)propyl]amino][1,1'-biphenyl]-2-yl)carbonyl]amino]-4-(methylsulfanyl)butanoate | C46H51N3O5S2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XIII)Protected L-cysteine (XI) was converted to aldehyde (XIII) via formation of the corresponding N-methoxy amide (XII) and further reduction with LiAlH4. Reductive condensation of amine (X) with aldehyde (XIII) in the presence of NaBH4CN furnished (XIV). The Boc group of (XIV) was finally deprotected by treatment with trifluoroacetic acid in the presence of triethylsilane.
| 【1】 Dong, Z.X.; Kim, S.H. (Biomeasure Inc.); Inhibitors of prenyl transferases. WO 9800409 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 38790 | methyl (2S)-2-[([(4R)-3-[(2S,3S)-2-amino-3-methylpentyl]-5,5-dimethyl-1,3-thiazolidin-4-yl]carbonyl)amino]-4-(methylsulfanyl)butanoate | C18H35N3O3S2 | 详情 | 详情 | |
| (XI) | 38791 | (2R)-2-[(tert-butoxycarbonyl)amino]-3-(tritylsulfanyl)propionic acid | 21947-98-8 | C27H29NO4S | 详情 | 详情 |
| (XII) | 38792 | tert-butyl (1R)-2-[methoxy(methyl)amino]-2-oxo-1-[(tritylsulfanyl)methyl]ethylcarbamate | C29H34N2O4S | 详情 | 详情 | |
| (XIII) | 17953 | tert-butyl (1R)-1-formyl-2-(tritylsulfanyl)ethylcarbamate | C27H29NO3S | 详情 | 详情 | |
| (XIV) | 38793 | methyl (2S)-2-([[(4R)-3-((2S,3S)-2-[[(2R)-2-[(tert-butoxycarbonyl)amino]-3-(tritylsulfanyl)propyl]amino]-3-methylpentyl)-5,5-dimethyl-1,3-thiazolidin-4-yl]carbonyl]amino)-4-(methylsulfanyl)butanoate | C45H64N4O5S3 | 详情 | 详情 |