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【结 构 式】 
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【分子编号】28284 【品名】D-proline 【CA登记号】344-25-2 |
【 分 子 式 】C5H9NO2 【 分 子 量 】115.132 【元素组成】C 52.16% H 7.88% N 12.17% O 27.79% |
合成路线1
该中间体在本合成路线中的序号：(IV)Treatment of N,N'-di-Cbz-lysine (I) with ethyl chloroformate and N-ethyl morpholine, followed by condensation of the resulting mixed anhydride with N,O-dimethylhydroxylamine provided the corresponding N-methoxyamide (II). This was reduced with LiAlH4 in cold Et2O to furnish aldehyde (III). The title compound was then obtained by reductive condensation of (III) with D-proline (IV) in the presence of NaBH3CN.
| 【1】 Masini, I.; Fantetti, L.; Giotti, A.; Roncucci, G.; Adembri, G.; Synthesis and antinociceptive activity of some novel nonpeptide derivatives of interleukin-1beta (193-195) sequence. Arzneim-Forsch Drug Res 1999, 49, 2, 137. |
| 【2】 Roncucci, G.; Giotti, A.; Adembri, G.; Fantetti, L.; Masini, I. (Molteni L. & C. SpA); Amines exhibiting analgesic action, their preparation and use. WO 9633210 . |
| 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) | 28281 | (2S)-2,6-bis[[(benzyloxy)carbonyl]amino]hexanoic acid | C22H26N2O6 | 详情 | 详情 | |
| (II) | 28282 | benzyl (1S)-5-[[(benzyloxy)carbonyl]amino]-1-[[methoxy(methyl)amino]carbonyl]pentylcarbamate | C24H31N3O6 | 详情 | 详情 | |
| (III) | 28283 | benzyl (1S)-5-[[(benzyloxy)carbonyl]amino]-1-formylpentylcarbamate | C22H26N2O5 | 详情 | 详情 | |
| (IV) | 28284 | D-proline | 344-25-2 | C5H9NO2 | 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 title peptide was originally isolated from the venom of the marine cone snail Conus radiatus in small quantities. The compound has also been obtained by solid-phase peptide synthesis starting from Fmoc-L-proline linked to p-alkoxybenzylalcohol resin (I). Removal of the Fmoc group was effected by treatment with tetrabutylammonium fluoride in DMF. Chain elongation was carried out by coupling with the respective Fmoc-protected amino acids using diisopropyl carbodiimide and 1-hydroxybenzotriazole in CH2Cl2-DMF, followed by deprotection cycles with tetrabutylammonium fluoride. Gamma-carboxy glutamic acid was incorporated as the protected bis-tert-butyl ester. The final protected peptide resin (III) was liberated and deprotected by using a mixture of trifluoroacetic acid, thioanisole, water, ethanedithiol and dichloromethane, and the resulting peptide was air oxidized at a pH of 7.8 to form the required disulfide bridge.
| 【1】 White, H.S.; McCabe, R.T.; Armstrong, H.; et al.; In vitro and in vivo characterization of conantokin-R, a selective NMDA receptor antagonist isolated from the venom of the fish-hunting snail Conus radiatus. The Journal of Pharmacology and Experimental Therapeutics 2000, 292, 1, 425. |
| 【2】 McCabe, R.T.; Zhou, L.-M.; Layer, R.T. (Cognetix, Inc.); Use of conantokins. US 6172041; WO 9803189 . |
| 【3】 Shen, G.S.; Layer, R.T.; Colledge, C.; Abogadie, F.C.; Zhou, L.-M.; Cruz, L.J.; Rivier, J.E.; McCabe, R.T.; Hyllyard, D.R.; Jimenez, E.; Walker, C.; Olivera, B.M. (Cognetix, Inc.; University of Utah); Conantokins. WO 9803541 . |
合成路线3
该中间体在本合成路线中的序号：(I)Coupling of the chiral auxiliary (R)-proline (I) with methacryloyl chloride (II) under Schotten-Baumann conditions provided amide (III). This was converted to bromolactone (IV) by asymmetric bromolactonization in the presence of N-bromosuccinimide. Subsequent acid hydrolysis yielded the chiral (R)-bromoacid (V), that was converted to acid chloride (VI) and then coupled with 4-amino-2-trifluoromethylbenzonitrile (VII) in DMA at low temperature to afford anilide (VIII). Coupling with 4-aminothiophenol (IX) using NaH in THF produced sulfide (X). Finally, conversion of the aniline precursor (X) to the target isothiocyanate was achieved by reaction with thiophosgene in the presence of NaHCO3.
| 【1】 Mukherjee, A.; et al.; Affinity labeling of the androgen receptor with nosteroidal chemoaffinity ligands. Biochem Pharmacol 1999, 58, 8, 1259. |
| 【2】 Dalton, J.T.; Miller, D.D.; Kirkovsky, L.; Mukherjee, A.; Yin, D.; Chiral nonsteroidal affinity ligands for the androgen receptor. 1. Bicalutamide analogues bearing electrophilic groups in the B aromatic ring. J Med Chem 2000, 43, 4, 581. |
| 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) | 28284 | D-proline | 344-25-2 | C5H9NO2 | 详情 | 详情 |
| (II) | 33553 | 2-methylacryloyl chloride | 920-46-7 | C4H5ClO | 详情 | 详情 |
| (III) | 40972 | (2R)-1-methacryloyl-2-pyrrolidinecarboxylic acid | C9H13NO3 | 详情 | 详情 | |
| (IV) | 40967 | (3R,8aR)-3-(bromomethyl)-3-methyltetrahydro-1H-pyrrolo[2,1-c][1,4]oxazine-1,4(3H)-dione | C9H12BrNO3 | 详情 | 详情 | |
| (V) | 40968 | (2R)-3-bromo-2-hydroxy-2-methylpropionic acid | C4H7BrO3 | 详情 | 详情 | |
| (VI) | 40969 | (2R)-3-bromo-2-hydroxy-2-methylpropanoyl chloride | C4H6BrClO2 | 详情 | 详情 | |
| (VII) | 18743 | 4-amino-2-(trifluoromethyl)benzonitrile；5-Amino-2-cyanobenzotrifluoride | 654-70-6 | C8H5F3N2 | 详情 | 详情 |
| (VIII) | 40970 | (2R)-3-bromo-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methylpropanamide | C12H10BrF3N2O2 | 详情 | 详情 | |
| (IX) | 16490 | 4-aminophenylhydrosulfide; 4-aminothiophenol; 4-aminobenzenethiol | 1193-02-8 | C6H7NS | 详情 | 详情 |
| (X) | 40971 | (2R)-3-[(4-aminophenyl)sulfanyl]-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methylpropanamide | C18H16F3N3O2S | 详情 | 详情 |