|
【结 构 式】 
|
【分子编号】33013 【品名】O-[tert-butyl(diphenyl)silyl]hydroxylamine; (aminooxy)(tert-butyl)diphenylsilane 【CA登记号】 |
【 分 子 式 】C16H21NOSi 【 分 子 量 】271.43438 【元素组成】C 70.8% H 7.8% N 5.16% O 5.89% Si 10.35% |
合成路线1
该中间体在本合成路线中的序号：(IX)Acylation of 3-chloro-4-methylaniline (VII) with chloroacetonitrile in the presence of BCl3 and Et2AlCl produced the chloroacetophenone (VIII). Subsequent condensation of (VIII) with ethylmalonyl chloride gave amide (IX), which was cyclized to the quinolinone (X) upon treatment with ethanolic NaOEt. Reaction of the quinolinone (X) with POCl3 afforded chloroquinoline (XI). The ester group of (XI) was then reduced to alcohol (XII) by means of diisobutylaluminum hydride. Condensation of (XII) with 4-methylpiperidine (XIII) gave adduct (IV), which was further coupled with pyridinone (VI) under Mitsunobu conditions to yield (Xv). Finally, intramolecular Heck reaction in the presence of palladium diacetate and triphenylphosphine provided the desired pentacyclic compound, which was isolated as the hydrochloride salt.
| 【1】 Coulomb, H.; Huchet, M.; Harnett, J.; Rolland, A.; Lanco, C.; Lavergne, O.; Demarquay, D.; Lesueur-Ginot, L.; Bigg, D.C.H.; BN 80927: A novel homocamptothecin with inhibitory activities on both topoisomerase I and topoisomerase II. Bioorg Med Chem Lett 1999, 9, 17, 2599. |
| 【2】 Cazaux, J.-B.; Manginot, E.; Lavergne, O.; Le Breton, C.; Bigg, D. (SCRAS (Societé de Conseils de Recherches et d'Applications Scientifiques)); Optically pure camptothecin analogues, optically pure synthesis intermediate and method for preparing same. EP 1007527; FR 2768431; WO 9911646 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 33100 | (5R)-5-ethyl-5-hydroxy-1,4,5,8-tetrahydrooxepino[3,4-c]pyridine-3,9-dione | C11H13NO4 | 详情 | 详情 | |
| (VII) | 26794 | 3-Chloro-4-methylaniline; 4-Amino-2-chlorotoluene | 95-74-9 | C7H8ClN | 详情 | 详情 |
| (VIII) | 33102 | 1-(2-amino-4-chloro-5-methylphenyl)-2-chloro-1-ethanone | C9H9Cl2NO | 详情 | 详情 | |
| (IX) | 33013 | O-[tert-butyl(diphenyl)silyl]hydroxylamine; (aminooxy)(tert-butyl)diphenylsilane | C16H21NOSi | 详情 | 详情 | |
| (X) | 33104 | ethyl 7-chloro-4-(chloromethyl)-6-methyl-2-oxo-1,2-dihydro-3-quinolinecarboxylate | C14H13Cl2NO3 | 详情 | 详情 | |
| (XI) | 33105 | ethyl 2,7-dichloro-4-(chloromethyl)-6-methyl-3-quinolinecarboxylate | C14H12Cl3NO2 | 详情 | 详情 | |
| (XII) | 33106 | [2,7-dichloro-4-(chloromethyl)-6-methyl-3-quinolinyl]methanol | C12H10Cl3NO | 详情 | 详情 | |
| (XIII) | 10192 | 4-Methylpiperidine; gamma-Pipecoline | 626-58-4 | C6H13N | 详情 | 详情 |
| (XIV) | 33107 | [2,7-dichloro-6-methyl-4-[(4-methyl-1-piperidinyl)methyl]-3-quinolinyl]methanol | C18H22Cl2N2O | 详情 | 详情 | |
| (XV) | 33101 | (5R)-8-[(2-chloro-6,7-difluoro-3-quinolinyl)methyl]-5-ethyl-5-hydroxy-1,4,5,8-tetrahydrooxepino[3,4-c]pyridine-3,9-dione | C21H17ClF2N2O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(III)(S)-Pipecolinic acid (I) was protected as the Fmoc-derivative (II) using 9-fluorenylmethyl chloroformate and Na2CO3. Subsequent coupling of (II) with O-(tert-butyldiphenylsilyl)hydroxylamine (III) by means of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) provided the silyl hydroxamate (IV). Removal of the Fmoc group of (IV) was then achieved by treatment with diethylamine in THF to provide (V). Treatment of N-(2-pyridyl)piperazine (VI) with chlorosulfonic acid and then with phosphorus pentachloride afforded the sulfamyl chloride (VII). This was coupled with piperidine (V) in the presence of Et3N to yield the sulfamide derivative (VIII). Finally, removal of the silyl protecting group of (VIII) was carried out with tetrabutylammonium fluoride in CH2Cl2.
| 【1】 Mitchell, L.J. Jr.; Burke, B.; Dagostino, E.; et al.; Novel sulfamides and sulfonamide inhibitors of matrix metalloproteases. 218th ACS Natl Meet (Aug 22 1999, New Orleans) 1999, Abst MEDI 76. |
| 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) | 17380 | (2S)hexahydro-2-pyridinecarboxylic acid; (S)-pipecolic acid | 3105-95-1 | C6H11NO2 | 详情 | 详情 |
| (II) | 25357 | (2S)-1-[(9H-fluoren-9-ylmethoxy)carbonyl]-2-piperidinecarboxylic acid | C21H21NO4 | 详情 | 详情 | |
| (III) | 33013 | O-[tert-butyl(diphenyl)silyl]hydroxylamine; (aminooxy)(tert-butyl)diphenylsilane | C16H21NOSi | 详情 | 详情 | |
| (IV) | 33009 | 9H-fluoren-9-ylmethyl (2R)-2-[([[tert-butyl(diphenyl)silyl]oxy]amino)carbonyl]-1-piperidinecarboxylate | C37H40N2O4Si | 详情 | 详情 | |
| (V) | 33010 | (2R)-N-[[tert-butyl(diphenyl)silyl]oxy]-2-piperidinecarboxamide | C22H30N2O2Si | 详情 | 详情 | |
| (VI) | 24399 | 1-(2-pyridinyl)piperazine | 34803-66-2 | C9H13N3 | 详情 | 详情 |
| (VII) | 33011 | 4-(2-pyridinyl)-1-piperazinesulfonyl chloride | C9H12ClN3O2S | 详情 | 详情 | |
| (VIII) | 33012 | (2R)-N-[[tert-butyl(diphenyl)silyl]oxy]-1-[[4-(2-pyridinyl)-1-piperazinyl]sulfonyl]-2-piperidinecarboxamide | C31H41N5O4SSi | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(III)(S)-Pipecolinic acid (I) was protected as the Fmoc-derivative (II) using 9-fluorenylmethyl chloroformate and Na2CO3. Subsequent coupling of (II) with O-(tert-butyldiphenylsilyl)hydroxylamine (III) by means of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) provided the silyl hydroxamate (IV). Removal of the Fmoc group of (IV) was then achieved by treatment with diethylamine in THF to provide (V). Treatment of 4-[4-(imidazol-1-yl)phenoxy]piperidine (VI) with chlorosulfonic acid and then with phosphorus pentachloride afforded the sulfamyl chloride (VII). This was coupled with piperidine (V) in the presence of Et3N to yield the sulfamide derivative (VIII). Finally, removal of the silyl protecting group of (VIII) was carried out with tetrabutylammonium fluoride in CH2Cl2.
| 【1】 Mitchell, L.J. Jr.; Burke, B.; Dagostino, E.; et al.; Novel sulfamides and sulfonamide inhibitors of matrix metalloproteases. 218th ACS Natl Meet (Aug 22 1999, New Orleans) 1999, Abst MEDI 76. |
| 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) | 17380 | (2S)hexahydro-2-pyridinecarboxylic acid; (S)-pipecolic acid | 3105-95-1 | C6H11NO2 | 详情 | 详情 |
| (II) | 25337 | (1S,2S,3R,4S,7R,9S,10R,12R,15S)-4,12-bis(acetoxy)-9-[[(E)-3-(3-benzoylphenyl)-2-propenoyl]oxy]-15-([(2R,3S)-3-[(tert-butoxycarbonyl)amino]-3-phenyl-2-[(triisopropylsilyl)oxy]propanoyl]oxy)-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[1 | C70H85NO17Si | 详情 | 详情 | |
| (III) | 33013 | O-[tert-butyl(diphenyl)silyl]hydroxylamine; (aminooxy)(tert-butyl)diphenylsilane | C16H21NOSi | 详情 | 详情 | |
| (IV) | 33009 | 9H-fluoren-9-ylmethyl (2R)-2-[([[tert-butyl(diphenyl)silyl]oxy]amino)carbonyl]-1-piperidinecarboxylate | C37H40N2O4Si | 详情 | 详情 | |
| (V) | 33010 | (2R)-N-[[tert-butyl(diphenyl)silyl]oxy]-2-piperidinecarboxamide | C22H30N2O2Si | 详情 | 详情 | |
| (VI) | 33014 | 4-[4-(1H-imidazol-1-yl)phenoxy]piperidine; 4-(1H-imidazol-1-yl)phenyl 4-piperidinyl ether | C14H17N3O | 详情 | 详情 | |
| (VII) | 33015 | 4-[4-(1H-imidazol-1-yl)phenoxy]-1-piperidinesulfonyl chloride | C14H16ClN3O3S | 详情 | 详情 | |
| (VIII) | 33016 | (2R)-N-[[tert-butyl(diphenyl)silyl]oxy]-1-([4-[4-(1H-imidazol-1-yl)phenoxy]-1-piperidinyl]sulfonyl)-2-piperidinecarboxamide | C36H45N5O5SSi | 详情 | 详情 |