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【结 构 式】 
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【分子编号】32016 【品名】(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-[[(2R,3S)-3-(benzoylamino)-2-hydroxy-3-phenylpropanoyl]oxy]-9-[[(benzyloxy)carbonyl]oxy]-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoa 【CA登记号】 |
【 分 子 式 】C55H57NO16 【 分 子 量 】988.05472 【元素组成】C 66.86% H 5.81% N 1.42% O 25.91% |
合成路线1
该中间体在本合成路线中的序号：(XI)5) The selective protection of baccatin III (I) with benzyloxycarbonyl anhydride and Li-HMDS in DMF gives 7-O-(benzyloxycarbonyl)baccatin III (V), which is condensed with the chiral azetidinone (IX) by means of lithium tert-butoxide or Li-HMDS in THF and the reaction product, without isolation, is treated with trifluoroacetic acid and acetic acid to afford the protected taxol derivative (XI). Finally, this compound is deprotected by hydrogenation with H2 over Pd/C in ethanol.
| 【1】 Gibson, F.S. (Bristol-Myers Squibb Co.); Synthesis of paclitaxel baccatin III by protecting the 7-hydroxyl using a strong base and an electrophile. WO 9945001 . |
| 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) | 10447 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-1,9,15-trihydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | C31H38O11 | 详情 | 详情 | |
| (V) | 32009 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-9-[[(benzyloxy)carbonyl]oxy]-1,15-dihydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | C39H44O13 | 详情 | 详情 | |
| (IX) | 32011 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-9-[(tert-butoxycarbonyl)oxy]-1,15-dihydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | C36H46O13 | 详情 | 详情 | |
| (XI) | 32016 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-[[(2R,3S)-3-(benzoylamino)-2-hydroxy-3-phenylpropanoyl]oxy]-9-[[(benzyloxy)carbonyl]oxy]-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoa | C55H57NO16 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(III)The condensation between 3-(bromoacetyl)pyridine (I) and either formamide or formamidine acetate produced the intermediate 4-(3-pyridyl)imidazole (II). Alternatively, intermediate (II) was prepared by palladium-catalyzed coupling between 1-trityl-4-iodoimidazole (III) and diethyl(3-pyridyl)borane (IV), followed by acidic deprotection of the resultant 1-trityl-4-(3-pyridyl)imidazole (V). In a further procedure, iodoimidazole (III) was converted to the corresponding Grignard reagent (VI), which was then coupled with 3-bromopyridine (VII) in the presence of ZnCl2 and palladium catalyst, yielding adduct (V). Subsequent acid-catalyzed deprotection gave intermediate (II). Michael addition of crotonaldehyde (VIII) to imidazole (II) furnished the (pyridylimidazolyl)butyraldehyde (IX). Condensation of aldehyde (IX) with the macrocyclic N-amino carbamate (X) produced the intermediate imine (XI), which was reduced to the corresponding amino derivative using sodium cyanoborohydride. The resultant epimeric mixture was separated by chromatography to provide the title (3R)-diastereoisomer. Alternatively, the reductive alkylation of (X) with aldehyde (IX) was carried out in the presence of sodium triacetoxyborohydride.
| 【1】 Su, W.; et al.; The in vitro and in vivo activity of CP-642,959 and its related diastereomers. 41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001, Chicago) 2001, Abst F-1168. |
| 【2】 Kaneko, T.; Su, W.-G.; Wu, Y.-J. (Pfizer Inc.); Carbamate and carbazate ketolide antibiotics. EP 1115732; WO 0017218 . |
| 【3】 Kaneko, T.; McMillen, W.T.; McLaughlin, R.W.; Ripin, D.H.B.; Vanerplas, B.C. (Pfizer Inc.); Synthesis of carbamate ketolide antibiotics. EP 1088828; JP 2001151792 . |
| 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) | 53085 | 2-bromo-1-(3-pyridinyl)-1-ethanone | n/a | C7H6BrNO | 详情 | 详情 |
| (II) | 17164 | 3-(1H-imidazol-4-yl)pyridine | C8H7N3 | 详情 | 详情 | |
| (III) | 32016 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-[[(2R,3S)-3-(benzoylamino)-2-hydroxy-3-phenylpropanoyl]oxy]-9-[[(benzyloxy)carbonyl]oxy]-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoa | C55H57NO16 | 详情 | 详情 | |
| (IV) | 20086 | 3-(diethylboryl)pyridine | C9H14BN | 详情 | 详情 | |
| (V) | 53086 | 3-(1-trityl-1H-imidazol-4-yl)pyridine | n/a | C27H21N3 | 详情 | 详情 |
| (VI) | 32017 | (2S)-5-amino-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-5-oxopentanoic acid | C13H12N2O5 | 详情 | 详情 | |
| (VII) | 13265 | 3-Bromopyridine | 626-55-1 | C5H4BrN | 详情 | 详情 |
| (VIII) | 22517 | (E)-2-butenal | 4170-30-3 | C4H6O | 详情 | 详情 |
| (IX) | 53087 | 3-[4-(3-pyridinyl)-1H-imidazol-1-yl]butanal | n/a | C12H13N3O | 详情 | 详情 |
| (X) | 45787 | (3aS,4R,7R,9R,10R,11R,13R,15R,15aR)-1-amino-10-[[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy]-4-ethyl-11-methoxy-3a,7,9,11,13,15-hexamethyloctahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazole-2,6,8,14(1H,7H,9H)-tetrone 14-(O-methyloxime) | C32H56N4O10 | 详情 | 详情 | |
| (XI) | 53088 | (3aS,4R,7R,9R,10R,11R,13R,15R,15aR)-10-{[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}-4-ethyl-11-methoxy-3a,7,9,11,13,15-hexamethyl-1-({(Z)-3-[4-(3-pyridinyl)-1H-imidazol-1-yl]butylidene}amino)octahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazole-2,6,8,14(1H,7H,9H)-tetrone 14-(O-methyloxime) | n/a | C44H67N7O10 | 详情 | 详情 |