(2S,3R,4S,6R)-2-[[(3R,5R,6R,7S,9R,11R,12R,13S,14R)-7-(allyloxy)-14-ethyl-12,13-dihydroxy-3,5,7,9,11,13-hexamethyl-2,4,10-trioxooxacyclotetradecanyl]oxy]-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-yl benzoate -Drug Synthesis Database

【结构式】

【分子编号】28431

【品名】(2S,3R,4S,6R)-2-[[(3R,5R,6R,7S,9R,11R,12R,13S,14R)-7-(allyloxy)-14-ethyl-12,13-dihydroxy-3,5,7,9,11,13-hexamethyl-2,4,10-trioxooxacyclotetradecanyl]oxy]-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-yl benzoate

【CA登记号】

【分子式】C₃₉H₅₉NO₁₁

【分子量】717.8976

【元素组成】C 65.25% H 8.28% N 1.95% O 24.52%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(XIb)

Acidic hydrolysis of the cladinose sugar of 6-O-allylerythromycin A (III) with HCl in ethanol/water yields the 3-hydroxy intermediate (IX), which is first protected at the 2'-OH group with acetic anhydride or benzoyl anhydride to (Xa) or (Xb) and then oxidized with NCS and dimethyl sulfide to the 3-oxoerythromycin derivatives (XIa) or (XIb). The reaction of (XIa) with CDI and LiH or (XIb) first with CDI and NaHMDS, then with DBU and finally with CDI and NaH, provides the 12-O-(1-imidazolylcarbonyl)erythromycin derivatives (XIIa) and (XIIb), which are cyclized with aqueous ammonia to the cyclic carbamates (VII) and (XIIIb). Finally, these compounds are condensed with 3-bromoquinoline (VIII) by means of palladium acetate, tris(o-tolyl)phosphine and Et3N in acetonitrile and deprotected with methanol 60-80%.

参考文献中间体

合成目标

【1】 Ma, Z.; et al.; Novel erythromycin derivatives with aryl groups tethered to the C-6 position are potent protein synthesis inhibitors and active against multidrug-resistant respiratory pathogens. J Med Chem 2001, 44, 24, 4137.
【2】 Or, Y.; Clark, R.F.; Ma, Z.; Design, synthesis, and characterization of ABT-773: A novel ketolide highly active against multidrug-resistant pathogens. 39th Intersci Conf Antimicrob Agents Chemother (Sept 26 1999, San Francisco) 1999, Abst F2133.
【3】 Ewing, P.; Or, Y.S.; Nilius, A.M.; Wang, S.; Clark, R.F.; Alder, J.; Chu, D.T.W.; Mitten, M.; Flamm, R.K.; Ma, Z.; Design, synthesis, and antimicrobial activity of 6-O-substituted ketolides active against resistant respiratory tract pathogens. J Med Chem 2000, 43, 6, 1045-49.
【4】 Rabasseda, X.; Sorbera, L.A.; Castañer, J.; ABT-773. Drugs Fut 2000, 25, 5, 445.
【5】 Or, Y.S.; Ma, Z.; Clark, R.F.; Chu, D.T.; Plattner, J.J. (Abbott Laboratories Inc.); 6-O-Substd. ketolides having antibacterial activity. EP 0929563; US 5866549; WO 9809978 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(Xb)	28430	(2S,3R,4S,6R)-2-[[(3R,4S,5S,6R,7S,9R,11R,12R,13S,14R)-7-(allyloxy)-14-ethyl-4,12,13-trihydroxy-3,5,7,9,11,13-hexamethyl-2,10-dioxooxacyclotetradecanyl]oxy]-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-yl benzoate		C₃₉H₆₁NO₁₁	详情	详情
(XIb)	28431	(2S,3R,4S,6R)-2-[[(3R,5R,6R,7S,9R,11R,12R,13S,14R)-7-(allyloxy)-14-ethyl-12,13-dihydroxy-3,5,7,9,11,13-hexamethyl-2,4,10-trioxooxacyclotetradecanyl]oxy]-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-yl benzoate		C₃₉H₅₉NO₁₁	详情	详情
(Xa)	35296	(2S,3R,4S,6R)-2-[[(3R,4S,5S,6R,7S,9R,11R,12R,13S,14R)-7-(allyloxy)-14-ethyl-4,12,13-trihydroxy-3,5,7,9,11,13-hexamethyl-2,10-dioxooxacyclotetradecanyl]oxy]-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-yl acetate		C₃₄H₅₉NO₁₁	详情	详情
(XIa)	35297	(2S,3R,4S,6R)-2-[[(3R,5R,6R,7S,9R,11R,12R,13S,14R)-7-(allyloxy)-14-ethyl-12,13-dihydroxy-3,5,7,9,11,13-hexamethyl-2,4,10-trioxooxacyclotetradecanyl]oxy]-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-yl acetate		C₃₄H₅₇NO₁₁	详情	详情
(XIIa)	35298	(2R,3S,7R,9S,10R,11R,13R)-10-[[(2S,3R,4S,6R)-3-(acetoxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl]oxy]-9-(allyloxy)-2-ethyl-3,5,7,9,11,13-hexamethyl-6,12,14-trioxooxa-4-cyclotetradecen-3-yl 1H-imidazole-1-carboxylate		C₃₈H₅₇N₃O₁₁	详情	详情
(XIIb)	35299	(2R,3S,7R,9S,10R,11R,13R)-9-(allyloxy)-10-[[(2S,3R,4S,6R)-3-(benzoyloxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl]oxy]-2-ethyl-3,5,7,9,11,13-hexamethyl-6,12,14-trioxooxa-4-cyclotetradecen-3-yl 1H-imidazole-1-carboxylate		C₄₃H₅₉N₃O₁₁	详情	详情
(XIIIb)	35300	(2S,3R,4S,6R)-2-[[(3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-11-(allyloxy)-4-ethyl-3a,7,9,11,13,15-hexamethyl-2,6,8,14-tetraoxotetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl]oxy]-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-yl benzoate		C₄₀H₅₈N₂O₁₁	详情	详情
(III)	28391	(3R,4S,5R,6R,7S,9R,11R,12R,13S,14R)-7-(allyloxy)-6-[[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy]-14-ethyl-12,13-dihydroxy-4-[[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl]oxy]-3,5,7,9,11,13-hexamethyl-2,10-oxacyclotetradecanedione		C₄₀H₇₁NO₁₃	详情	详情
(VII)	35295			C₃₅H₅₆N₂O₁₁	详情	详情
(VIII)	28432	3-bromoquinoline	5332-24-1	C₉H₆BrN	详情	详情
(IX)	28249	2-[3-benzyl-8-(benzyloxy)-2-ethyl-1-indolizinyl]acetamide		C₂₆H₂₆N₂O₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VII)

Oxidation of the 3-hydroxyl group of (VI) by means of N-chlorosuccinimide in the presence of Me2S and Et3N produced ketone (VII). A 3-quinolinyl moiety was further introduced on the allyl group of (VII) by treatment with 3-bromoquinoline (VIII) in the presence of Pd(OAc)2 and tri-o-tolyl phosphine to yield (IX). Finally, the benzoate ester of (IX) was cleaved by treatment with boiling MeOH.

参考文献中间体

合成目标

【1】 Flamm, R.K.; Raney, P.M.; Nilius, A.M.; Bui, M.; Or, Y.S.; Wang, S.; Plattner, J.J.; Ma, Z.; Clark, R.; Chu, D.T.W.; Synthesis and antibacterial activity of 6-O-substituted ketolides. 38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998, San Diego) 1998, Abst F-126.
【2】 Or, Y.S.; Ma, Z.; Clark, R.F.; Chu, D.T.; Plattner, J.J. (Abbott Laboratories Inc.); 6-O-Substd. ketolides having antibacterial activity. EP 0929563; US 5866549; WO 9809978 .

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)	28430	(2S,3R,4S,6R)-2-[[(3R,4S,5S,6R,7S,9R,11R,12R,13S,14R)-7-(allyloxy)-14-ethyl-4,12,13-trihydroxy-3,5,7,9,11,13-hexamethyl-2,10-dioxooxacyclotetradecanyl]oxy]-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-yl benzoate		C₃₉H₆₁NO₁₁	详情	详情
(VII)	28431	(2S,3R,4S,6R)-2-[[(3R,5R,6R,7S,9R,11R,12R,13S,14R)-7-(allyloxy)-14-ethyl-12,13-dihydroxy-3,5,7,9,11,13-hexamethyl-2,4,10-trioxooxacyclotetradecanyl]oxy]-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-yl benzoate		C₃₉H₅₉NO₁₁	详情	详情
(VIII)	28432	3-bromoquinoline	5332-24-1	C₉H₆BrN	详情	详情
(IX)	28433	(2S,3R,4S,6R)-4-(dimethylamino)-2-[((3R,5R,6R,7S,9R,11R,12R,13S,14R)-14-ethyl-12,13-dihydroxy-3,5,7,9,11,13-hexamethyl-2,4,10-trioxo-7-[[(E)-3-(3-quinolinyl)-2-propenyl]oxy]oxacyclotetradecanyl)oxy]-6-methyltetrahydro-2H-pyran-3-yl benzoate		C₄₈H₆₄N₂O₁₁	详情	详情

Extended Information