2-[3-benzyl-8-(benzyloxy)-2-ethyl-1-indolizinyl]acetamide -Drug Synthesis Database

【结构式】

【分子编号】28249

【品名】2-[3-benzyl-8-(benzyloxy)-2-ethyl-1-indolizinyl]acetamide

【CA登记号】

【分子式】C₂₆H₂₆N₂O₂

【分子量】398.50472

【元素组成】C 78.36% H 6.58% N 7.03% O 8.03%

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：(IX)

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：(IX)

The hydrogenation of pyridineacrylate (I) produced a mixture of the benzyl-protected pyridinepropionate (II) and the debenzylated analogue (III), which were separated by column chromatography. Ester (III) was converted into amide (IV) upon treatment with aqueous ammonia, and further protected with benzyl chloride to afford (V). Cyclization with 1-bromo-2-butanone (VI) in the presence of NaHCO3 furnished indolizidine (VII). This was acylated with benzoyl chloride in boiling benzene to give ketone (VIII), which was reduced to the benzyl derivative (IX) by means of borane-tert-butyl amine complex and AlCl3. Hydrogenolytic deprotection of the benzyl ether of (IX) afforded phenol (X), which was alkylated with methyl bromoacetate and NaH to yield the corresponding esther (XI). Finally, hydrolysis of the methyl ester (XI) with LiOH provided the target carboxylic acid.

参考文献中间体

合成目标

【1】 Hagishita, S.; Yamda, M.; Shirahase, K.; et al.; Potent inhibitors of secretory phospholipase A2: Synthesis and inhibitory activities on indolizine and indene derivatives. J Med Chem 1996, 39, 19, 3636.
【2】 Dillard, R.D.; Hagishita, S.; Ohtani, M. (Eli Lilly and Company; Shionogi & Co. Ltd.); Indolizine sPLA2 inhibitors. EP 0772596; JP 1998505584; WO 9603383 .

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)	28241	ethyl (E)-3-[3-(benzyloxy)-2-pyridinyl]-2-propenoate		C₁₇H₁₇NO₃	详情	详情
(II)	28242	ethyl 3-[3-(benzyloxy)-2-pyridinyl]propanoate		C₁₇H₁₉NO₃	详情	详情
(III)	28243	ethyl 3-(3-hydroxy-2-pyridinyl)propanoate		C₁₀H₁₃NO₃	详情	详情
(IV)	28244	3-(3-hydroxy-2-pyridinyl)propanamide		C₈H₁₀N₂O₂	详情	详情
(V)	28245	3-[3-(benzyloxy)-2-pyridinyl]propanamide		C₁₅H₁₆N₂O₂	详情	详情
(VI)	28246	1-bromo-2-butanone	816-40-0	C₄H₇BrO	详情	详情
(VII)	28247	2-[8-(benzyloxy)-2-ethyl-1-indolizinyl]acetamide		C₁₉H₂₀N₂O₂	详情	详情
(VIII)	28248	2-[3-benzoyl-8-(benzyloxy)-2-ethyl-1-indolizinyl]acetamide		C₂₆H₂₄N₂O₃	详情	详情
(IX)	28249	2-[3-benzyl-8-(benzyloxy)-2-ethyl-1-indolizinyl]acetamide		C₂₆H₂₆N₂O₂	详情	详情
(X)	28250	2-(3-benzyl-2-ethyl-8-hydroxy-1-indolizinyl)acetamide		C₁₉H₂₀N₂O₂	详情	详情
(XI)	28251	methyl 2-[[1-(2-amino-2-oxoethyl)-3-benzyl-2-ethyl-8-indolizinyl]oxy]acetate		C₂₂H₂₄N₂O₄	详情	详情

Extended Information