3-[4-(3-pyridinyl)-1H-imidazol-1-yl]butanal -Drug Synthesis Database

【结构式】

【分子编号】53087

【品名】3-[4-(3-pyridinyl)-1H-imidazol-1-yl]butanal

【CA登记号】n/a

【分子式】C₁₂H₁₃N₃O

【分子量】215.25484

【元素组成】C 66.96% H 6.09% N 19.52% O 7.43%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(IX)

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.

参考文献中间体

合成目标

【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

合成路线2

该中间体在本合成路线中的序号：(IX)

A related synthetic procedure started from 2',4''-bis-O-acetyl-6-O-methylerythromycin A (XII). Treatment of diol (XII) with carbonyldiimidazole in the presence of DBU generated the anhydro imidazolide (XIII). Reaction of (XIII) with hydrazine gave rise to the N-amino cyclic carbamate (XIV). Selective cleavage of the cladinose moiety at position 3 under acidic conditions afforded (XV). The keto group of (XV) was then converted to the oxime (XVI) upon treatment with O-methyl hydroxylamine. Reductive alkylation of (XVI) with aldehyde (IX) in the presence of NaBH(OAc)3 provided adduct (XVII). Then, Swern oxidation of the 3-hydroxy group of (XVII) to the corresponding ketone, followed by hydrolysis of the acetate ester, furnished the title ketolide as a diastereomeric mixture.

参考文献中间体

合成目标

【1】 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
(IX)	53087	3-[4-(3-pyridinyl)-1H-imidazol-1-yl]butanal	n/a	C₁₂H₁₃N₃O	详情	详情
(XII)	53089	(2S,3S,4R,6R)-6-[((3R,4S,5R,6R,7R,9R,11R,12R,13S,14R)-6-{[(2S,3R,4S,6R)-3-(acetyloxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-14-ethyl-12,13-dihydroxy-7-methoxy-3,5,7,9,11,13-hexamethyl-2,10-dioxooxacyclotetradecanyl)oxy]-4-methoxy-2,4-dimethyltetrahydro-2H-pyran-3-yl acetate	n/a	C₄₂H₇₃NO₁₅	详情	详情
(XIII)	53090	(2R,3S,7R,9R,10R,11R,12S,13R)-10-{[(2S,3R,4S,6R)-3-(acetyloxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-12-{[(2R,4R,5S,6S)-5-(acetyloxy)-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl]oxy}-2-ethyl-9-methoxy-3,5,7,9,11,13-hexamethyl-6,14-dioxooxa-4-cyclotetradecen-3-yl 1H-imidazole-1-carboxylate	n/a	C₄₆H₇₃N₃O₁₅	详情	详情
(XIV)	53091	(2S,3S,4R,6R)-6-[((3aS,4R,7R,8S,9R,10R,11R,13R,15R)-10-{[(2S,3R,4S,6R)-3-(acetyloxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-1-amino-4-ethyl-11-methoxy-3a,7,9,11,13,15-hexamethyl-2,6,14-trioxotetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-8-yl)oxy]-4-methoxy-2,4-dimethyltetrahydro-2H-pyran-3-yl acetate	n/a	C₄₃H₇₃N₃O₁₅	详情	详情
(XV)	53092	(2S,3R,4S,6R)-2-{[(3aS,4R,7R,8S,9S,10R,11R,13R,15R)-1-amino-4-ethyl-8-hydroxy-11-methoxy-3a,7,9,11,13,15-hexamethyl-2,6,14-trioxotetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl]oxy}-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-yl acetate	n/a	C₃₃H₅₇N₃O₁₁	详情	详情
(XVI)	53093	(2S,3R,4S,6R)-2-{[(3aS,4R,7R,8S,9S,10R,11R,13R,15R)-1-amino-4-ethyl-8-hydroxy-11-methoxy-14-(methoxyimino)-3a,7,9,11,13,15-hexamethyl-2,6-dioxotetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl]oxy}-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-yl acetate	n/a	C₃₄H₆₀N₄O₁₁	详情	详情
(XVII)	53094	(2S,3R,4S,6R)-2-{[(3aS,4R,7R,8S,9S,10R,11R,13R,15R)-4-ethyl-8-hydroxy-11-methoxy-14-(methoxyimino)-3a,7,9,11,13,15-hexamethyl-2,6-dioxo-1-({3-[4-(3-pyridinyl)-1H-imidazol-1-yl]butyl}amino)tetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl]oxy}-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-yl acetate	n/a	C₄₆H₇₃N₇O₁₁	详情	详情

合成路线3

该中间体在本合成路线中的序号：(IX)

In an alternative synthesis of hydrazine (XXIII), aldehyde (IX) was condensed with tert-butyl hydrazinecarboxylate (XXIV), producing hydrazone (XXV), which was further reduced to the hydrazinecarboxylate (XXVI) in the presence of NaBH(OAc)3. Acidic cleavage of the N-Boc group of (XXVI) provided hydrazine (XXIII).

参考文献中间体

合成目标

【1】 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
(IX)	53087	3-[4-(3-pyridinyl)-1H-imidazol-1-yl]butanal	n/a	C₁₂H₁₃N₃O	详情	详情
(XXIII)	53100	3-{1-[(1R)-3-hydrazino-1-methylpropyl]-1H-imidazol-4-yl}pyridine	n/a	C₁₂H₁₇N₅	详情	详情
(XXIV)	10893	tert-butyl 1-hydrazinecarboxylate; tert-butyl carbazate	870-46-2	C₅H₁₂N₂O₂	详情	详情
(XXV)	53101	tert-butyl 2-{(E,3R)-3-[4-(3-pyridinyl)-1H-imidazol-1-yl]butylidene}-1-hydrazinecarboxylate	n/a	C₁₇H₂₃N₅O₂	详情	详情
(XXVI)	53102	tert-butyl 2-{(3R)-3-[4-(3-pyridinyl)-1H-imidazol-1-yl]butyl}-1-hydrazinecarboxylate	n/a	C₁₇H₂₅N₅O₂	详情	详情

Extended Information