3-(1H-imidazol-4-yl)pyridine -Drug Synthesis Database

【结构式】

【分子编号】17164

【品名】3-(1H-imidazol-4-yl)pyridine

【CA登记号】

【分子式】C₈H₇N₃

【分子量】145.1638

【元素组成】C 66.19% H 4.86% N 28.95%

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：(VIII)

The selective mesylation of 2'-O-acetyl-3-des(2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyloxy)-6-O-methyl-3-oxoerythromycin A (I) with methanesulfonic anhydride in pyridine gives the expected 11-O-methanesulfonyl derivative (II), which is treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in acetone to yield the 10,11-didehydro derivative (III). The acylation of (III) with carbonyl diimidazole (IV) by means of NaH in THF affords the 12-O-acyl derivative (V), which is finally cyclocondensed with 4-[4-(3-pyridyl)imidazol-1-yl]butylamine (VI) in hot acetonitrile. The intermediate compound 4-[4-(3-pyridyl)imidazol-1-yl]butylamine (VI) is obtained as follows: The condensation of N-(4-bromobutyl)phthalimide (VII) with 4-(3-pyridyl)imidazole (VIII) by means of NaH in DMF gives N-[4-[4-(3-pyridyl)imidazol-1-yl]butyl]phthalimide (IX), which is then treated with hydrazine in refluxing ethanol.

参考文献中间体

合成目标

【1】 Castañer, J.; Graul, A.; HMR-3647. Drugs Fut 1998, 23, 6, 591.
【2】 Agouridas, C.; Denis, A.; Auger, J.-M.; et al.; Synthesis and antibacterial activity of HMR 3647 a new ketolide highly potent against erythromycin-resistant and susceptible pathogens. Bioorg Med Chem Lett 1999, 9, 21, 3075.
【3】 Agouridas, C.; Chantot, J.-F.; Denis, A.; Gouin d'Ambrieres, S.; Le Martret, O. (Aventis Pharma SA); Novel erythromycin derivs., method for their preparation and their use as drugs. EP 0680967; FR 2719587; JP 1996053489; JP 1999152296; US 5635485; WO 9529929 .
【4】 Agouridas, C.; Chantot, J.F.; Denis, A.; Gouin d'Ambrieres, S.; Le Martret, O. (Aventis Pharma SA); Novel erythromycin derivs., their process of preparation and their application as medicines. FR 2732684 .

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)	17157	(2S,3R,4S,6R)-4-(dimethylamino)-2-[[(3R,5R,6R,7R,9R,11R,12R,13S,14R)-14-ethyl-12,13-dihydroxy-7-methoxy-3,5,7,9,11,13-hexamethyl-2,4,10-trioxooxacyclotetradecanyl]oxy]-6-methyltetrahydro-2H-pyran-3-yl acetate		C₃₂H₅₅NO₁₁	详情	详情
(II)	17158	(2S,3R,4S,6R)-4-(dimethylamino)-2-([(3R,5R,6R,7R,9R,11R,12R,13R,14R)-14-ethyl-13-hydroxy-7-methoxy-3,5,7,9,11,13-hexamethyl-12-[(methylsulfonyl)oxy]-2,4,10-trioxooxacyclotetradecanyl]oxy)-6-methyltetrahydro-2H-pyran-3-yl acetate		C₃₃H₅₇NO₁₃S	详情	详情
(III)	17159	(2S,3R,4S,6R)-4-(dimethylamino)-2-[[(3R,5R,6R,7R,9R,13S,14R)-14-ethyl-13-hydroxy-7-methoxy-3,5,7,9,11,13-hexamethyl-2,4,10-trioxooxa-11-cyclotetradecen-6-yl]oxy]-6-methyltetrahydro-2H-pyran-3-yl acetate		C₃₂H₅₃NO₁₀	详情	详情
(IV)	11353	1,1'-Carbonyldiimidazole; Di(1H-imidazol-1-yl)methanone; N,N-Carbonyldiimidazole; 1,1'-Carbonylbis(1H-imidazole)	530-62-1	C₇H₆N₄O	详情	详情
(V)	17161	(2R,3S,7R,9R,10R,11R,13R)-10-[[(2S,3R,4S,6R)-3-(acetoxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl]oxy]-2-ethyl-9-methoxy-3,5,7,9,11,13-hexamethyl-6,12,14-trioxooxa-4-cyclotetradecen-3-yl 1H-imidazole-1-carboxylate		C₃₆H₅₅N₃O₁₁	详情	详情
(VI)	17162	4-[4-(3-pyridinyl)-1H-imidazol-1-yl]butylamine; 4-[4-(3-pyridinyl)-1H-imidazol-1-yl]-1-butanamine	173838-63-6	C₁₂H₁₆N₄	详情	详情
(VII)	17163	N-(4-Bromobutyl)phthalimide; 2-(4-Bromobutyl)-1H-isoindole-1,3(2H)-dione	5394-18-3	C₁₂H₁₂BrNO₂	详情	详情
(VIII)	17164	3-(1H-imidazol-4-yl)pyridine		C₈H₇N₃	详情	详情
(IX)	17165	2-[4-[4-(3-pyridinyl)-1H-imidazol-1-yl]butyl]-1H-isoindole-1,3(2H)-dione	173838-67-0	C₂₀H₁₈N₄O₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(II)

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3

该中间体在本合成路线中的序号：(II)

The intermediate hydrazine (XXIII) was obtained by two alternative methods. Alkylation of 4-(3-pyridyl)imidazole (II) with the chiral mesylate (XIX), prepared from (R)-1,3-butanediol (XVIII), furnished, after desilylation with tetrabutylammonium fluoride, the imidazolyl butanol (XX). Condensation of alcohol (XX) with di-tert-butyl azodicarboxylate in the presence of PPh3 yielded the hydrazine dicarboxylate (XXII), which was then deprotected to hydrazine (XXIII) under acidic conditions.

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
(II)	17164	3-(1H-imidazol-4-yl)pyridine		C₈H₇N₃	详情	详情
(XVIII)	53095	(R)-(-)-1,3-Butanediol; (R)-(-)-1,3-Butylene glycol; (R)-(-)-1,3-Dihydroxybutane; (R)-1,3-Butanediol	6290-03-5	C₄H₁₀O₂	详情	详情
(XIX)	53096	(1R)-3-{[tert-butyl(dimethyl)silyl]oxy}-1-methylpropyl methanesulfonate	n/a	C₁₁H₂₆O₄SSi	详情	详情
(XX)	53097	(3R)-3-[4-(3-pyridinyl)-1H-imidazol-1-yl]-1-butanol	n/a	C₁₂H₁₅N₃O	详情	详情
(XXI)	53098	Azodicarboxylic acid di-tert-butyl ester	870-50-8	C₁₀H₁₈N₂O₄	详情	详情
(XXII)	53099	di(tert-butyl) 1-{(3R)-3-[4-(3-pyridinyl)-1H-imidazol-1-yl]butyl}-1,2-hydrazinedicarboxylate	n/a	C₂₂H₃₃N₅O₄	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

Extended Information