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【结 构 式】 
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【药物名称】CP-642959 【化学名称】11-Amino-11-deoxy-3-des(hexopyranosyloxy)-9-deoxo-9-(methoxyimino)-6-O-methyl-3-oxo-11-[3(R)-[4-(3-pyridyl)imidazol-1-yl]butylhydrazino]erythromycin A 11- N1,12-O-cyclic carbamate 【CA登记号】271795-55-2 【 分 子 式 】C44H69N7O10 【 分 子 量 】856.08143 |
【开发单位】Pfizer (Originator) 【药理作用】Antibiotics, ANTIINFECTIVE THERAPY, Ketolides |
合成路线1
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 |
合成路线2
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.
| 【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
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.
| 【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 |
合成路线4
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).
| 【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 |
合成路线5
The condensation of anhydro imidazolide (XIII) with the substituted hydrazine (XXIII) generated the cyclic carbamate (XXVII). After acidic cleavage of the cladinose moiety, the resultant ketone (XXVIII) was converted to the O-methyl oxime (XXIX). The title compound was then obtained by Swern oxidation of (XXIX) followed by basic hydrolysis.
| 【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 |
|---|---|---|---|---|---|---|
| (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 |
| (XXIII) | 53100 | 3-{1-[(1R)-3-hydrazino-1-methylpropyl]-1H-imidazol-4-yl}pyridine | n/a | C12H17N5 | 详情 | 详情 |
| (XXVII) | 53103 | (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}-4-ethyl-11-methoxy-3a,7,9,11,13,15-hexamethyl-2,6,14-trioxo-1-({(3R)-3-[4-(3-pyridinyl)-1H-imidazol-1-yl]butyl}amino)tetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-8-yl]oxy}-4-methoxy-2,4-dimethyltetrahydro-2H-pyran-3-yl acetate | n/a | C55H86N6O15 | 详情 | 详情 |
| (XXVIII) | 53104 | (2S,3R,4S,6R)-2-{[(3aS,4R,7R,8S,9S,10R,11R,13R,15R)-4-ethyl-8-hydroxy-11-methoxy-3a,7,9,11,13,15-hexamethyl-2,6,14-trioxo-1-({(3R)-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 | C45H70N6O11 | 详情 | 详情 |
| (XXIX) | 53105 | (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-({(3R)-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 |