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【结 构 式】 
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【药物名称】 【化学名称】(6R,7S)-3-(Acetoxymethyl)-N-(3-iodobenzyl)-7-methoxy-3-cephem-4-carboxamide S,S-dioxide 【CA登记号】 【 分 子 式 】C18H19IN2O7S 【 分 子 量 】534.32973 |
【开发单位】GlaxoSmithKline (Originator) 【药理作用】Antiarthritic Drugs, Bone Diseases, Treatment of, METABOLIC DRUGS, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, Treatment of Osteoporosis, IL-1beta Converting Enzyme Inhibitors, TNF-alpha Antagonists |
合成路线1
7-Aminocephalosporanic acid (I) was converted to tert-butyl ester (II) by treatment with isobutylene and sulfuric acid. Subsequent diazotization, followed by reaction with methanol and rhodium catalyst, provided the 7-methoxy derivative (IIIa-b) as a diastereomeric mixture. The desired 7S-isomer was then deprotected with trifluoroacetic acid in anisole, yielding carboxylic acid (IV). Coupling of acid (IV) with 3-iodobenzylamine (VI) via activation as the mixed anhydride (V) with ethyl chloroformate gave rise to amide (VII). The sulfide group of (VII) was finally converted into the title sulfone by oxidation with oxone.
| 【1】 Levy, M.A.; Gleason, J.G. (SmithKline Beecham plc); Interleukin converting enzyme and apoptosis. EP 0851760; JP 1999514345; WO 9707805 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IIIa) | 43145 | tert-butyl (6R,7R)-3-[(acetoxy)methyl]-7-methoxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C15H21NO6S | 详情 | 详情 | |
| (IIIb) | 43146 | tert-butyl (6R,7S)-3-[(acetoxy)methyl]-7-methoxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C15H21NO6S | 详情 | 详情 | |
| (I) | 22747 | (6R,7R)-3-[(acetoxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C10H12N2O5S | 详情 | 详情 | |
| (II) | 32660 | tert-butyl (6R,7R)-3-[(acetoxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C14H20N2O5S | 详情 | 详情 | |
| (IV) | 43147 | (6R,7S)-3-[(acetoxy)methyl]-7-methoxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C11H13NO6S | 详情 | 详情 | |
| (V) | 43148 | C14H17NO8S | 详情 | 详情 | ||
| (VI) | 20865 | 3-iodobenzylamine; (3-iodophenyl)methanamine | C7H8IN | 详情 | 详情 | |
| (VII) | 43149 | ((6R,7S)-2-[[(3-iodobenzyl)amino]carbonyl]-7-methoxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl)methyl acetate | C18H19IN2O5S | 详情 | 详情 |
合成路线2
The synthesis of the 125I-labeled compound is shown in Scheme 2. Carboxylic acid (IV) was coupled with 3-(tri-n-butylstannyl)benzylamine (VIII) via the mixed anhydride (V) to produce amide (IX). Subsequent oxidation with oxone afforded the sulfone (X). Finally, iododestannylation of (X) employing Na125I and chloramine-T furnished the radiolabeled compound.
| 【1】 Garnes, K.T.; et al.; Preparation of 3-125I-benzyl-(6R,7S9-7-methoxy-3-acetoxymethyl-3-cephem-4-carboxamide-1,1-dioxide. J Label Compd Radiopharm 1999, 42, 1, 77. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 43147 | (6R,7S)-3-[(acetoxy)methyl]-7-methoxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C11H13NO6S | 详情 | 详情 | |
| (V) | 43148 | C14H17NO8S | 详情 | 详情 | ||
| (VIII) | 43150 | 3-(tributylstannyl)benzylamine; [3-(tributylstannyl)phenyl]methanamine | C19H35NSn | 详情 | 详情 | |
| (IX) | 43151 | [(6R,7S)-7-methoxy-8-oxo-2-([[3-(tributylstannyl)benzyl]amino]carbonyl)-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl acetate | C30H46N2O5SSn | 详情 | 详情 | |
| (X) | 43152 | [(6R,7S)-7-methoxy-5,5,8-trioxo-2-([[3-(tributylstannyl)benzyl]amino]carbonyl)-5lambda(6)-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl acetate | C30H46N2O7SSn | 详情 | 详情 |