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【结 构 式】 
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【药物名称】Peldesine, BCX-34 【化学名称】2-Amino-7-(3-pyridylmethyl)-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-4-one 【CA登记号】133432-71-0 【 分 子 式 】C12H11N5O 【 分 子 量 】241.25437 |
【开发单位】BioCryst (Originator), Torii (Licensee) 【药理作用】AIDS Medicines, Antiarthritic Drugs, Anti-HIV Agents, ANTIINFECTIVE THERAPY, Antipsoriatics, DERMATOLOGIC DRUGS, GASTROINTESTINAL DRUGS, Immunologic Neuromuscular Disorders, Treatment of, Inflammatory Bowel Disease, Agents for, Lymphoma Therapy, Multiple Sclerosis, Agents for, NEUROLOGIC DRUGS, Oncolytic Drugs, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, Purine-Nucleoside Phosphorylase Inhibitors |
合成路线1
BCX-34 is synthesized from 3-pyridylcarboxaldehyde in ten steps in 10% overall yield as described by Montgomery et al. and depicted in Scheme 19337601a. The reaction of (I) with cyanoacetic acid followed by sodium borohydride reduction of the substituted acrylonitrile intermediate gave (II) in good yield. A key step in the synthesis is the formation of aldehyde (III) using sodium hydride and ethyl formate. The enamine (IV) is then prepared from (III) and glycine methyl ester hydrochloride buffered with sodium acetate. Protection of the enamine nitrogen of (IV) is required to yield (V) before cyclization to pyrrole (VI) is carried out using 1,5-diazabicyclo[4.3.0]non-5-ene (DBN). This reaction gives a mixture of (VI) and (VII) as products and the mixture is all converted to (VII) by sodium carbonate hydrolysis before isolation of solid (VII). The cyclization of the pyrimidine ring portion of BCX-34 is accomplished in three steps from (VII) through a sequence first described by Yamazaki et al. A study of the reaction conditions for the final cyclization step of the synthesis of Peldesine described in scheme 19337601a, in order to improve the yield of the target compound, and to minimize the side products, is presented in Org Proc Res Develop 2000, 4: 129.
| 【1】 Yamazaki, A.; Takenishi, T.; Kumashiro, L.; Synthesis of guanosine and its derivatives from 5-amino-1-beta-D-ribofuranosyl-4-imidazolecarboxamide. I. Ring closure with benzoyl isothiocyanate. J Org Chem 1967, 32, 1825-8. |
| 【2】 Pathak, V.P.; Selective formation of pyrrolo[3,2-d]pyrimidines from methyl[(N-benzoyl-S-methylisothiocarbamoyl)amino]-1H-pyrrole-2-carboxylate. Org Process Res Dev 2000, 4, 2, 129. |
| 【3】 Niwas, S.; Secrist, J.A. III, Babu, Y.S.; Ealick, S.E.; Montgomery, J.A.; Guida, W.C.; Bugg, C.E.; Rose, J.D.; Erion, M.D.; Structure-based design of inhibitors of purine nucleoside phosphorylase. 1. 9-(Arylmethyl) derivatives of 9-deazaguanine. J Med Chem 1993, 36, 1, 55-9. |
| 【4】 Walsh, D.A.; Walsh, G.M.; Montgomery, J.A.; Snyder, H.W. Jr.; BCX-34. Drugs Fut 1993, 18, 10, 887. |
| 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) | 12849 | Nicotinaldehyde; 3-Pyridinecarboxaldehyde | 500-22-1 | C6H5NO | 详情 | 详情 |
| (II) | 16026 | 3-(3-pyridinyl)propanenitrile | C8H8N2 | 详情 | 详情 | |
| (III) | 16027 | 2-formyl-3-(3-pyridinyl)propanenitrile | C9H8N2O | 详情 | 详情 | |
| (IV) | 16028 | methyl 2-[[(Z)-2-cyano-3-(3-pyridinyl)-1-propenyl]amino]acetate | C12H13N3O2 | 详情 | 详情 | |
| (V) | 16029 | methyl 2-[[(Z)-2-cyano-3-(3-pyridinyl)-1-propenyl](ethoxycarbonyl)amino]acetate | C15H17N3O4 | 详情 | 详情 | |
| (VI) | 16030 | methyl 3-amino-4-(3-pyridinylmethyl)-1H-pyrrole-2-carboxylate | C12H13N3O2 | 详情 | 详情 | |
| (VII) | 16031 | 1-ethyl 2-methyl 3-amino-4-(3-pyridinylmethyl)-1H-pyrrole-1,2-dicarboxylate | C15H17N3O4 | 详情 | 详情 | |
| (VIII) | 16032 | methyl 3-[[(benzoylamino)carbothioyl]amino]-4-(3-pyridinylmethyl)-1H-pyrrole-2-carboxylate | C20H18N4O3S | 详情 | 详情 | |
| (IX) | 16033 | methyl 3-[[(Z)-(benzoylamino)(methylsulfanyl)methylidene]amino]-4-(3-pyridinylmethyl)-1H-pyrrole-2-carboxylate | C21H20N4O3S | 详情 | 详情 |
合成路线2
An improved synthesis of [14C]-peldesine has been reported: The reaction of S-methyl-[14C]-isothiourea (I) with methyl chloroformate (II) by means of tetrabutylammonium bromide in dichloromethane gives N,N'-bis(methoxycarbonyl)-S-methyl-[14C]-isothiourea (III). This compound is condensed with 3-amino-4-(3-pyridylmethyl)-1H-pyrrole-2-carboxylic acid methyl ester (IV) by means of acetic acid in methanol yielding the labeled guanidine (V). The cyclization of (V) by means of sodium methoxide in methanol affords the carbamate precursor (VI), which is finally deprotected with NaOH in hot water.
| 【1】 Elliott, A.J.; Kwong, C.D.; Montgomery, J.A.; An improved synthesis of 9-(3-pyridylmethyl)-[2-14C]-9-deazaguanine. J Label Compd Radiopharm 1998, 41, 10, 879. |
| 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) | 10272 | [[Amino(imino)methyl]sulfanyl]methane | 2986-19-8 | C2H6N2S | 详情 | 详情 |
| (I) | 44636 | [[amino(imino)methyl]sulfanyl]methane | C2H6N2S | 详情 | 详情 | |
| (II) | 16993 | methyl chlorocarbonate;Carbonochloridic acid methyl ester；[(chlorocarbonyl)oxy]methane；methyl chloroformate | 79-22-1 | C2H3ClO2 | 详情 | 详情 |
| (III) | 28696 | methyl (Z)-[(methoxycarbonyl)amino](methylsulfanyl)methylidenecarbamate | C6H10N2O4S | 详情 | 详情 | |
| (III) | 45292 | methyl (Z)-[(methoxycarbonyl)amino](methylsulfanyl)methylidenecarbamate | C6H10N2O4S | 详情 | 详情 | |
| (IV) | 16030 | methyl 3-amino-4-(3-pyridinylmethyl)-1H-pyrrole-2-carboxylate | C12H13N3O2 | 详情 | 详情 | |
| (V) | 28697 | methyl 3-([bis[(methoxycarbonyl)amino]methylene]amino)-4-(3-pyridinylmethyl)-1H-pyrrole-2-carboxylate | C17H19N5O6 | 详情 | 详情 | |
| (V) | 45293 | methyl 3-([bis[(methoxycarbonyl)amino]methylene]amino)-4-(3-pyridinylmethyl)-1H-pyrrole-2-carboxylate | C17H19N5O6 | 详情 | 详情 | |
| (VI) | 28698 | methyl 4-oxo-7-(3-pyridinylmethyl)-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-ylcarbamate | C14H13N5O3 | 详情 | 详情 | |
| (VI) | 45294 | methyl 4-oxo-7-(3-pyridinylmethyl)-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-ylcarbamate | C14H13N5O3 | 详情 | 详情 |