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【结 构 式】 
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【药物名称】ULODESINE 【化学名称】7-[(R)-Hydroxy-4(R)-(hydroxymethyl)pyrrolidine-1-ylmethyl]-5Hpyrrolo[3,2-d]pyrimidin-4-ol 【CA登记号】548486-59-5;615580-53-5 (as hydrochloride) 【 分 子 式 】C12H16N4O3 【 分 子 量 】264.2804 |
【开发单位】 【药理作用】Purine nucleoside phosphorylase inhibitor;Treatment of gout |
合成路线1
Condensation of ethyl(ethoxymethylene)cyanoacetate (I) with diethyl aminomalonate hydrochloride (II) in the presence of NaOMe in refluxing MeOH gives the pyrrole derivative (III), which is cyclized with formamidine acetate (IV) in refluxing EtOH to yield methyl 4-hydroxy-pyrrolo[3,2-d]pyrimidine-7-carboxylate (V). Decarbomethoxylation of ester (V) by means of aqueous KOH at reflux provides 4-hydroxy-pyrrolo[3,2-d]pyrimidine (VI), which by chlorination with POCl3 at reflux and subsequent chloride displacement with NaOBn in refluxing benzyl alcohol leads to 4-(benzyloxy)pyrrolo[3,2-d]pyrimidine (VII). Mannich reaction of deazapurine derivative (VII) with 4(R)-(hydroxymethyl)pyrrolidin-3(R)-ol (VIII) [obtained by debenzylation of compound (IX) with H2 and Pd/C in EtOH at 58 °C and formaldehyde in H2O at 58 °C yields the O-benzyl ulodesine derivative (X), which is finally deprotected by hydrogenolysis over Pd/C in aqueous ammonia .
In a related procedure, Mannich reaction of 4-hydroxypyrrolo-[3,2-d]pyrimidine (VI) with 4(R)-(hydroxymethyl)pyrrolidin-3(R)-ol hydrochloride (XI) [obtained by N-deprotection of 1-Boc-4(R)-(hydroxymethyl)pyrrolidin-3(R)-ol (XII) using HCl in MeOH (4)] and formaldehyde in the presence of NaOAc in H2O at 95 °C provides ulodesine as the corresponding acetate salt .
Alternatively, ulodesine can be obtained by deprotection of precursor (XIII) with H2 and Pd(OH)2/C in EtOH/AcOH .
| 【1】 Bradley, P.A., de Koning, P.D., Johnson, P.S., Lecouturier, Y.C., McManus, D.J., Robin, A., Underwood, T.J. Development of a practical synthesis of the progesterone receptor antagonist 4-[[3-cyclopropyl-1(mesylmethyl)-5-methyl-1H-pyrazol-4-yl]oxy]-2,6-dimethylbenzonitrile. Org Process Res Dev 2009, 13(5): 848. |
| 【2】 Evans, G.B., Furneaux, R.H., Tyler, P.C., Schramm, V.L. Synthesis of a transition state analogue inhibitor of purine nucleoside phosphorylate via the Mannich reaction. Org Lett 2003, 5(20): 3639-40. |
| 【3】 Evans, G.B., Tyler, P.C. (Callaghan Innovation Research, Ltd.; Albert Einstein College of Medicine). Process for preparing inhibitors of nucleoside phosphorylase and nucleosidases. JP 2006516615, US 7655795, US 2010094003, WO 2004069856. |
| 【4】 Furneaux, R.H., Schramm, V.L., Lenz, D.H., Evans, G.B., Tyler, P.C., Zubkova, O.V. (Albert Einstein College of Medicine; Callaghan Innovation Research, Ltd.). Inhibitors of nucleoside phosphorylases and nucleosidases. CA 2496698, EP 1539783, JP 2006501239, US 2006160765, US 2009239885, US 8173662, WO 2004018496. |
| 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) | 43041 | ethyl (Z)-2-cyano-3-ethoxy-2-propenoate | 94-05-3 | C8H11NO3 | 详情 | 详情 |
| (II) | 67707 | diethyl aminomalonate hydrochloride | 13433-00-6 | C7H13NO4.HCl | 详情 | 详情 |
| (III) | 67708 | dimethyl 3-amino-1H-pyrrole-2,4-dicarboxylate | 180059-04-5 | C8H10N2O4 | 详情 | 详情 |
| (IV) | 67709 | formamidine acetate | 3473-63-0 | CH4N2.C2H4O2 | 详情 | 详情 |
| (V) | 67710 | methyl 4-hydroxy-pyrrolo[3,2-d]pyrimidine-7-carboxylate | C8H7N3O3 | 详情 | 详情 | |
| (VI) | 67711 | 4-hydroxy-pyrrolo[3,2-d]pyrimidine | C6H5N3O | 详情 | 详情 | |
| (VII) | 67712 | 4-(benzyloxy)pyrrolo[3,2-d]pyrimidine | C13H11N3O | 详情 | 详情 | |
| (VIII) | 67713 | 4(R)-(hydroxymethyl)pyrrolidin-3(R)-ol | C5H11NO2 | 详情 | 详情 | |
| (IX) | 67714 | (3R,4R)-1-benzyl-4-(hydroxymethyl)pyrrolidin-3-ol | 253129-03-2 | C12H17NO2 | 详情 | 详情 |
| (X) | 67715 | (3R,4R)-1-((4-(benzyloxy)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methyl)-4-(hydroxymethyl)pyrrolidin-3-ol | C19H22N4O3 | 详情 | 详情 | |
| (XI) | 67716 | 4(R)-(hydroxymethyl)pyrrolidin-3(R)-ol hydrochloride | C5H11NO2.HCl | 详情 | 详情 | |
| (XII) | 67718 | 1-Boc-4(R)-(hydroxymethyl)pyrrolidin-3(R)-ol | C10H19NO4 | 详情 | 详情 | |
| (XIII) | 67717 | 7-(((3R,4R)-3-(benzyloxy)-4-((benzyloxy)methyl)pyrrolidin-1-yl)methyl)-5-((benzyloxy)methyl)-5H-pyrrolo[3,2-d]pyrimidin-4-ol | C34H36N4O4 | 详情 | 详情 |
合成路线2
Protection of the chiral aza-sugar (XIV) using Boc2O in MeOH provides the corresponding N-Boc derivative (XV) , which by oxidative cleavage of the vicinal diol with NaIO4, and subsequent reductive treatment with NaBH4 in EtOH leads to 1-Boc-3(R)-hydroxy-4(R)-(hydroxymethyl) pyrrolidine (XII). Protection of both hydroxyl groups of compound (XII) using PhCH2Br and NaH in DMF, followed by acidic cleavage of the Boc group, the resulting dibenzyl ether using methanolic HCl provides the protected pyrrolidine (XVI) . Reductive condensation of pyrrolidine (XVI) with the deazapurine aldehyde derivative (XVII) [obtained by metalation of the bromodeazapurine derivative (XVIII) with butyllithium in Et2O/PhOMe or THF at −78 °C, followed by quenching with DMF] using NaBH3CN in MeOH yields the fully protected compound (XIX) . Finally, selective cleavage of the t-butyl ether of (XIX) by means of HCl in MeOH or TFA in CH2Cl2 affords intermediate (XIII) .
| 【1】 Furneaux, R.H., Schramm, V.L., Lenz, D.H., Evans, G.B., Tyler, P.C., Zubkova, O.V. (Albert Einstein College of Medicine; Callaghan Innovation Research, Ltd.). Inhibitors of nucleoside phosphorylases and nucleosidases. CA 2496698, EP 1539783, JP 2006501239, US 2006160765, US 2009239885, US 8173662, WO 2004018496. |
| 【2】 Evans, G.B., Furneaux, R.H., Lewandowicz, A., Schramm, V.L., Tyler, P.C.Synthesis of second-generation transition state analogues of human purine nucleoside phosphorylase. J Med Chem 2003, 46(24): 5271-6. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XII) | 67718 | 1-Boc-4(R)-(hydroxymethyl)pyrrolidin-3(R)-ol | C10H19NO4 | 详情 | 详情 | |
| (XIII) | 67717 | 7-(((3R,4R)-3-(benzyloxy)-4-((benzyloxy)methyl)pyrrolidin-1-yl)methyl)-5-((benzyloxy)methyl)-5H-pyrrolo[3,2-d]pyrimidin-4-ol | C34H36N4O4 | 详情 | 详情 | |
| (XIV) | 67719 | (R)-1-((3R,4R)-4-hydroxypyrrolidin-3-yl)ethane-1,2-diol | C6H13NO3 | 详情 | 详情 | |
| (XV) | 67720 | (3R,4R)-tert-butyl 3-(R-1,2-dihydroxyethyl)-4-hydroxypyrrolidine-1-carboxylate | C11H21NO5 | 详情 | 详情 | |
| (XVI) | 67721 | (3R,4R)-3-(benzyloxy)-4-((benzyloxy)methyl)pyrrolidine hydrochloride | C19H23NO2.HCl | 详情 | 详情 | |
| (XVII) | 67722 | 5-((benzyloxy)methyl)-4-(tert-butoxy)-5H-pyrrolo[3,2-d]pyrimidine-7-carbaldehyde | C19H21N3O3 | 详情 | 详情 | |
| (XVIII) | 67723 | 5-((benzyloxy)methyl)-7-bromo-4-(tert-butoxy)-5H-pyrrolo[3,2-d]pyrimidine | 299916-78-2 | C18H20BrN3O2 | 详情 | 详情 |
| (XIX) | 67724 | 7-(((3R,4R)-3-(benzyloxy)-4-((benzyloxy)methyl)pyrrolidin-1-yl)methyl)-5-((benzyloxy)methyl)-4-(tert-butoxy)-5H-pyrrolo[3,2-d]pyrimidine | C38H44N4O4 | 详情 | 详情 |