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【结 构 式】 
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【分子编号】65909 【品名】N-Benzoyl-3',5'-di-O-benzoyl-2'-C-methyl-D-cytidine 【CA登记号】 |
【 分 子 式 】C31H27N3O8 【 分 子 量 】569.5708 【元素组成】C 65.37% H 4.78% N 7.38% O 22.47% |
合成路线1
该中间体在本合成路线中的序号： (XVII)Reaction of cytidine (XII) with benzoyl anhydride in DMF gives Nbenzoylcytidine (XIII), which is selectively protected with 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane (TIPDSCl2) in pyridine to yield the silylated cytidine (XIV). Oxidation of the remaining OH group of (XIV) by means of DMSO, TFAA and TEA produces the ketone (XV), which by a Grignard condensation with MeLi, followed by a desilylation with AcOH provides the tertiary alcohol (XVI). Selective benzoylation of the primary and secondary OH groups of compound (XVI) with benzoyl chloride and pyridine results in tribenzoate (XVII) with a remaining free tertiary OH group. Finally, benzoate (XVII) is fluorinated with DAST to yield the tribenzoylated fluorocytidine (II) .
| 【1】 Clark, J. (Pharmasset, Inc.). Modified fluorinated nucleoside analogues, WO 2005003147. |
| 【2】 Clark, J.L., Hollecker, L., Mason, J.C. et al. Design, synthesis, and antiviral activity of 2’-deoxy-2’-fluoro-2’-C-methylcytidine, a potent inhibitor of hepatitis C virus replication. J Med Chem 2005, 45(17): 5504-8. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVII) | 65909 | N-Benzoyl-3',5'-di-O-benzoyl-2'-C-methyl-D-cytidine | C31H27N3O8 | 详情 | 详情 | |
| (II) | 65910 | (2'R)-N-Benzoyl-2'-deoxy-2'-fluoro-2'-methylcytidine 3',5'-dibenzoate | 817204-32-3 | C31H26FN3O7 | 详情 | 详情 |
| (XII) | 27920 | Cytidine; 4-amino-1-((2S,3S,4S,5S)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidin-2(1H)-one;4-amino-1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-2(1H)-pyrimidinone | 65-46-3 | C9H13N3O5 | 详情 | 详情 |
| (XIII) | 61580 | N-Benzoylcytidine;N-[1-[3,4-Dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-2-oxopyrimidin-4-yl]benzamide;N-{1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-2-oxo-1,2-dihydro-4-pyrimidinyl}benzamide | 13089-48-0 | C16H17N3O6 | 详情 | 详情 |
| (XIV) | 65906 | N-Benzoyl-3',5'-O-[1,1,3,3-tetrakis(1-methylethyl)-1,3-disiloxanediyl]cytidine; N-[1-[(6aR,8R,9R,9aS)-9-hydroxy-2,2,4,4-tetra(propan-2-yl)-6a,8,9,9a-tetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-8-yl]-2-oxopyrimidin-4-yl]benzamide | 69304-43-4 | C28H43N3O7Si2 | 详情 | 详情 |
| (XV) | 65907 | N-Benzoyl-2'-deoxy-2'-oxo-3',5'-O-[1,1,3,3-tetrakis(1-methylethyl)-1,3-disiloxanediyl]cytidine | 119411-03-9 | C28H41N3O7Si2 | 详情 | 详情 |
| (XVI) | 65908 | N-Benzoyl-2'-C-methyl-D-cytidine | C17H19N3O6 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)Acylation of cytidine (I) with benzoic anhydride in DMF provides N4-benzoylcytidine (II), which is regioselectively protected at the 3’- and 5’-hydroxyl groups with 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane in pyridine, giving the cyclic siloxane derivative (III). Subsequent Swern oxidation of the 2’-alcohol group of compound (III) using DMSO, TFAA and Et3N followed by addition of methyllithium to the obtained ketone (IV) and desilylation with AcOH leads to the 2’-C-methylcytidine derivative (V). After reprotection of the primary and secondary hydroxyl groups of the cytidine (V) with benzoyl chloride in pyridine, the tertiary hydroxyl of compound (VI) is fluorinated using DAST in cold toluene to give the benzoyl-protected 2’-deoxy-2’-fluoro-2’-methylcytidine (VII) (1-3). In a different strategy, the nucleoside derivative (VII) is prepared by coupling of the methyl (VIIIa) (1-3) or acetyl (VIIIb) glycosides (4) or the glycosyl chloride (VIIIc) (5) with silylated N4-benzoylcytosine (IX) by means of either trimethylsilyl triflate or tin tetrachloride. The tribenzoylated precursor (VII) is then deprotected with methanolic NaOMe (1, 2) or ammonia (3, 4) to obtain PSI-6130 (X), which is finally esterified with isobutyryl chloride (XI) in the presence of DMAP and Et3N in THF/H2O (6). Scheme 1.
| 【1】 Clark, J. (Pharmasset Ltd.). Modified fluorinated nucleoside analogues. WO 2005003147. |
| 【2】 Clark, J.L., Hollecker, L., Mason, J.C. Design, synthesis, and antiviral activity of 2’-deoxy-2’-fluoro-2’-C-methylcytidine, a potent inhibitor of hepatitis C virus replication. J Med Chem 2005, 48(17): 5504-8. |
| 【3】 Clark, J. (Pharmasset, Inc.). Modified fluorinated nucleoside analogues. US 20080070861. |
| 【4】 Chun, B.-K., Wang, P. (Pharmasset, Inc.). Preparation of 2’-fluoro-2’-alkyl-substituted or other optionally substituted ribofuranosyl pyrimidines and purines and their derivatives. WO 2006031725. |
| 【5】 Axt, S.D., Sarma, K., Vitale, J. et al. (Pharmasset, Inc.; F. Hoffmann La Roche AG). Preparation of nucleosides ribofuranosyl pyrimidines. WO 2008045419. |
| 【6】 Chun, B.-K., Clark, J., Sarma, K., Wang, P. (F. Hoffmann-La Roche AG; Pharmasset, Inc.). Antiviral nucleosides. WO 2007065829. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIIIA) | 65911 | ((2S,3S,4S)-3-(benzoyloxy)-4-fluoro-5-methoxy-4-methyltetrahydrofuran-2-yl)methyl benzoate | C21H21FO6 | 详情 | 详情 | |
| (VIIIB) | 65912 | C22H21FO6 | 详情 | 详情 | ||
| (VIIIC) | 65913 | C20H17ClFO5 | 详情 | 详情 | ||
| (I) | 27920 | Cytidine; 4-amino-1-((2S,3S,4S,5S)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidin-2(1H)-one;4-amino-1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-2(1H)-pyrimidinone | 65-46-3 | C9H13N3O5 | 详情 | 详情 |
| (II) | 61580 | N-Benzoylcytidine;N-[1-[3,4-Dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-2-oxopyrimidin-4-yl]benzamide;N-{1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-2-oxo-1,2-dihydro-4-pyrimidinyl}benzamide | 13089-48-0 | C16H17N3O6 | 详情 | 详情 |
| (III) | 65906 | N-Benzoyl-3',5'-O-[1,1,3,3-tetrakis(1-methylethyl)-1,3-disiloxanediyl]cytidine; N-[1-[(6aR,8R,9R,9aS)-9-hydroxy-2,2,4,4-tetra(propan-2-yl)-6a,8,9,9a-tetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-8-yl]-2-oxopyrimidin-4-yl]benzamide | 69304-43-4 | C28H43N3O7Si2 | 详情 | 详情 |
| (IV) | 65907 | N-Benzoyl-2'-deoxy-2'-oxo-3',5'-O-[1,1,3,3-tetrakis(1-methylethyl)-1,3-disiloxanediyl]cytidine | 119411-03-9 | C28H41N3O7Si2 | 详情 | 详情 |
| (V) | 65908 | N-Benzoyl-2'-C-methyl-D-cytidine | C17H19N3O6 | 详情 | 详情 | |
| (VI) | 65909 | N-Benzoyl-3',5'-di-O-benzoyl-2'-C-methyl-D-cytidine | C31H27N3O8 | 详情 | 详情 | |
| (VII) | 65910 | (2'R)-N-Benzoyl-2'-deoxy-2'-fluoro-2'-methylcytidine 3',5'-dibenzoate | 817204-32-3 | C31H26FN3O7 | 详情 | 详情 |
| (IX) | 12715 | N-(2-Oxo-1,2-dihydro-4-pyrimidinyl)benzamide; N-Benzoylcytosine | 26661-13-2 | C11H9N3O2 | 详情 | 详情 |
| (X) | 65914 | 2'-Deoxy-2'-fluoro-2'-C-methylcytidine | 817204-33-4 | C10H14FN3O4 | 详情 | 详情 |
| (XI) | 14932 | isobutyryl chloride; 2-methylpropanoyl chloride | 79-30-1 | C4H7ClO | 详情 | 详情 |