|
【结 构 式】 
|
【分子编号】12715 【品名】N-(2-Oxo-1,2-dihydro-4-pyrimidinyl)benzamide; N-Benzoylcytosine 【CA登记号】26661-13-2 |
【 分 子 式 】C11H9N3O2 【 分 子 量 】215.21148 【元素组成】C 61.39% H 4.22% N 19.53% O 14.87% |
合成路线1
该中间体在本合成路线中的序号：(XXVII)Oxidation of unsaturated ester (XVIII) with sodium permanganate and NaHCO3 produces dihydroxy ester (XIX), which is converted to the cyclic sulfite (XX) by treatment with SOCl2 in the presence of Et3N. After oxidation of sulfite (XX) to the corresponding sulfate (XXI) by means of NaOCl, addition of triethylamine trihydrofluoride in triethylamine solution at 85 °C leads the fluorolactone (XXIII) via intermediate (XXII). Subsequent acylation of diol (XXIII) with benzoyl chloride and DMAP, followed by reduction of the resulting dibenzoyloxy lactone (XXIV) with Red-Al in CH2Cl2/toluene/trifluoroethanol produces lactol (XXV), which is converted to the furanosyl chloride (XXVI) by addition of sulfuryl chloride and catalytic TBAB. Finally, silylation of N-benzoylcytosine (XXVII) by heating with hexamethyldisilazane and ammonium sulfate, followed by coupling with the glycosyl chloride (XXVII) by means of SnCl4, yields the tribenzoyl fluorocytidine derivative (II) .
| 【1】 Axt, S.D., Sarma, K., Vitale, J. et al. (Pharmasset, Inc., F. Hoffmann-La Roche AG). Preparation of nucleosides ribofuranosyl pyrimidines, WO 2008045419. |
| 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) | 65910 | (2'R)-N-Benzoyl-2'-deoxy-2'-fluoro-2'-methylcytidine 3',5'-dibenzoate | 817204-32-3 | C31H26FN3O7 | 详情 | 详情 |
| (XVIII) | 65919 | (2E)-3-[(4R)-2,2-Dimethyl-1,3-dioxolan-4-yl]-2-methyl-2-propenoic acid ethyl ester | C11H18O4 | 详情 | 详情 | |
| (XIX) | 65920 | (2S,3R)-3-((4R)-2,2-Dimethyldioxolan-4-yl)-2-methyl-2,3-dihydroxypropanoic acid ethyl ester | 93635-76-8 | C11H20O6 | 详情 | 详情 |
| (XX) | 65921 | (4S,5S)-ethyl 5-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-4-methyl-1,3,2-dioxathiolane-4-carboxylate 2-oxide | C11H18O7S | 详情 | 详情 | |
| (XXI) | 65922 | (4S,5S)-ethyl 5-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-4-methyl-1,3,2-dioxathiolane-4-carboxylate 2,2-dioxide | C11H18O8S | 详情 | 详情 | |
| (XXII) | 65923 | triethylammonium (1R,2S)-1-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-3-ethoxy-2-fluoro-2-methyl-3-oxopropyl sulfate | C17H34FNO8S | 详情 | 详情 | |
| (XXIII) | 65926 | (3R,4R,5R)-3-Fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyloxolan-2-one; (2R)-2-Deoxy-2-fluoro-2-methyl-D-erythro-pentonic acid gamma-lactone | 879551-04-9 | C6H9FO4 | 详情 | 详情 |
| (XXIV) | 65927 | (2R)-2-Deoxy-2-fluoro-2-methyl-D-erythropentonic acid gamma-lactone 3,5-dibenzoate | 874638-80-9 | C20H17FO6 | 详情 | 详情 |
| (XXV) | 65928 | C20H19FO6 | 详情 | 详情 | ||
| (XXVI) | 65913 | C20H17ClFO5 | 详情 | 详情 | ||
| (XXVII) | 12715 | N-(2-Oxo-1,2-dihydro-4-pyrimidinyl)benzamide; N-Benzoylcytosine | 26661-13-2 | C11H9N3O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXI)3) The reaction of 2(S),3-O-isopropylideneglycerol (XV) with methanesulfonyl chloride and triethylamine in dichloromethane gives the corresponding mesylate (XVI), which is condensed with cytosine (XII) by means of cesium carbonate as before yielding 1-[2(S),3-(isopropylidenedioxy)propyl]cytosine (XVII). The deprotection of (XVII) with aqueous acetic acid at 100 C affords the corresponding diol (XVIII), which is treated with trityl chloride, DMAP and triethylamine in DMF to give the monotrityl compound (XIX). The condensation of (XIX) with diethyl tosyloxymethylphosphonate (VIII) [obtained by reaction of diethylphosphite (XX) with paraformaldehyde, followed by tosylation with tosyl chloride] by a previous treatment of (XX) with DMF dimethylacetal, then condensation by means of NaH in DMF, and a final hydrolysis with hot aqueous acetic acid yields the 1-[2(S)-(diethoxyphosphorylmethoxy)-3-hydroxypropyl]cytosine (XIV) (already obtained), which is finally treated with bromotrimethylsilane as before. 4) The reaction of the acetonide (XVI) with N4-benzoylcytosine (XXI) by means of potassium tert-butoxide or cesium carbonate gives the condensation product (XXII), which is deprotected with HCl in acetic acid yielding the diol (XXIII). The reaction of (XXIII) with trityl chloride and DMAP in refluxing pyridine affords the monotritylated compound (XXIV), which is condensed with the phosphonate (VIII) by means of NaH in DMF to give the fully protected HPMPC compound (XXV). The successive deprotections of (XXV), first with HCl in dichloromethane to eliminate the trityl group yielding (XXVI), then with bromotrimethylsilane to obtain the free phosphono group giving (XXVII), and finally with concentrated aqueous NH4OH to eliminate the benzoyl group affords cidofovir. 5) The benzoylation of acetonide derivative (XVII) with benzoyl anhydride in refluxing pyridine gives the benzoyl citosine derivative (XXII) already obtained.
| 【1】 Fromtling, R.A.; Castaner, J.; Cidofovir. Drugs Fut 1996, 21, 10, 1003. |
| 【2】 Bronson, J.J.; Ferrara, L.M.; Howell, H.G.; Brodfuehrer, P.R.; Martin, J.C.; A new synthesis of the potent and selective anti-herpesvirus agent (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine. Nucleosides Nucleotides 1990, 9, 6, 745-69. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIII) | 12702 | (diethoxyphosphoryl)methyl 4-methylbenzenesulfonate | 31618-90-3 | C12H19O6PS | 详情 | 详情 |
| (XII) | 12706 | Cytosine; 4-Amino-2(1H)-pyrimidinone | 71-30-7 | C4H5N3O | 详情 | 详情 |
| (XIV) | 12708 | diethyl [[(1S)-2-[4-amino-2-oxo-1(2H)-pyrimidinyl]-1-(hydroxymethyl)ethyl]oxy]methylphosphonate | C12H22N3O6P | 详情 | 详情 | |
| (XV) | 12709 | [(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]methanol | 22323-82-6 | C6H12O3 | 详情 | 详情 |
| (XVI) | 12710 | [(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl methanesulfonate | C7H14O5S | 详情 | 详情 | |
| (XVII) | 12711 | 4-Amino-1-[[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl]-2(1H)-pyrimidinone | C10H15N3O3 | 详情 | 详情 | |
| (XVIII) | 12695 | 4-Amino-1-[(2S)-2,3-dihydroxypropyl]-2(1H)-pyrimidinone | C7H11N3O3 | 详情 | 详情 | |
| (XIX) | 12713 | 4-Amino-1-[(2S)-2-hydroxy-3-(trityloxy)propyl]-2(1H)-pyrimidinone | C26H25N3O3 | 详情 | 详情 | |
| (XX) | 12714 | diethyl phosphonate; diethyl phosphite | 762-04-9 | C4H11O3P | 详情 | 详情 |
| (XXI) | 12715 | N-(2-Oxo-1,2-dihydro-4-pyrimidinyl)benzamide; N-Benzoylcytosine | 26661-13-2 | C11H9N3O2 | 详情 | 详情 |
| (XXII) | 12716 | N-(1-[[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]methyl]-2-oxo-1,2-dihydro-4-pyrimidinyl)benzamide | C17H19N3O4 | 详情 | 详情 | |
| (XXIII) | 12717 | N-[1-[(2S)-2,3-Dihydroxypropyl]-2-oxo-1,2-dihydro-4-pyrimidinyl]benzamide | C14H15N3O4 | 详情 | 详情 | |
| (XXIV) | 12718 | N-[1-[(2S)-2-Hydroxy-3-(trityloxy)propyl]-2-oxo-1,2-dihydro-4-pyrimidinyl]benzamide | C33H29N3O4 | 详情 | 详情 | |
| (XXV) | 12719 | diethyl ([(1S)-2-[4-(benzoylamino)-2-oxo-1(2H)-pyrimidinyl]-1-[(trityloxy)methyl]ethyl]oxy)methylphosphonate | C38H40N3O7P | 详情 | 详情 | |
| (XXVI) | 12720 | diethyl [[(1S)-2-[4-(benzoylamino)-2-oxo-1(2H)-pyrimidinyl]-1-(hydroxymethyl)ethyl]oxy]methylphosphonate | C19H26N3O7P | 详情 | 详情 | |
| (XXVII) | 12721 | [[(1S)-2-[4-(Benzoylamino)-2-oxo-1(2H)-pyrimidinyl]-1-(hydroxymethyl)ethyl]oxy]methylphosphonic acid | C15H18N3O7P | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IX)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 |