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【结 构 式】 
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【分子编号】65927 【品名】(2R)-2-Deoxy-2-fluoro-2-methyl-D-erythropentonic acid gamma-lactone 3,5-dibenzoate 【CA登记号】874638-80-9 |
【 分 子 式 】C20H17FO6 【 分 子 量 】372.3497832 【元素组成】C 64.51% H 4.6% F 5.1% O 25.78% |
合成路线1
该中间体在本合成路线中的序号：(XXIV)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：(XXIV)The glycosyl intermediates (VIIIb) and (VIIIc) can be prepared by several related methods. Wittig condensation of 2,3-O-isopropylidene-D-glyceraldehyde (XVI) with (1-carbethoxyethylidene)triphenylphosphorane (XVII) in dry CH2Cl2 provides the unsaturated ester (XVIII) (7). Diastereoselective dihydroxylation of (XVIII) to give diol (XIX) is accomplished using a variety of reagents, including Sharpless oxidation with AD-mix-beta/methanesulfonamide (7), NMMO or t-BuOOH and catalytic OsO4, K3Fe(CN)6 and catalytic K2OsO2(OH)4, tetradecyltrimethylammonium permanganate (TDTAP) and KMnO4, optionally in the presence of crown ether or RuCl3/CeCl3/NaIO4 (4) and NaMnO4/NaHCO3 (5). After conversion of dihydroxy ester (XIX) to the cyclic sulfite (XX) by means of SOCl2 and Et3N, oxidation employing TEMPO/NaOCl or RuCl3/NaIO4 provides the correspondng sulfate ester (XXI). Ring opening of the cyclic sulfate (XXI) with HF-triethylamine complex or with tetrabutyl- or tetraethylammonium fluoride produces the respective ammonium fluorosulfates (XXIIa-c), which undergo cyclization to fluorolactone (XXXIII) under acidic conditions. Subsequent acylation of the dihydroxy ribonolactone (XXIII) with benzoyl chloride and DMAP followed by reduction of the resulting dibenzoyloxy lactone (XXIV) with either Red-Al or LiAlH(O-t-Bu)3 yields lactol (XXV) (4, 5), which is either acetylated to (VIIIb) using Ac2O and DMAP in THF (4) or chlorinated to (VIIIc) with sulfuryl chloride and TBAB (5). Alternatively, cyclization and deprotection of dihydroxy ester (XIX) with ethanolic HCl leads to 2-methyl-D-arabino-γ-lactone (XXVI), which, after protection as the dibenzoate ester (XXVII) with benzoyl chloride in dry pyridine, is fluorinated to (XXIV) using either diethylaminosulfur trifluoride (DAST) or bis(2-methoxyethyl)aminosulfur trifluoride (Deoxofluor) in THF (7). In a further method, dihydroxy ester (XIX) is selectively acylated at the secondary hydroxyl group with benzoyl chloride in pyridine to produce compound (XXVIII), which is fluorinated to (XXIX) by treatment with DAST or Deoxofluor in THF. Deprotection and cyclization of compound (XXIX) with TFA in hot CH3CN/H2O gives 3-O-benzoyl-2-methyl-2-deoxy-2-fluoro-D-ribono-γ-lactone (XXX), which is further benzoylated to (XXIV) by means of benzoyl chloride n the presence of DMAP and pyridine in AcOEt (7). Scheme 3.
| 【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. |
| 【7】 Wang, P., Stec, W., Clark, J., Chun, B.-K., Shi, J., Du, J. (Pharmasset, Inc.). Preparation of alkyl-substituted 2-deoxy-2-fluoro-D-ribofuranosyl pyrimidines and purines and their derivatives. WO 2006012440. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXIIA) | 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 | |
| (XXIIB) | 65924 | C27H54FNO8S | 详情 | 详情 | ||
| (XXIIC) | 65925 | C19H38FNO8S | 详情 | 详情 | ||
| (VIIIB) | 65912 | C22H21FO6 | 详情 | 详情 | ||
| (VIIIC) | 65913 | C20H17ClFO5 | 详情 | 详情 | ||
| (XVI) | 36759 | (4R)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde | 15186-48-8 | C6H10O3 | 详情 | 详情 |
| (XVII) | 37071 | ethyl 2-(triphenylphosphoranylidene)propanoate | 5717-37-3 | C23H23O2P | 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 | |
| (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) | 65929 | 2-C-Methyl-D-ribono-1,4-lactone; 3,4-Dihydroxy-5-(hydroxymethyl)-3-methyloxolan-2-one | 492-30-8 | C6H10O5 | 详情 | 详情 |
| (XXVII) | 65930 | C20H18O7 | 详情 | 详情 | ||
| (XXVIII) | 65931 | C18H24O7 | 详情 | 详情 | ||
| (XXIX) | 65932 | C18H23FO6 | 详情 | 详情 | ||
| (XXX) | 65933 | C13H13FO5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XXIV)The synthetic precursor (XXIV) can be prepared by a number of alternative methods.
Condensation of 2,3-O-isopropylidene-D-glyceraldehyde (XVI) with ethyl 2-fluoropropionate (XXXI) by means of LDA in cold THF gives a mixture of diastereomeric fluoro-hydroxy esters (XXXIIa) and (XXXI-Ib) along with minor amounts of isomer (XXXIIc). After removal of the undesired (2S,3R)-isomer (XXXIIb) by selective enzymatic hydrolysis with Candida antarctica lipase form B (CALB), the remaining mixture of fluoro-hydroxy esters (XXXIIa) and (XXXIIc) undergoes cyclization to the respective lactones (XXIII) and (XXXIII) upon heating with aqueous H2SO4 (8). Esterification of the mixture of diols (XXIII) and (XXXIII) with benzoyl chloride and DMAP in Et3N/CH3CN followed by recrystallization of the resulting dibenzoates from isopropanol provides compound (XXIV) (8, 9). Scheme 4.
In a related method, chlorination of 2-fluoropropionic acid (XXXIV) with oxalyl chloride and catalytic DMF in toluene followed by reaction with pyrrolidine leads to amide (XXXV). Subsequent condensation of fluoro-amide (XXXV) with glyceraldehyde acetonide (XVI) by means of LDA in THF produces fluoro-hydroxyamide (XXXVIa), which upon heating with aqueous AcOH generates lactone (XXIII) along with minor amounts of its diastereoisomer (XXXIII). Similarly, condensation of S-phenyl 2-fluoropropanethioate (XXXVII) with aldehyde (XVI) yields hydroxy thioester (XXXVIb), which undergoes cyclization to lactones (XXIII) and (XXXIII) under acidic conditions (9). Scheme 4.
In a further related method, acyl benzoxazolone (XXXIX) —prepared by coupling 2-fluoropropionic acid (XXXIV) with benzoxazolone (XXXVIII) in the presence of DCC and DMAP— is condensed with glyceraldehyde acetonide (XVI) by means of TiCl4 and Et3N in CH2Cl2 to furnish adduct (XL). Subsequent hydrolysis and cyclization of (XL) in AcOH/H2O at 90 °C produces the mixture of lactones (XXIII) and (XXXIII) (9). Scheme 4.
| 【8】 Cedilote, M., Cleary, T.P., Iding, H., Zhang, P. (F. Hoffmann-La Roche AG). Process for preparing 3,5-di-Omicron-acyl-2-fluoro-2-C-methyl-D-ribono-gamma-lactone. WO 2008074693. |
| 【9】 Cedilote, M., Cleary, T.P., Zhang, P. (F. Hoffmann-La Roche AG). Alternate process for preparing 3,5-di-Omicron-acyl-2-fluoro-2-C-methyl-D-ribono-gamma-lactone. WO 2008090046. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXXIIA) | 65935 | C11H19FO5 | 详情 | 详情 | ||
| (XXXIIB) | 65936 | C11H19FO5 | 详情 | 详情 | ||
| (XXXIIC) | 65937 | C11H19FO5 | 详情 | 详情 | ||
| (XXXVIA) | 65941 | C13H22FNO4 | 详情 | 详情 | ||
| (XXXVIB) | 65942 | C15H19FO4S | 详情 | 详情 | ||
| (XVI) | 36759 | (4R)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde | 15186-48-8 | C6H10O3 | 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 |
| (XXXI) | 65934 | Ethyl 2-fluoropropionate; Ethyl 2-fluoropropanoate; 2-Fluoropropanoic acid ethyl ester | 349-43-9 | C5H9FO2 | 详情 | 详情 |
| (XXXIII) | 65938 | (3S,4R,5R)-3-Fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyloxolan-2-one | C6H9FO4 | 详情 | 详情 | |
| (XXXIV) | 65939 | 2-Fluoropropionic acid | 6087-13-4 | C3H5FO2 | 详情 | 详情 |
| (XXXV) | 65940 | C7H12FNO | 详情 | 详情 | ||
| (XXXVII) | 65943 | C9H9FOS | 详情 | 详情 | ||
| (XXXVIII) | 41299 | 2-Benzoxazolinone; 2(3H)-benzoxazolone; 1,3-benzoxazol-2(3H)-one | 59-49-4 | C7H5NO2 | 详情 | 详情 |
| (XXXIX) | 65944 | C10H8FNO3 | 详情 | 详情 | ||
| (XL) | 65945 | C16H8FNO6 | 详情 | 详情 |