• English
  • 简体中文
Login Register
Current Location: Home > Feedback Help Print

【结 构 式】

【分子编号】65926

【品名】(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

【CA登记号】879551-04-9

【 分 子 式 】C6H9FO4

【 分 子 量 】164.1334632

【元素组成】C 43.91% H 5.53% F 11.57% O 38.99%

与该中间体有关的原料药合成路线共 3 条

合成路线1

该中间体在本合成路线中的序号:(XXIII)

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:(XXIII)

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:(XXIII)

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
Extended Information