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【结 构 式】

【药物名称】SGI-110;S-110

【化学名称】2'-Deoxy-5'-O-[(2'-deoxy-5-azacytidin-3'-O-yl)(hydroxy)phosphoryl]guanosine sodium salt

【CA登记号】929904-85-8;929901-49-5 (free acid)

【 分 子 式 】C18H23N9O10P.Na

【 分 子 量 】579.3931

【开发单位】Astex Pharmaceuticals, Inc. (US)

【药理作用】DNA Methyltransferase Inhibitor;Oncolytic

合成路线1

In one method, condensation of decitabine (I) with N,N-dimethylformamide dimethylacetal (II) gives the formamidine derivative (III), which by enzymatic acetylation with vinyl acetate in the presence of immobilized lipozyme in acetonitrile/1,4-dioxane yields the primary acetate (IV). Condensation of the deoxyribofuranose derivative (IV) with 2-cyanoethyl N,N,N’,N’-tetraisopropylphosphorodiamidate (V) in CH2Cl2 provides the phosphorodiamidate (VI), which then condenses with the deoxyguanosine derivative (VII) in CH2Cl2 to afford the trisubstituted phosphite (VIII) . oxidation of phosphite (VIII) with t-BuOOH provides the corresponding phosphate (IX), which is fully deprotected by means of NH3 in MeOH, and finally salified using naoAc in H2O/EtoH .

1 Redkar, S. Scaleup and development of a process for a low-volume subcutaneous formulation of SGI-110, a potent hypomethylating agent. 103rd Annu Meet Am Assoc Cancer Res (AACR) (March 31-April 4, Chicago) 2012, Abst.
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) 68188 decitabine;2-Desoxy-5-azacytidine;2'-Deoxy-5-azacytidine;5-Aza-2'-deoxycytidine;5-Azadeoxycytidine;Dacogen;1,3,5-Triazin-2(1H)-one,4-amino-1-(2-deoxy-b-D-erythro-pentofuranosyl)-;b-decitabine;s-Triazin-2(1H)-one,4-amino-1-(2-deoxy-b-D-erythro-pentofuranosyl)-(7CI,8CI) 2353-33-5 C8H12N4O4 详情 详情
(II) 11984 N-(Dimethoxymethyl)-N,N-dimethylamine;dimethylformamide dimethylacetal;1,1-dimethoxy-N,N-dimethylmethanamine; Dimethoxy-N,N-dimethylmethanamine; N,N-Dimethylformamide dimethyl acetal 4637-24-5 C5H13NO2 详情 详情
(III) 68189 (Z)-N'-(5-((2S,4R,5S)-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-4-oxo-4,5-dihydro-1,3,5-triazin-2-yl)-N,N-dimethylformimidamide   C11H17N5O4 详情 详情
(IV) 68190 ((2S,3R,5S)-5-(4-((Z)-((dimethylamino)methylene)amino)-2-oxo-1,3,5-triazin-1(2H)-yl)-3-hydroxytetrahydrofuran-2-yl)methyl acetate   C13H19N5O5 详情 详情
(V) 48656 2-Cyanoethyl N,N,N',N'-tetraisopropylphosphoramidite; 2-Cyanoethyl N,N,N',N'-tetraisopropylphosphorodiamidite; Bis(diisopropylamino)-2-cyanoethoxyphosphine 102691-36-1 C15H32N3OP 详情 详情
(VI) 68191 ((2S,3R,5S)-3-(((2-cyanoethoxy)(diisopropylamino)phosphino)oxy)-5-(4-((Z)-((dimethylamino)methylene)amino)-2-oxo-1,3,5-triazin-1(2H)-yl)tetrahydrofuran-2-yl)methyl acetate   C22H36N7O6P 详情 详情
(VII) 68194 (2S,3R,5S)-5-(2-(2-(4-(tert-butyl)phenoxy)acetamido)-6-oxo-1H-purin-9(6H)-yl)-2-(hydroxymethyl)tetrahydrofuran-3-yl 2-(4-(tert-butyl)phenoxy)acetate   C34H41N5O8 详情 详情
(VIII) 68193 (2S,3R,5S)-2-((((((2S,3R,5S)-2-(acetoxymethyl)-5-(4-((Z)-((dimethylamino)methylene)amino)-2-oxo-1,3,5-triazin-1(2H)-yl)tetrahydrofuran-3-yl)oxy)(2-cyanoethoxy)phosphino)oxy)methyl)-5-(2-(2-(4-(tert-butyl)phenoxy)acetamido)-6-oxo-1H-purin-9(6H)-yl)tetrahydrofuran-3-yl 2-(4-(tert-butyl)phenoxy)acetate   C50H62N11O14P 详情 详情
(IX) 68192 (2S,3R,5S)-2-((((((2S,3R,5S)-2-(acetoxymethyl)-5-(4-((Z)-((dimethylamino)methylene)amino)-2-oxo-1,3,5-triazin-1(2H)-yl)tetrahydrofuran-3-yl)oxy)(2-cyanoethoxy)phosphoryl)oxy)methyl)-5-(2-(2-(4-(tert-butyl)phenoxy)acetamido)-6-oxo-1H-purin-9(6H)-yl)tetrahydrofuran-3-yl 2-(4-(tert-butyl)phenoxy)acetate   C50H62N11O15P 详情 详情

合成路线2

In an alternative, solid-phase method, O-protection of decitabine (I) by means of HMDS in DMF, followed by N-acylation of the obtained bis-TMS ether (X) with phenoxyacetic anhydride (XI) in pyridine gives amide (XII). Desilylation of compound (XII) using TASF in DMF, followed by selective protection of the primary alcohol group in the resulting diol (XIII) with 4,4’-dimethoxytrityl chloride (DMT-Cl) in pyridine furnishes ether (XIV). Condensation of the free secondary alcohol of (XIV) with 2-cyanoethyl N,N,N’,N’-tetraisopropylphosphorodiamidate (V) using benzylthiotetrazole (BTT) in acetonitrile provides phosphoramidate (XV), which is then condensed with the 3’-deoxyguanosine derivative (XVI) linked onto controlled pore glass (CPG) support in the presence of BTT in MeoH to afford trisubstituted phosphite (XVII) . oxidation of phosphite (XVII) with t-BuOOH in acetonitrile provides the corresponding phosphate (XVIII), which is then O-deprotected by means of Cl2CHCOOH in toluene to give the primary alcohol (XIX). Finally, CPG-bound dinucleotide (XIX) is submitted to deprotection and cleavage from the solid support with aqueous Et3N·AcOH, followed by precipitation of the resulting triethylammonium salt in the presence of naClo4 in H2O/acetone .

1 Phiasivongsa, P., Redkar, S. (Astex Pharmaceuticals, Inc.). Oligonucleotide analogues incorporating 5-aza-cytosine therein. CA 2623090, CN 101282986, EP 1943264, JP 2009509531, KR 2008059612, US 2007072796, US 7700567, Wo 2007041071.
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) 68188 decitabine;2-Desoxy-5-azacytidine;2'-Deoxy-5-azacytidine;5-Aza-2'-deoxycytidine;5-Azadeoxycytidine;Dacogen;1,3,5-Triazin-2(1H)-one,4-amino-1-(2-deoxy-b-D-erythro-pentofuranosyl)-;b-decitabine;s-Triazin-2(1H)-one,4-amino-1-(2-deoxy-b-D-erythro-pentofuranosyl)-(7CI,8CI) 2353-33-5 C8H12N4O4 详情 详情
(V) 48656 2-Cyanoethyl N,N,N',N'-tetraisopropylphosphoramidite; 2-Cyanoethyl N,N,N',N'-tetraisopropylphosphorodiamidite; Bis(diisopropylamino)-2-cyanoethoxyphosphine 102691-36-1 C15H32N3OP 详情 详情
(X) 68199 4-amino-1-((2S,4R,5S)-4-((trimethylsilyl)oxy)-5-(((trimethylsilyl)oxy)methyl)tetrahydrofuran-2-yl)-1,3,5-triazin-2(1H)-one   C14H28N4O4Si2 详情 详情
(XI) 68195 phenoxyacetic anhydride 14316-61-1 C16H14O5 详情 详情
(XII) 68198 N-(4-oxo-5-((2S,4R,5S)-4-((trimethylsilyl)oxy)-5-(((trimethylsilyl)oxy)methyl)tetrahydrofuran-2-yl)-4,5-dihydro-1,3,5-triazin-2-yl)-2-phenoxyacetamide   C22H34N4O6Si2 详情 详情
(XIII) 68197 N-(5-((2S,4R,5S)-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-4-oxo-4,5-dihydro-1,3,5-triazin-2-yl)-2-phenoxyacetamide   C16H18N4O6 详情 详情
(XIV) 68196 N-(5-((2S,4R,5S)-5-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-4-hydroxytetrahydrofuran-2-yl)-4-oxo-4,5-dihydro-1,3,5-triazin-2-yl)-2-phenoxyacetamide   C37H36N4O8 详情 详情
(XV) 68203 (2S,3R,5S)-2-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-5-(2-oxo-4-(2-phenoxyacetamido)-1,3,5-triazin-1(2H)-yl)tetrahydrofuran-3-yl (2-cyanoethyl) diisopropylphosphoramidite   C46H53N6O9P 详情 详情
(XVI) 68204 N-(9-((2S,4R,5S)-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-6-oxo-6,9-dihydro-1H-purin-2-yl)-2-phenoxyacetamide   C18H18N5O6 详情 详情
(XVII) 68202 (2S,3R,5S)-2-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-5-(2-oxo-4-(2-phenoxyacetamido)-1,3,5-triazin-1(2H)-yl)tetrahydrofuran-3-yl (2-cyanoethyl) (((3R)-3-hydroxy-5-(6-oxo-2-(2-phenoxyacetamido)-1H-purin-9(6H)-yl)tetrahydrofuran-2-yl)methyl) phosphite   C58H56N10O15P 详情 详情
(XVIII) 68201 (2S,3R,5S)-2-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-5-(2-oxo-4-(2-phenoxyacetamido)-1,3,5-triazin-1(2H)-yl)tetrahydrofuran-3-yl (2-cyanoethyl) (((3R)-3-hydroxy-5-(6-oxo-2-(2-phenoxyacetamido)-1H-purin-9(6H)-yl)tetrahydrofuran-2-yl)methyl) phosphate   C58H56N10O16P 详情 详情
(XXI) 68200 2-cyanoethyl (((3R)-3-hydroxy-5-(6-oxo-2-(2-phenoxyacetamido)-1H-purin-9(6H)-yl)tetrahydrofuran-2-yl)methyl) ((2S,3R,5S)-2-(hydroxymethyl)-5-(2-oxo-4-(2-phenoxyacetamido)-1,3,5-triazin-1(2H)-yl)tetrahydrofuran-3-yl) phosphate   C37H38N10O14P 详情 详情
Extended Information