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

【结 构 式】

【分子编号】48656

【品名】2-Cyanoethyl N,N,N',N'-tetraisopropylphosphoramidite; 2-Cyanoethyl N,N,N',N'-tetraisopropylphosphorodiamidite; Bis(diisopropylamino)-2-cyanoethoxyphosphine

【CA登记号】102691-36-1

【 分 子 式 】C15H32N3OP

【 分 子 量 】301.412462

【元素组成】C 59.77% H 10.7% N 13.94% O 5.31% P 10.28%

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:(VIII)

Silylation of 1-O-benzylglycerol (I) with tert-butyldimethylsilyl chloride afforded the 1,3-diprotected glycerol (II). After methylation of the free secondary hydroxyl of (II) using MeI and NaH to yield (III), its O-benzyl protecting group was cleaved by hydrogenolysis, yielding (IV). Acylation of alcohol (IV) with oleoyl chloride (V) in the presence of pyridine provided the corresponding ester (VI). Desilylation of (VI) to give alcohol (VII) was carried out by treatment with tetrabutylammonium fluoride. Alcohol (VII) was then condensed with (2-cyanoethyl)-N,N,N',N'-tetraisopropylphosphorodiamidite (VIII) in the presence of 3-hydroxypropionitrile and tetrazole, followed by reaction with elemental sulfur to furnish the thiophosphate (IX). Finally, cleavage of the cyanoethyl ester groups with Et3N and bis(trimethylsilyl)acetamide provided the title compound.

1 Boyd, E.A.; Umansky, S.R.; Baxter, A.D.; Price, S.; Goddard, J.G.; Picker, D.H.; Wijkmans, J.C.H.M. (Evotec Biosystems AG; LXR Biotechnology Inc.); Compsns. containing lysophosphatidic acids which inhibit apoptosis and uses thereof. WO 9947101 .
2 Vmansky, S.R.; Goddard, J.G.; Picker, D.H.; Bathurst, I.C.; Bradley, J.D.; Foehr, M.W. (LXR Biotechnology Inc.); Compsns. containing lysophosphatidic acids which inhibit apoptosis and uses thereof. WO 9841213 .
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) 12699 (2S)-3-(Benzyloxy)-1,2-propanediol; (S)-(-)-1-Benzylglycerol 17325-85-8 C10H14O3 详情 详情
(II) 48651 1-(benzyloxy)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-propanol C16H28O3Si 详情 详情
(III) 48652 benzyl 3-[[tert-butyl(dimethyl)silyl]oxy]-2-methoxypropyl ether; [3-(benzyloxy)-2-methoxypropoxy](tert-butyl)dimethylsilane C17H30O3Si 详情 详情
(IV) 48653 3-[[tert-butyl(dimethyl)silyl]oxy]-2-methoxy-1-propanol C10H24O3Si 详情 详情
(V) 28280 Oleoyl chloride; (E)-9-Octadecenoyl chloride C18H33ClO 详情 详情
(VI) 48654 3-[[tert-butyl(dimethyl)silyl]oxy]-2-methoxypropyl (Z)-9-octadecenoate C28H56O4Si 详情 详情
(VII) 48655 3-hydroxy-2-methoxypropyl (Z)-9-octadecenoate C22H42O4 详情 详情
(VIII) 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
(IX) 48657 3-([(2-cyanoethoxy)[(2-cyanoethyl)sulfanyl]phosphoryl]oxy)-2-methoxypropyl (Z)-9-octadecenoate C28H49N2O6PS 详情 详情

合成路线2

该中间体在本合成路线中的序号:(V)

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3

该中间体在本合成路线中的序号:(V)

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