2-Cyanoethyl N,N,N',N'-tetraisopropylphosphoramidite; 2-Cyanoethyl N,N,N',N'-tetraisopropylphosphorodiamidite; Bis(diisopropylamino)-2-cyanoethoxyphosphine -Drug Synthesis Database

【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 合成路线2 合成路线3

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.

参考文献中间体

合成目标

【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 .

参考文献中间体

合成目标

【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 .

参考文献中间体

合成目标

【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