(2R)-2-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methyl]-4,4-diethoxybutyl stearate -Drug Synthesis Database

【结构式】

【分子编号】52976

【品名】(2R)-2-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methyl]-4,4-diethoxybutyl stearate

【CA登记号】

【分子式】C₃₂H₅₇N₅O₅

【分子量】591.83528

【元素组成】C 64.94% H 9.71% N 11.83% O 13.52%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(XXVIII)

In a different protection strategy, (diethoxyethyl)malonate (XIX) was obtained by alkylation of diethyl malonate (XVII) with bromoacetaldehyde diethyl acetal (XVIII). Reduction of the ester groups of (XIX) with LiBH4 provided diol (XX). The asymmetric mono-acetate ester (XXI) was generated by enantioselective acylation of the prochiral diol (XX) with vinyl acetate in the presence of lipase PS 30. Reaction of the free hydroxyl of (XXI) with p-toluenesulfonyl chloride afforded tosylate (XXII), which was subsequently condensed with 2-amino-6-chloropurine (I), yielding adduct (XXIII). Conversion of the chloropurine ring of (XXIII) to the target guanine derivative (XXV) was achieved by displacement of the chloro group with benzyl alcohol, with concomitant acetate ester hydrolysis, followed by hydrogenolytic cleavage of the resultant benzyl ether (XXIV). Alternatively, initial acetate ester hydrolysis in (XXIII) gave alcohol (XXVI), which was further subjected to chloro group hydrolysis in the presence of either KOH or tertiary amines to yield (XXV). Conversion of alcohol (XXV) to the target stearate ester (XXVIII) was achieved by treatment with stearoyl chloride (IX) or with the mixed anhydride of stearic acid (XXVII) with pivaloyl chloride or with tosyl chloride.

参考文献中间体

合成目标

【1】 Engelhardt, P.; Hoberg, M.; Zhou, X.-X.; Lindborg, B.; Johansson, N.G. (Medivir AB); Acyclic nucleoside derivs.. EP 0888348; JP 2000504720; JP 2000504721; US 5869493; WO 9730051; WO 9730052 .
【2】 Synthesis of acyclic nucleoside derivs.. WO 9834917 .
【3】 Synthesis of acyclic nucleoside derivs.. WO 0008025 .

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)	11644	6-Chloro-9H-purin-2-amine; 6-Chloro-9H-purin-2-ylamine; 2-Amino-6-chloropurine	10310-21-1	C₅H₄ClN₅	详情	详情
(IX)	52961	n-Octadecanoyl chloride; Octadecanoyl Chloride; Stearic acid chloride; Stearoyl chloride	112-76-5	C₁₈H₃₅ClO	详情	详情
(XVII)	16829	Diethyl malonate	105-53-3	C₇H₁₂O₄	详情	详情
(XVIII)	12113	2-Bromo-1-ethoxyethyl ethyl ether; 2-Bromo-1,1-diethoxyethane; Bromoacetaldehyde diethylacetal	2032-35-1	C₆H₁₃BrO₂	详情	详情
(XIX)	52968	3,3-Diethoxypropane-1,1-dicarboxylic acid diethyl ester; Diethyl 3,3-Diethoxypropane-1,1-dicarboxylate	21339-47-9	C₁₃H₂₄O₆	详情	详情
(XX)	52969	2-(2,2-Diethoxyethyl)-1,3-propanediol; 2-Hydroxymethyl-4,4-diethoxybutanol	55387-85-4	C₉H₂₀O₄	详情	详情
(XXI)	52970	(2R)-4,4-diethoxy-2-(hydroxymethyl)butyl acetate		C₁₁H₂₂O₅	详情	详情
(XXII)	52971	(2S)-4,4-diethoxy-2-({[(4-methylphenyl)sulfonyl]oxy}methyl)butyl acetate		C₁₈H₂₈O₇S	详情	详情
(XXIII)	52972	(2R)-2-[(2-amino-6-chloro-9H-purin-9-yl)methyl]-4,4-diethoxybutyl acetate		C₁₆H₂₄ClN₅O₄	详情	详情
(XXIV)	52973	(2R)-2-{[2-amino-6-(benzyloxy)-9H-purin-9-yl]methyl}-4,4-diethoxy-1-butanol		C₂₁H₂₉N₅O₄	详情	详情
(XXV)	52974	2-amino-9-[(2R)-4,4-diethoxy-2-(hydroxymethyl)butyl]-1,9-dihydro-6H-purin-6-one		C₁₄H₂₃N₅O₄	详情	详情
(XXVI)	52975	(2R)-2-[(2-amino-6-chloro-9H-purin-9-yl)methyl]-4,4-diethoxy-1-butanol		C₁₄H₂₂ClN₅O₃	详情	详情
(XXVII)	27095	stearic acid	57-11-4	C₁₈H₃₆O₂	详情	详情
(XXVIII)	52976	(2R)-2-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methyl]-4,4-diethoxybutyl stearate		C₃₂H₅₇N₅O₅	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XXVIII)

Acid hydrolysis of diethyl acetal (XXVIII) gave aldehyde (XXIX). Reduction of this to the corresponding alcohol (XXX) was carried out by using either NaBH4 or borane-tert-butylamine complex. Alcohol (XXX) was then coupled to the N-Cbz-valine anhydride, prepared from N-Cbz-valine (XVI) and DCC, to produce (XIII), which was finally deprotected by catalytic hydrogenation as above.

参考文献中间体

合成目标

【1】 Engelhardt, P.; Hoberg, M.; Zhou, X.-X.; Lindborg, B.; Johansson, N.G. (Medivir AB); Acyclic nucleoside derivs.. EP 0888348; JP 2000504720; JP 2000504721; US 5869493; WO 9730051; WO 9730052 .
【2】 Synthesis of acyclic nucleoside derivs.. WO 0008025 .
【3】 Synthesis of acyclic nucleoside derivs.. WO 9834917 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XIII)	52965	(2R)-2-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methyl]-4-[((2S)-2-{[(benzyloxy)carbonyl]amino}-3-methylbutanoyl)oxy]butyl stearate	C₄₁H₆₄N₆O₇	详情	详情
(XVI)	18092	(2S)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutyric acid	C₁₃H₁₇NO₄	详情	详情
(XXVIII)	52976	(2R)-2-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methyl]-4,4-diethoxybutyl stearate	C₃₂H₅₇N₅O₅	详情	详情
(XXIX)	52977	(2R)-2-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methyl]-4-oxobutyl stearate	C₂₈H₄₇N₅O₄	详情	详情
(XXX)	52978	(2R)-2-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methyl]-4-hydroxybutyl stearate	C₂₈H₄₉N₅O₄	详情	详情

Extended Information