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【结 构 式】 
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【分子编号】52969 【品名】2-(2,2-Diethoxyethyl)-1,3-propanediol; 2-Hydroxymethyl-4,4-diethoxybutanol 【CA登记号】55387-85-4 |
【 分 子 式 】C9H20O4 【 分 子 量 】192.2554 【元素组成】C 56.23% H 10.49% O 33.29% |
合成路线1
该中间体在本合成路线中的序号：(XX)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.
| 【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：(XX)In a further procedure, the prochiral diol (XX) was converted to the asymmetric mono-stearate ester (XXXII) employing vinyl stearate (XXXI) and lipase PS 30. After tosylation of alcohol (XXXII), the resulting diethoxy acetal (XXXIII) was hydrolyzed to aldehyde (XXXIV) employing different acidic catalysts. Reduction of aldehyde (XXXIV) to the corresponding alcohol (XXXV) was effected by means of catalytic hydrogenation over Ra-Ni or borane-tert-butylamine complex. Alcohol (XXXV) was further condensed with N-Cbz-L-valine (XVI), producing the diester tosylate (XXXVI). The analogous N-Boc- and N-Alloc-protected valine esters were similarly prepared. 6-Benzyloxy-2-aminopurine (XXXVII) was prepared by treatment of chloropurine (I) with benzyl alcohol and NaH or NaOH. Alkylation of purine (XXXVII) with tosylate (XXXVI) furnished adduct (XXXVIII), which was finally deprotected by catalytic hydrogenation. Optionally, tosylate (XXXVI) was condensed with chloropurine (I) to give (XXXIX). Hydrolysis of the chloropurine ring of (XXXIX) to the guanine derivative (XIII) employing either Et3N or HOAc, followed by catalytic hydrogenation as above, provided an alternative access to the title compound.
| 【1】 Synthesis of acyclic nucleoside derivs.. WO 9834917 . |
| 【2】 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 |
| (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 | |
| (XX) | 52969 | 2-(2,2-Diethoxyethyl)-1,3-propanediol; 2-Hydroxymethyl-4,4-diethoxybutanol | 55387-85-4 | C9H20O4 | 详情 | 详情 |
| (XXXI) | 52979 | vinyl stearate | 111-63-7 | C20H38O2 | 详情 | 详情 |
| (XXXII) | 52980 | (2R)-4,4-diethoxy-2-(hydroxymethyl)butyl stearate | n/a | C27H54O5 | 详情 | 详情 |
| (XXXIII) | 52981 | (2S)-4,4-diethoxy-2-({[(4-methylphenyl)sulfonyl]oxy}methyl)butyl stearate | n/a | C34H60O7S | 详情 | 详情 |
| (XXXIV) | 52982 | (2S)-2-({[(4-methylphenyl)sulfonyl]oxy}methyl)-4-oxobutyl stearate | n/a | C30H50O6S | 详情 | 详情 |
| (XXXV) | 52983 | (2S)-4-hydroxy-2-({[(4-methylphenyl)sulfonyl]oxy}methyl)butyl stearate | n/a | C30H52O6S | 详情 | 详情 |
| (XXXVI) | 52984 | (2S)-4-[((2S)-2-{[(benzyloxy)carbonyl]amino}-3-methylbutanoyl)oxy]-2-({[(4-methylphenyl)sulfonyl]oxy}methyl)butyl stearate | n/a | C43H67NO9S | 详情 | 详情 |
| (XXXVII) | 14383 | 6-(benzyloxy)-9H-purin-2-ylamine; 6-(benzyloxy)-9H-purin-2-amine | 19916-73-5 | C12H11N5O | 详情 | 详情 |
| (XXXVIII) | 52985 | (2R)-2-[(2-amino-6-chloro-9H-purin-9-yl)methyl]-4-[((2S)-2-{[(benzyloxy)carbonyl]amino}-3-methylbutanoyl)oxy]butyl stearate | n/a | C41H63ClN6O6 | 详情 | 详情 |
| (XXXIX) | 52986 | (2R)-2-{[2-amino-6-(benzyloxy)-9H-purin-9-yl]methyl}-4-[((2S)-2-{[(benzyloxy)carbonyl]amino}-3-methylbutanoyl)oxy]butyl stearate | n/a | C48H70N6O7 | 详情 | 详情 |