|
【结 构 式】 
|
【分子编号】52961 【品名】n-Octadecanoyl chloride; Octadecanoyl Chloride; Stearic acid chloride; Stearoyl chloride 【CA登记号】112-76-5 |
【 分 子 式 】C18H35ClO 【 分 子 量 】302.928 【元素组成】C 71.37% H 11.65% Cl 11.7% O 5.28% |
合成路线1
该中间体在本合成路线中的序号：(IX)The precursor (R)-9-[4-hydroxy-2-(hydroxymethyl)]guanine (VI) was prepared by conjugate addition of dimethyl itaconate (II) to 2-amino-6-chloropurine (I), followed by reduction of the resultant diester (III) with LiBH4 to yield (IV). Subsequent displacement of the 6-chloro group of (IV) with ammonia under pressure furnished the racemic 2,6-diaminopurine (V). Then, enantioselective deamination of (V) in the presence of adenosine deaminase provided the target (R)-guanine derivative (VI). Esterification of the 4-hydroxy group of (VI) with N-Boc-L-valine (VII) by means of DCC gave the valine ester (VIII). The remaining free hydroxyl group of (VIII) was further esterified with stearoyl chloride (IX) in pyridine, yielding stearate (X). Finally, acid-promoted N-Boc group cleavage in (IX) furnished the title compound.
| 【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 . |
| 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 |
| (II) | 21416 | dimethyl 2-methylenesuccinate | 617-52-7 | C7H10O4 | 详情 | 详情 |
| (III) | 52956 | dimethyl 2-[(2-amino-6-chloro-9H-purin-9-yl)methyl]succinate | C12H14ClN5O4 | 详情 | 详情 | |
| (IV) | 52957 | 2-[(2-amino-6-chloro-9H-purin-9-yl)methyl]-1,4-butanediol | C10H14ClN5O2 | 详情 | 详情 | |
| (V) | 52958 | 2-[(2,6-diamino-9H-purin-9-yl)methyl]-1,4-butanediol | C10H16N6O2 | 详情 | 详情 | |
| (VI) | 52959 | 2-amino-9-[(2R)-4-hydroxy-2-(hydroxymethyl)butyl]-1,9-dihydro-6H-purin-6-one | C10H15N5O3 | 详情 | 详情 | |
| (VII) | 19733 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid | C10H19NO4 | 详情 | 详情 | |
| (VIII) | 52960 | (3R)-4-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)-3-(hydroxymethyl)butyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoate | C20H32N6O6 | 详情 | 详情 | |
| (IX) | 52961 | n-Octadecanoyl chloride; Octadecanoyl Chloride; Stearic acid chloride; Stearoyl chloride | 112-76-5 | C18H35ClO | 详情 | 详情 |
| (X) | 52962 | (2R)-2-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methyl]-4-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoyl}oxy)butyl stearate | C38H66N6O7 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IX)A related method was based in the acylation of the diol precursor (VI) with the p-nitrophenyl ester of N-Cbz-L-valine (XI) to afford the valyl ester (XII), which was further esterified with stearoyl chloride (IX). The resultant N-Cbz diester (XIII) was finally deprotected by hydrogenolysis over Pd/C.
| 【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 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 52959 | 2-amino-9-[(2R)-4-hydroxy-2-(hydroxymethyl)butyl]-1,9-dihydro-6H-purin-6-one | C10H15N5O3 | 详情 | 详情 | |
| (IX) | 52961 | n-Octadecanoyl chloride; Octadecanoyl Chloride; Stearic acid chloride; Stearoyl chloride | 112-76-5 | C18H35ClO | 详情 | 详情 |
| (XI) | 52963 | 4-nitrophenyl (2S)-2-{[(benzyloxy)carbonyl]amino}-3-methylbutanoate | C19H20N2O6 | 详情 | 详情 | |
| (XII) | 52964 | (3R)-4-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)-3-(hydroxymethyl)butyl (2S)-2-{[(benzyloxy)carbonyl]amino}-3-methylbutanoate | C23H30N6O6 | 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 |
合成路线3
该中间体在本合成路线中的序号：(IX)In an alternative method, (R)-9-[4-hydroxy-2-(hydroxymethyl)]guanine (VI) was selectively silylated at the 4-hydroxyl by means of tert-butyldiphenylsilyl chloride. The resultant mono-silylated compound (XIV) was acylated with stearoyl chloride (IX), producing stearate ester (XV). Desilylation of (XV) with tetrabutylammonium fluoride, followed by coupling with either N-Boc-L-valine (VII) or N-Cbz-L-valine (XVI), furnished the respective N-protected valyl esters (X) and (XIII). The title compound was then obtained by N-deprotection of (X) and (XIII) under acidic conditions or by catalytic hydrogenation, respectively.
| 【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 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 52959 | 2-amino-9-[(2R)-4-hydroxy-2-(hydroxymethyl)butyl]-1,9-dihydro-6H-purin-6-one | C10H15N5O3 | 详情 | 详情 | |
| (VII) | 19733 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid | C10H19NO4 | 详情 | 详情 | |
| (IX) | 52961 | n-Octadecanoyl chloride; Octadecanoyl Chloride; Stearic acid chloride; Stearoyl chloride | 112-76-5 | C18H35ClO | 详情 | 详情 |
| (X) | 52962 | (2R)-2-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methyl]-4-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoyl}oxy)butyl stearate | C38H66N6O7 | 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 | |
| (XIV) | 52966 | 2-amino-9-[(2R)-4-{[tert-butyl(diphenyl)silyl]oxy}-2-(hydroxymethyl)butyl]-1,9-dihydro-6H-purin-6-one | C26H33N5O3Si | 详情 | 详情 | |
| (XV) | 52967 | (2R)-2-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methyl]-4-{[tert-butyl(diphenyl)silyl]oxy}butyl stearate | C44H67N5O4Si | 详情 | 详情 | |
| (XVI) | 18092 | (2S)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutyric acid | C13H17NO4 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(IX)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 |