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【结 构 式】 
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【分子编号】52965 【品名】(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 【CA登记号】 |
【 分 子 式 】C41H64N6O7 【 分 子 量 】752.9954 【元素组成】C 65.4% H 8.57% N 11.16% O 14.87% |
合成路线1
该中间体在本合成路线中的序号：(XIII)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2
该中间体在本合成路线中的序号：(XIII)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3
该中间体在本合成路线中的序号：(XIII)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.
| 【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 | CAS号 | 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 |
合成路线4
该中间体在本合成路线中的序号：(XIII)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 |
合成路线5
该中间体在本合成路线中的序号：(XIII)A related strategy required previous conversion of chloropurine (I) to the iodopurine (XL), which was effected by means of HI. Alkylation of purine (XL) with tosylate (XXXVI) provided (XLI), which was hydrolyzed to the guanine (XIII) using NaOAc/HOAc.
| 【1】 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 | |
| (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 |
| (XL) | 14386 | 6-iodo-9H-purin-2-ylamine; 6-iodo-9H-purin-2-amine | C5H4IN5 | 详情 | 详情 | |
| (XLI) | 52987 | (3R)-4-(2-amino-6-iodo-9H-purin-9-yl)-3-[(octadecyloxy)methyl]butyl (2S)-2-{[(benzyloxy)carbonyl]amino}-3-methylbutanoate | n/a | C41H65IN6O5 | 详情 | 详情 |