|
【结 构 式】 
|
【分子编号】12008 【品名】(5S)-5-(Hydroxymethyl)dihydro-2(3H)-furanone; (S)-(+)-Dihydro-5-(hydroxymethyl)-2(3h)-furanone 【CA登记号】32780-06-6 |
【 分 子 式 】C5H8O3 【 分 子 量 】116.11672 【元素组成】C 51.72% H 6.94% O 41.34% |
合成路线1
该中间体在本合成路线中的序号：(IV)A new synthesis of 2',3'-dideoxyadenosine has been described: The stereospecific deamination - lactonization of L-glutamic acid (I) with NaNO2 - HCl in water gives (S)-(+)-gamma-carboxy-gamma-butyrolactone (II), which is esterified with ethanol - p-toluenesulfonic acid to the ester (III). The selective reduction of (III) with NaBH4 in ethanol yields (S)-(+)-gamma-(hydroxymethyl)-gamma-butyrolactone (IV), which is benzoylated with benzoyl chloride as usual, affording the benzoate (V). The selective reduction of (V) with disiamyl borane in THF gives the alcohol (VI), which is acetylated with acetic anhydride in pyridine to the acetate (VII). The reaction of (VII) with trimethylsilyl bromide in dichloromethane yields the tetrahydrofuryl bromide (VIII), which is condensed with the silylated adenine (IX) to afford 5'-O-benzoyl-2',3'-dideoxyadenosine (X). Finally, this compound is deprotected with NH3 in methanol.
| 【1】 Farina, V.; Benigni, D.A.; 2',3'-dideoxynucleosides for AIDS chemotherapy. Tetrahedron Lett 1988, 29, 11, 1239-42. |
| 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) | 12005 | L-2-Amino propane dicarboxylic acid; (-)-2-Aminoglutaric acid; L-2-Aminopentanoic acid; L-Glutamic acid | 56-86-0 | C5H9NO4 | 详情 | 详情 |
| (II) | 12006 | (R)-(-)-5-Oxo-2-tetrahydrofurancarboxylic acid; (2S)-5-oxotetrahydro-2-furancarboxylic acid | 53558-93-3 | C5H6O4 | 详情 | 详情 |
| (III) | 12007 | ethyl (2S)-5-oxotetrahydro-2-furancarboxylate; (S)-(+)-gamma-Ethoxycarbonyl-gamma-butyrolactone | 55094-96-7 | C7H10O4 | 详情 | 详情 |
| (IV) | 12008 | (5S)-5-(Hydroxymethyl)dihydro-2(3H)-furanone; (S)-(+)-Dihydro-5-(hydroxymethyl)-2(3h)-furanone | 32780-06-6 | C5H8O3 | 详情 | 详情 |
| (V) | 12009 | [(2S)-5-oxotetrahydro-2-furanyl]methyl benzoate | C12H12O4 | 详情 | 详情 | |
| (VI) | 12010 | [(2S)-5-hydroxytetrahydro-2-furanyl]methyl benzoate | C12H14O4 | 详情 | 详情 | |
| (VII) | 12011 | [(2S)-5-(acetoxy)tetrahydro-2-furanyl]methyl benzoate | C14H16O5 | 详情 | 详情 | |
| (VIII) | 12012 | [(2S)-5-bromotetrahydro-2-furanyl]methyl benzoate | C12H13BrO3 | 详情 | 详情 | |
| (IX) | 12013 | N,9-Bis(trimethylsilyl)-9H-purin-6-amine; N-(Trimethylsilyl)-N-[9-(trimethylsilyl)-9H-purin-6-yl]amine | 17995-04-9 | C11H21N5Si2 | 详情 | 详情 |
| (X) | 12014 | [(2S,5R)-5-(6-amino-9H-purin-9-yl)tetrahydro-2-furanyl]methyl benzoate | C17H17N5O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIX)Other methods based on the modification of carbohydrates have also been described: 7) Protection of readily available (S)-(+)-gamma-(hydroxymethyl)-gamma-butyrolactone (XIX) with tert-butyldiphenylsilyl chloride gives ether (XX), which is converted to the seleno derivative (XXI) on treatment with lithium hexamethyldisilazide and trimethylchlorosilane in tetrahydrofuran, followed by reaction with phenylselenylbromide. Reduction of (XXI) with diisobutylaluminum hydride in toluene followed by acetylation gives compound (XXII), which is reacted with (XXIII) and trimethylsilyltriflate in dichloroethane to afford stereoselectively compound (XXIV). The latter is finally submitted to elimination and deprotected by successive treatment with hydrogen peroxide in pyridine and tetrabutylammonium fluoride in tetrahydrofuran. 8) A related route involves treatment of (XX) with lithium diisopropylamide in tetrahydrofuran and diphenylsulfide in HMPA to give (XXV), which is reduced and acetylated to yield (XXVI). Compound (XXVI) is treated with (XXIII) in the presence of tin tetrachloride in dichloromethane to afford (XXVII), which is oxidized with sodium periodate and submitted to elimination by treating in toluene-pyridine, to yield compound (XXVIII). Finally, compound (XXVIII) is deprotected with tetrabutylammonium fluoride in tetrahydrofuran. 9) A third procedure begins with the protection of (XIX) as a tert-butoxycarbonyl ester to yield (XXIX), reduction with diisobutylaluminum hydride in tetrahydrofuran to afford (XXX) and elimination after treatment with thionyl chloride in dichloromethane and potassium tert-butoxide in tetrahydrofuran to give (XXXI). Subsequent reaction of compound (XXXI) with thymine (IX) in the presence of hexamethyldisilazane and trimethylsilyl chloride and N-chlorosuccinimide in tetrahydrofuran gives compound (XXXII), which is treated with potassium tert-butoxide in tetrahydrofuran and deprotected with sodium methoxide in methanol.
| 【1】 Kim, C.U.; Martin, J.C. (Bristol-Myers Squibb Co.); Processes for preparation of nucleoside derivs. EP 0501511 . |
| 【2】 Hammoudeh, A.J.; Haft, J.I.; Conte, P.J.; A general method for controlled glycosylation stereochemistry in the synthesis of 2'-deoxyribose nucleosides. Tetrahedron Lett 1990, 31, 2, 1815-8. |
| 【3】 Robinson, C.; Castaner, J.; Stavudine. Drugs Fut 1994, 19, 10, 925. |
| 【4】 Babu, J.R.; Beach, J.W.; Ahn, S.K.; Jeong, L.S.; Chu, C.K.; Huang, Huang, H.; Lee, S.J.; A highly stereoselective glycosylation of 2-(phenylselenyl)-2,3-dideoxyribose derivative with thymine: Synthesis of 3'-deoxy-2',3'-didehydrothymidine and 3'-deoxythymidine. J Org Chem 1990, 55, 1418-20. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IX) | 12204 | 5-Methyl-2,4(1H,3H)-pyrimidinedione; Thymine | 65-71-4 | C5H6N2O2 | 详情 | 详情 |
| (XIX) | 12008 | (5S)-5-(Hydroxymethyl)dihydro-2(3H)-furanone; (S)-(+)-Dihydro-5-(hydroxymethyl)-2(3h)-furanone | 32780-06-6 | C5H8O3 | 详情 | 详情 |
| (XX) | 12215 | (5S)-5-([[tert-Butyl(diphenyl)silyl]oxy]methyl)dihydro-2(3H)-furanone | C21H26O3Si | 详情 | 详情 | |
| (XXI) | 12216 | (3R,5S)-5-([[tert-Butyl(diphenyl)silyl]oxy]methyl)-3-(phenylselanyl)dihydro-2(3H)-furanone | C27H30O3SeSi | 详情 | 详情 | |
| (XXII) | 12217 | (3R,5S)-5-([[tert-butyl(diphenyl)silyl]oxy]methyl)-3-(phenylselanyl)tetrahydro-2-furanyl acetate | C29H34O4SeSi | 详情 | 详情 | |
| (XXIII) | 12218 | 5-Methyl-2,4-bis[(trimethylsilyl)methyl]pyrimidine | C13H26N2Si2 | 详情 | 详情 | |
| (XXIV) | 12219 | 1-[(2R,3R,5S)-5-([[tert-Butyl(diphenyl)silyl]oxy]methyl)-3-(phenylselanyl)tetrahydro-2-furanyl]-5-methyl-2,4(1H,3H)-pyrimidinedione | C32H36N2O4SeSi | 详情 | 详情 | |
| (XXV) | 12220 | (3R,5S)-5-([[tert-Butyl(diphenyl)silyl]oxy]methyl)-3-(phenylsulfanyl)dihydro-2(3H)-furanone | C27H30O3SSi | 详情 | 详情 | |
| (XXVI) | 12221 | (3R,5S)-5-([[tert-butyl(diphenyl)silyl]oxy]methyl)-3-(phenylsulfanyl)tetrahydro-2-furanyl acetate | C29H34O4SSi | 详情 | 详情 | |
| (XXVII) | 12222 | 1-[(2R,3R,5S)-5-([[tert-Butyl(diphenyl)silyl]oxy]methyl)-3-(phenylsulfanyl)tetrahydro-2-furanyl]-5-methyl-2,4(1H,3H)-pyrimidinedione | C32H36N2O4SSi | 详情 | 详情 | |
| (XXVIII) | 12223 | 1-[(2R,5S)-5-([[tert-Butyl(diphenyl)silyl]oxy]methyl)-2,5-dihydro-2-furanyl]-5-methyl-2,4(1H,3H)-pyrimidinedione | C26H30N2O4Si | 详情 | 详情 | |
| (XXIX) | 12224 | [(2S)-5-oxotetrahydro-2-furanyl]methyl pivalate | C10H16O4 | 详情 | 详情 | |
| (XXX) | 12225 | [(2S)-5-hydroxytetrahydro-2-furanyl]methyl pivalate | C10H18O4 | 详情 | 详情 | |
| (XXXI) | 12226 | (2S)-2,3-dihydro-2-furanylmethyl pivalate | C10H16O3 | 详情 | 详情 | |
| (XXXII) | 12227 | [(2S,4R,5R)-4-chloro-5-[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl]methyl pivalate | C15H21ClN2O5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IV)1) The stereospecific deamination - lactonization of L-glutamic acid (I) with NaNO2 - HCl in water gives (S)-(+)-gamma-carboxy-gamma-butyrolactone (II), which is esterified with ethanol and p-toluenesulfonic acid in the usual way, yielding the ethyl ester (III). The selective reduction of (III) with NaBH4 in ethanol affords (S)-(+)-gamma-(hydroxymethyl)-gamma-butyrolactone (IV), which is benzoylated with benzoyl chloride to the benzoate (V). The selective reduction of (V) with disiamyl borane in THF yields the alcohol (VI), which is acetylated with acetic anhydride in pyridine to the acetate (VII). The reaction of (VII) with trimethylsilyl bromide in dichloromethane affords the tetrahydrofuryl bromide (VIII), which is then condensed with the adenine (IX), giving 5'-O-benzoyl-2',3'-dideoxyadenosine (X). The deprotection of (X) with NH3 in methanol yields 2',3'-dideoxyadenosine, which is finally deaminated enzymatically with the enzyme adenosine deaminase.
| 【1】 Farina, V.; Benigni, D.A.; 2',3'-dideoxynucleosides for AIDS chemotherapy. Tetrahedron Lett 1988, 29, 11, 1239-42. |
| 【2】 Prous, J.; Castaner, J.; DIDEOXYINOSINE. Drugs Fut 1990, 15, 6, 569. |
| 【3】 Taniguchi, M.; Koga, K.; Yamada, S.; Stereoselective synthesis of D-ribose from L-glutamic acid. Tetrahedron 1974, 30, 3547-52. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 60593 | p-xylene | C8H10 | 详情 | 详情 | ||
| (I) | 12005 | L-2-Amino propane dicarboxylic acid; (-)-2-Aminoglutaric acid; L-2-Aminopentanoic acid; L-Glutamic acid | 56-86-0 | C5H9NO4 | 详情 | 详情 |
| (II) | 12006 | (R)-(-)-5-Oxo-2-tetrahydrofurancarboxylic acid; (2S)-5-oxotetrahydro-2-furancarboxylic acid | 53558-93-3 | C5H6O4 | 详情 | 详情 |
| (III) | 12007 | ethyl (2S)-5-oxotetrahydro-2-furancarboxylate; (S)-(+)-gamma-Ethoxycarbonyl-gamma-butyrolactone | 55094-96-7 | C7H10O4 | 详情 | 详情 |
| (IV) | 12008 | (5S)-5-(Hydroxymethyl)dihydro-2(3H)-furanone; (S)-(+)-Dihydro-5-(hydroxymethyl)-2(3h)-furanone | 32780-06-6 | C5H8O3 | 详情 | 详情 |
| (V) | 12009 | [(2S)-5-oxotetrahydro-2-furanyl]methyl benzoate | C12H12O4 | 详情 | 详情 | |
| (VI) | 12010 | [(2S)-5-hydroxytetrahydro-2-furanyl]methyl benzoate | C12H14O4 | 详情 | 详情 | |
| (VII) | 12011 | [(2S)-5-(acetoxy)tetrahydro-2-furanyl]methyl benzoate | C14H16O5 | 详情 | 详情 | |
| (VIII) | 12012 | [(2S)-5-bromotetrahydro-2-furanyl]methyl benzoate | C12H13BrO3 | 详情 | 详情 | |
| (IX) | 12013 | N,9-Bis(trimethylsilyl)-9H-purin-6-amine; N-(Trimethylsilyl)-N-[9-(trimethylsilyl)-9H-purin-6-yl]amine | 17995-04-9 | C11H21N5Si2 | 详情 | 详情 |
| (X) | 12014 | [(2S,5R)-5-(6-amino-9H-purin-9-yl)tetrahydro-2-furanyl]methyl benzoate | C17H17N5O3 | 详情 | 详情 | |
| (XI) | 12787 | [(2S,5R)-5-(6-Amino-9H-purin-9-yl)tetrahydro-2-furanyl]methanol; Dideoxyadenosine | 4097-22-7 | C10H13N5O2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)The protection of 5(S)-(hydroxymethyl)tetrahydrofuran-2-one with Tbdps-Cl and imidazole gives the silyl ether (II), which is oxidized by means of LiHMDS and MoOPH in THF to yield 5(R)-(tert-butyldiphenylsilyloxymethyl)-3(R)-hydroxytetrahydrofuran-2-one (III). The fluorination of (III) by means of Et2N-SF3 (DAST) in dichloromethane affords 5(R)-(tert-butyldiphenylsilyloxymethyl)-3(S)-fluorotetrahydrofuran-2-one (IV), which is reduced with DIBAL to provide the alcohol (V). The acylation of (V) with Ac2O and pyridine gives the acetate (VI), which is converted into the bromide (VII) by reaction with Tms-Br and BiBr3. The condensation of (VII) with 6-chloro-9-(trimethylsilyl)purine (VIII) yields the glycosylated chloropurine (IX), which is then desilylated by means of TBAF in THF to afford the chloronucleoside (X). Finally, this compound is treated with ammonia in methanol at 100 C in a pressure vessel to provide the target Lodenosine.
| 【1】 Choudhury, A.; et al.; A concise synthesis of anti-viral agent F-ddA, starting from (S)-dihydro-5-(hydroxymethyl)-2(3H)-furanone. Tetrahedron Lett 2003, 44, 2, 247. |
| 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) | 12008 | (5S)-5-(Hydroxymethyl)dihydro-2(3H)-furanone; (S)-(+)-Dihydro-5-(hydroxymethyl)-2(3h)-furanone | 32780-06-6 | C5H8O3 | 详情 | 详情 |
| (II) | 12215 | (5S)-5-([[tert-Butyl(diphenyl)silyl]oxy]methyl)dihydro-2(3H)-furanone | C21H26O3Si | 详情 | 详情 | |
| (III) | 61756 | (3R,5S)-5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-3-hydroxydihydro-2(3H)-furanone | C21H26O4Si | 详情 | 详情 | |
| (IV) | 61757 | (3S,5S)-5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-3-fluorodihydro-2(3H)-furanone | C21H25FO3Si | 详情 | 详情 | |
| (V) | 61758 | (3S,5S)-5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-3-fluorotetrahydro-2-furanol | C21H27FO3Si | 详情 | 详情 | |
| (VI) | 61759 | (2R,3S,5S)-5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-3-fluorotetrahydro-2-furanyl acetate | C23H29FO4Si | 详情 | 详情 | |
| (VII) | 61760 | [(2S,4S,5R)-5-bromo-4-fluorotetrahydro-2-furanyl]methyl tert-butyl(diphenyl)silyl ether; {[(2S,4S,5R)-5-bromo-4-fluorotetrahydro-2-furanyl]methoxy}(tert-butyl)diphenylsilane | C21H26BrFO2Si | 详情 | 详情 | |
| (VIII) | 17727 | 6-chloro-9-(trimethylsilyl)-9H-purine | C8H11ClN4Si | 详情 | 详情 | |
| (IX) | 61761 | 9-[(2R,3S,5S)-5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-3-fluorotetrahydro-2-furanyl]-9H-purin-6-amine; 9-[(2R,3S,5S)-5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-3-fluorotetrahydro-2-furanyl]-9H-purin-6-ylamine | C26H30FN5O2Si | 详情 | 详情 | |
| (X) | 17712 | [(2S,4S,5R)-5-(6-chloro-9H-purin-9-yl)-4-fluorotetrahydro-2-furanyl]methanol | C10H10ClFN4O2 | 详情 | 详情 |