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【结 构 式】 
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【分子编号】38068 【品名】ethyl (1S,5R)-2-oxo-3-oxabicyclo[3.1.0]hexane-1-carboxylate 【CA登记号】 |
【 分 子 式 】C8H10O4 【 分 子 量 】170.165 【元素组成】C 56.47% H 5.92% O 37.61% |
合成路线1
该中间体在本合成路线中的序号：(I)The selective hydrolysis of the ester group of the chiral cyclopropafuranone (I) with an excess of NaOH, followed by ring closing with HCl, gives the carboxylic acid (II), which is treated with ethyl chloroformate and TEA in THF to yield the mixed anhydride (III). The reduction of the anhydride group of (III) with NaBH4 in THF/water affords the chiral hydroxymethyl cyclopropafuranone (IV). Alternatively, the selective hydrolysis of the lactone group of (I) with 1 equivalent of NaOH provides the malonic hemiester hemi sodium salt (V), which is reduced with NaBH4 and cyclized with conc. HCl to give the already reported hydroxymethyl cyclopropafuranone (IV). The reaction of (IV) with Ms-Cl and TEA or with SOCl2 and TEA yields the mesyloxymethyl (VI) or the chloromethyl (VII) compounds, which are condensed with 2-amino-6-chloropurine (VIII) by means of K2CO3 in hot DMF to afford the adduct (IX). The hydrolysis of the chlorine atom of (IX) by means of HCOOH at 100 C provides the guanine derivative (X). Finally, the lactone group of (X) is reduced with NaBH4 in hot ethanol to give the target cyclopropane nucleoside.
| 【1】 Onishi, T.; et al.; A practical synthesis of antiviral cyclopropane nucleoside A-5021. Tetrahedron Lett 1999, 40, 50, 8845. |
| 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) | 38068 | ethyl (1S,5R)-2-oxo-3-oxabicyclo[3.1.0]hexane-1-carboxylate | C8H10O4 | 详情 | 详情 | |
| (II) | 53916 | (1S,5R)-2-oxo-3-oxabicyclo[3.1.0]hexane-1-carboxylic acid | C6H6O4 | 详情 | 详情 | |
| (III) | 53917 | C8H8O6 | 详情 | 详情 | ||
| (IV) | 53918 | (1S,5R)-1-(hydroxymethyl)-3-oxabicyclo[3.1.0]hexan-2-one | C6H8O3 | 详情 | 详情 | |
| (V) | 53919 | sodium (1R,2R)-1-(ethoxycarbonyl)-2-hydroxycyclopropanecarboxylate | n/a | C7H9NaO5 | 详情 | 详情 |
| (VI) | 53920 | [(5R)-2-oxo-3-oxabicyclo[3.1.0]hex-1-yl]methyl methanesulfonate | C7H10O5S | 详情 | 详情 | |
| (VII) | 53921 | (1R,5R)-1-(chloromethyl)-3-oxabicyclo[3.1.0]hexan-2-one | C6H7ClO2 | 详情 | 详情 | |
| (VIII) | 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) | 53922 | (1S,5R)-1-[(2-amino-6-chloro-9H-purin-9-yl)methyl]-3-oxabicyclo[3.1.0]hexan-2-one | C11H10ClN5O2 | 详情 | 详情 | |
| (X) | 53923 | 2-amino-9-{[(5R)-2-oxo-3-oxabicyclo[3.1.0]hex-1-yl]methyl}-1,9-dihydro-6H-purin-6-one | C11H11N5O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(III)The condensation of diethyl malonate (I) with (R)-(-)-epichlorohydrin (II) by means of NaOEt in ethanol gives (3aS,4aR)-3-oxo-3,3a,4,4a-tetrahydro-1H-cyclopropa[c]furan-3a-carboxylic acid ethyl ester (III), which is selectively reduced at the lactone group by means of sodium borohydride in ethanol to yield (1R,2R)-1,2-bis(hydroxymethyl)cyclopropanecarboxylic acid ethyl ester (IV). The protection of (IV) with 2,2-dimethoxypropane (V) and Ts-OH in DMF affords the cyclic acetonide (VI), which is reduced with LiBH4 in THF to provide the hydroxymethyl acetonide (VII). The protection of the OH group of (VII) with benzyl bromide and NaH in DMF gives the benzyl ether (VIII), which is treated with HCl in THF/water to cleave the acetonide ring and yield the bis hydroxymethyl compound (IX). The acylation of (IX) with benzoyl chloride and pyridine affords the dibenzoate (X), which is debenzylated with H2 over Pd/C in ethanol/acetic acid to provide (1S,2R)-1,2-bis(benzoyloxymethyl)cyclopropanemethanol (XI). The reaction of (XI) with Ts-OH and DMAP in dichloromethane gives the corresponding tosylate (XII), which is condensed with 6-O-benzylguanine (XIII) by means of K2CO3 in DMF to yield the fully protected nucleoside (XIV). The hydrolysis of the benzoyl group of (XIV) by means of NaOMe in methanol affords the dihydroxy compound (XV), which is finally debenzylated by means of HCl in ethanol/water to provide the target guanine cyclopropyl nucleoside.
| 【1】 Sekiyama, T.; et al.; Synthesis and antiviral activity of novel acyclic nucleosides: Discovery of a cyclopropyl nucleoside with potent inhibitory activity against herpesviruses. J Med Chem 1998, 41, 8, 1284. |
| 【2】 Hatsuya, S.; Sekiyama, T.; Tsuji, T.; Iwayama, S.; Okunishi, M. (Ajinomoto Co., Inc.); Cyclopropane deriv.. EP 0502690; JP 1993194421; US 5342840; US 5449840 . |
| 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) | 16829 | Diethyl malonate | 105-53-3 | C7H12O4 | 详情 | 详情 |
| (II) | 38067 | (2R)-2-(Chloromethyl)oxirane; (R)-Epichlorohydrin | 51594-55-9 | C3H5ClO | 详情 | 详情 |
| (III) | 38068 | ethyl (1S,5R)-2-oxo-3-oxabicyclo[3.1.0]hexane-1-carboxylate | C8H10O4 | 详情 | 详情 | |
| (IV) | 38069 | ethyl (1R,2R)-1,2-bis(hydroxymethyl)cyclopropanecarboxylate | C8H14O4 | 详情 | 详情 | |
| (V) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (VI) | 53924 | ethyl (1R,7R)-4,4-dimethyl-3,5-dioxabicyclo[5.1.0]octane-1-carboxylate | C11H18O4 | 详情 | 详情 | |
| (VII) | 53925 | [(7R)-4,4-dimethyl-3,5-dioxabicyclo[5.1.0]oct-1-yl]methanol | C9H16O3 | 详情 | 详情 | |
| (VIII) | 53926 | benzyl [(7R)-4,4-dimethyl-3,5-dioxabicyclo[5.1.0]oct-1-yl]methyl ether; (1S,7R)-1-[(benzyloxy)methyl]-4,4-dimethyl-3,5-dioxabicyclo[5.1.0]octane | C16H22O3 | 详情 | 详情 | |
| (IX) | 53927 | [(1R,2R)-2-[(benzyloxy)methyl]-2-(hydroxymethyl)cyclopropyl]methanol | C13H18O3 | 详情 | 详情 | |
| (X) | 53928 | {(1R,2S)-2-[(benzoyloxy)methyl]-2-[(benzyloxy)methyl]cyclopropyl}methyl benzoate | C27H26O5 | 详情 | 详情 | |
| (XI) | 53929 | [(1R,2S)-2-[(benzoyloxy)methyl]-2-(hydroxymethyl)cyclopropyl]methyl benzoate | C20H20O5 | 详情 | 详情 | |
| (XII) | 53930 | [(1R,2R)-2-[(benzoyloxy)methyl]-2-({[(4-methylphenyl)sulfonyl]oxy}methyl)cyclopropyl]methyl benzoate | C27H26O7S | 详情 | 详情 | |
| (XIII) | 14383 | 6-(benzyloxy)-9H-purin-2-ylamine; 6-(benzyloxy)-9H-purin-2-amine | 19916-73-5 | C12H11N5O | 详情 | 详情 |
| (XIV) | 53931 | {(1R,2S)-2-{[2-amino-6-(benzyloxy)-9H-purin-9-yl]methyl}-2-[(benzoyloxy)methyl]cyclopropyl}methyl benzoate | C32H29N5O5 | 详情 | 详情 | |
| (XV) | 53932 | [(1S,2R)-1-{[2-amino-6-(benzyloxy)-9H-purin-9-yl]methyl}-2-(hydroxymethyl)cyclopropyl]methanol | n/a | C18H21N5O3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(III)The reaction of diethyl malonate (I) with (R)-(-)-epichlorohydrin (II) by means of sodium ethoxide in refluxing ethanol gives the 3-oxa-2-oxobicyclic compound (III), which by reduction with NaBH4 in ethanol yields (1S,2R)-1,2-bis(hydroxymethyl)cyclopropanecarboxylic acid ethyl ester (IV). The reaction of (IV) with diphenyldiazomethane by means of 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) in dichloroethane affords (1R,7R)-4,4-diphenyl-3,5-dioxabicyclo[5.1.0]octane-1-carboxylic acid ethyl ester (V), which is reduced with LiBH4 in THF giving the carbinol (VI). The reaction of (VI) with CBr4 and triphenylphosphine in dichloromethane yields the bromomethyl derivative (VII), which is condensed with 5-(2-(E)-bromovinyluracil (VIII) by means of K2CO3 and 18-crown-6 in hot DMF affording the expected addition compound (IX). Finally, this compound is deprotected with HCl in methanol.
| 【1】 Onishi, T.; Mukai, C.; Sekiyama, T.; Tsuji, T.; Iwayama, S.; Okunishi, M. (Ajinomoto Co., Inc.); Bis(hydroxymethyl)cyclopropylmethyl pyrimidine derivs.,their preparation and their use as anti-viral agents. EP 0649840; JP 1995165731; US 5496824 . |
| 【2】 Onishi, T.; Mukai, C.; Nakagawa, R.; et al.; Synthesis and antiviral activity of novel anti-VZV 5-substituted uracil nucleosides with a cyclopropane sugar moiety. J Med Chem 2000, 43, 2, 278. |
| 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) | 16829 | Diethyl malonate | 105-53-3 | C7H12O4 | 详情 | 详情 |
| (II) | 38067 | (2R)-2-(Chloromethyl)oxirane; (R)-Epichlorohydrin | 51594-55-9 | C3H5ClO | 详情 | 详情 |
| (III) | 38068 | ethyl (1S,5R)-2-oxo-3-oxabicyclo[3.1.0]hexane-1-carboxylate | C8H10O4 | 详情 | 详情 | |
| (IV) | 38069 | ethyl (1R,2R)-1,2-bis(hydroxymethyl)cyclopropanecarboxylate | C8H14O4 | 详情 | 详情 | |
| (V) | 38070 | ethyl (1R,7S)-4,4-diphenyl-3,5-dioxabicyclo[5.1.0]octane-1-carboxylate | C21H22O4 | 详情 | 详情 | |
| (VI) | 38071 | [(7S)-4,4-diphenyl-3,5-dioxabicyclo[5.1.0]oct-1-yl]methanol | C19H20O3 | 详情 | 详情 | |
| (VII) | 38072 | (1R,7S)-1-(bromomethyl)-4,4-diphenyl-3,5-dioxabicyclo[5.1.0]octane | C19H19BrO2 | 详情 | 详情 | |
| (VIII) | 38073 | 5-[(E)-2-bromoethenyl]-2,4(1H,3H)-pyrimidinedione | 69304-49-0 | C6H5BrN2O2 | 详情 | 详情 |
| (IX) | 38074 | 5-[(E)-2-bromoethenyl]-1-[[(7S)-4,4-diphenyl-3,5-dioxabicyclo[5.1.0]oct-1-yl]methyl]-2,4(1H,3H)-pyrimidinedione | C25H23BrN2O4 | 详情 | 详情 |