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【结 构 式】 
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【分子编号】14380 【品名】[(1S,2S)-2-[(benzoyloxy)methyl]-4-oxocyclobutyl]methyl benzoate 【CA登记号】 |
【 分 子 式 】C20H18O5 【 分 子 量 】338.35992 【元素组成】C 71% H 5.36% O 23.64% |
合成路线1
该中间体在本合成路线中的序号：(IX)1) The cyclization of ketene diethylketal (I) with diethyl fumarate (II) in hot tert-butanol gives trans-3,3-diethoxycyclobutane-1,2-dicarboxylic acid diethyl ester (III), which is saponified with KOH in hot methanol to the corresponding racemic diacid (IV). The condensation of (IV) with (R)-(-)-2-phenylglycinol (V) by means of dicyclohexylcarbodiimide (DCC) in dichloromethane followed by fractionated crystallization of the resulting diastereomeric mixture yields the diamide (VI). The hydrolytic reduction of (VI) by sequential treatments with trimethylsilyl chloride and imidazole, dinitrogen tetraoxide and finally with LiBH4 affords (S,S)-trans-3,3-diethoxycyclobutane-1,2-dimethanol (VII), which is benzoylated with benzoyl chloride in pyridine to the dibenzoate (VIII). The cleavage of the ketal group of (VIII) with H2SO4 in acetonitrile gives the cyclobutanone (IX), which is reduced with LS-Selectride in THF yielding [1S-(1alpha,2beta,3beta)]-3-hydroxycyclobutane-1,2-dimethanol 1,2-dibenzoate (X). The reaction of (X) with p-toluenesulfonyl chloride affords the corresponding tosylate (XI), which is condensed with 6-O-benzylguanidine (XII) by means of K2CO3 and 18-crown-6 in hot DMF giving [1R-(1alpha,2beta,3alpha)]-6-O-benzyl-9-[2,3-di(benzoyloxymethyl) cyclobutyl]guanine (XIII). Finally, this compound is treated with sodium methoxide in hot methanol. 2) The reaction of 6-chloropurine-2-amine (XIV) with 47% HI gives 6-iodopurine-2-amine (XV), which is condensed with [1S-(1alpha,2beta,3beta)]-3-(trifluoromethylsulfonyloxy)cyclobutane-1,2-dimethanol 1,2-dibenzoate (XVI) (obtained by treatment of the previously described cyclobutanol [X] with trifluromethanesulfonyl anhydride [Tf2O]) by means of benzyltriethylammonium hydroxide and pyridine in dichloromethane to afford the condensed iodopurine (XVII). The reaction of (XVII) with sodium methoxide hydrolyzes the benzoyl groups affording the 6-O-methylguanine derivative (XVIII), which is finally treated with aqueous HCl at 95 C.
| 【1】 Ireland, C.; Leeson, P.A.; Castaner, J.; Lobucavir. Drugs Fut 1997, 22, 4, 359. |
| 【2】 Bisacchi, G.S.; Singh, J.; Godfrey, J.D. Jr.; Kissick, T.P.; Mitt, T.; Malley, M.F.; Di Marco, J.D.; Gougoutas, J.Z.; Mueller, R.H.; Zahler, R.; Regioselective coupling of tetraalkylammonium salts of 6-iodo-2-aminopurine to a cyclobutyl triflate: Efficient preparation of homochiral BMS-180,194, a potent antiviral carbocyclic nucleoside. J Org Chem 1995, 60, 9, 2902-5. |
| 【3】 Singh, J.; Bisacchi, G.S.; Godfrey, J.D. Jr.; Mitt, T.; Mueller, R.H.; Zahler, R.; Kissick, T.P. (Bristol-Myers Squibb Co.); Process for preparing guanine-containing antiviral agents and purinyl salts useful in such process. EP 0579421 . |
| 【4】 Bisacchi, G.S.; Mitt, T. (Bristol-Myers Squibb Co.); Intermediates for an optically active cyclobutane nucleoside. US 5306837 . |
| 【5】 Bisacchi, G.S.; Braitman, A.; Cianci, C.W.; et al.; Synthesis and antiviral activity of enantiomeric forms of cyclobutyl nucleoside analogues. J Med Chem 1991, 34, 4, 1415-21. |
| 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) | 14372 | Ethene, 1,1-diethoxy-; 1-ethoxyvinyl ethyl ether; 1,1-diethoxyethylene | 2678-54-8 | C6H12O2 | 详情 | 详情 |
| (II) | 14373 | diethyl (E)-2-butenedioate; Diethyl Fumarate | 1520-50-9 | C8H12O4 | 详情 | 详情 |
| (III) | 14374 | diethyl (1S,2R)-3,3-diethoxy-1,2-cyclobutanedicarboxylate | C14H24O6 | 详情 | 详情 | |
| (IV) | 14375 | (1S,2R)-3,3-diethoxy-1,2-cyclobutanedicarboxylic acid | C10H16O6 | 详情 | 详情 | |
| (V) | 14376 | (2R)-2-amino-2-phenyl-1-ethanol; (R)-(-)-2-phenylglycinol; (R)-2-amino-2-phenyl-1-ethanol | 56613-80-0 | C8H11NO | 详情 | 详情 |
| (VI) | 14377 | (1S,2R)-3,3-diethoxy-N(2)-[(1R)-2-hydroxy-1-phenylethyl]-N(1)-[(1R)-2-methoxy-1-phenylethyl]-1,2-cyclobutanedicarboxamide | C27H36N2O6 | 详情 | 详情 | |
| (VII) | 14378 | [(1S,4S)-2,2-diethoxy-4-(hydroxymethyl)cyclobutyl]methanol | C10H20O4 | 详情 | 详情 | |
| (VIII) | 14379 | [(1S,4S)-4-[(benzoyloxy)methyl]-2,2-diethoxycyclobutyl]methyl benzoate | C24H28O6 | 详情 | 详情 | |
| (IX) | 14380 | [(1S,2S)-2-[(benzoyloxy)methyl]-4-oxocyclobutyl]methyl benzoate | C20H18O5 | 详情 | 详情 | |
| (X) | 14381 | [(1S,2S,4S)-2-[(benzoyloxy)methyl]-4-hydroxycyclobutyl]methyl benzoate | C20H20O5 | 详情 | 详情 | |
| (XI) | 14382 | ((1S,2S,3S)-2-[(benzoyloxy)methyl]-3-[[(4-methylphenyl)sulfonyl]oxy]cyclobutyl)methyl benzoate | C27H26O7S | 详情 | 详情 | |
| (XII) | 14383 | 6-(benzyloxy)-9H-purin-2-ylamine; 6-(benzyloxy)-9H-purin-2-amine | 19916-73-5 | C12H11N5O | 详情 | 详情 |
| (XIII) | 14384 | [(1S,2R,3R)-3-[2-amino-6-(benzyloxy)-9H-purin-9-yl]-2-[(benzoyloxy)methyl]cyclobutyl]methyl benzoate | C32H29N5O5 | 详情 | 详情 | |
| (XIV) | 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 |
| (XV) | 14386 | 6-iodo-9H-purin-2-ylamine; 6-iodo-9H-purin-2-amine | C5H4IN5 | 详情 | 详情 | |
| (XVI) | 14387 | ((1S,2S,4S)-2-[(benzoyloxy)methyl]-4-[[(trifluoromethyl)sulfonyl]oxy]cyclobutyl)methyl benzoate | C21H19F3O7S | 详情 | 详情 | |
| (XVII) | 14388 | [(1R,2R,4S)-2-(2-amino-6-iodo-9H-purin-9-yl)-4-[(benzoyloxy)methyl]cyclobutyl]methyl benzoate | C25H22IN5O4 | 详情 | 详情 | |
| (XVIII) | 14389 | [(1R,2S,4R)-2-(hydroxymethyl)-4-(6-methoxy-9H-purin-9-yl)cyclobutyl]methanol | C12H16N4O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IX)4) The reaction of the previously described chiral cyclobutanone (IX) with hydroxylamine gives the corresponding oxime (XXXI), which is reduced with H2 over PtO2 yielding [1R-(1alpha,2beta,3alpha)]-2,3-di(cyclohexylcarbonyloxymethyl) cyclobutane-1-amine (XXXII). The condensation of (XXXII) with 4,6-dichloropyrimidine-2-amine (XXXIII) affords (XXXIV), which is further condensed with 4-chlorophenyldiazonium chloride (XXXV) to give the 5-azo-pyrimidine derivative (XXXVI). The hydrogenation of the azo group of (XXXVI) with Zn/HCl yields the 2,5-diaminopyrimidine derivative (XXXVII), which is cyclized with triethyl orthoformate to afford [1R-(1alpha,2beta,3alpha)]-2-amino-9-[2,3-bis (cyclohexylcarbonyloxymethyl)cyclobutyl]-6-chloropurine (XXXVIII). Finally, this compound is converted into the final product in the usual way.
| 【1】 Ireland, C.; Leeson, P.A.; Castaner, J.; Lobucavir. Drugs Fut 1997, 22, 4, 359. |
| 【2】 Honjo, M.; Maruyama, T.; Sato, Y. (Nippon Kayaku Co., Ltd.); Production of carboxetanocin G or A and intermediates therefor. WO 9110665 . |
| 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) | 14380 | [(1S,2S)-2-[(benzoyloxy)methyl]-4-oxocyclobutyl]methyl benzoate | C20H18O5 | 详情 | 详情 | |
| (XXXI) | 14402 | [(1S,2R)-2-[(benzoyloxy)methyl]-3-(hydroxyimino)cyclobutyl]methyl benzoate | C20H19NO5 | 详情 | 详情 | |
| (XXXII) | 14403 | ((1S,2R,3R)-3-amino-2-[[(cyclohexylcarbonyl)oxy]methyl]cyclobutyl)methyl cyclohexanecarboxylate | C20H33NO4 | 详情 | 详情 | |
| (XXXIII) | 14404 | 4,6-dichloro-2-pyrimidinamine; 2-Amino-4,6-dichloropyrimidine; 4,6-dichloro-2-pyrimidinylamine | 56-05-3 | C4H3Cl2N3 | 详情 | 详情 |
| (XXXIV) | 14405 | ((1S,2R,3R)-3-[(2-amino-6-chloro-4-pyrimidinyl)amino]-2-[[(cyclohexylcarbonyl)oxy]methyl]cyclobutyl)methyl cyclohexanecarboxylate | C24H35ClN4O4 | 详情 | 详情 | |
| (XXXV) | 10197 | 4-Chlorobenzenediazonium chloride | C6H4Cl2N2 | 详情 | 详情 | |
| (XXXVI) | 14407 | ((1S,2R,3R)-3-([2-amino-6-chloro-5-[(E)-2-(4-chlorophenyl)diazenyl]-4-pyrimidinyl]amino)-2-[[(cyclohexylcarbonyl)oxy]methyl]cyclobutyl)methyl cyclohexanecarboxylate | C30H38Cl2N6O4 | 详情 | 详情 | |
| (XXXVII) | 14408 | [(1R,2S,4S)-2-[[(cyclohexylcarbonyl)oxy]methyl]-4-[(2,5-diamino-6-chloro-4-pyrimidinyl)amino]cyclobutyl]methyl cyclohexanecarboxylate | C24H36ClN5O4 | 详情 | 详情 | |
| (XXXVIII) | 14409 | ((1S,2R,3R)-3-(2-amino-6-chloro-9H-purin-9-yl)-2-[[(cyclohexylcarbonyl)oxy]methyl]cyclobutyl)methyl cyclohexanecarboxylate | C25H34ClN5O4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IX)5) The thermal rearrangement of 3-bromo-4,6-dimethyl-2-oxo-2H-pyran-5-carboxylic acid ethyl ester (XXXIX) with NaOH in refluxing water gives (rac)-trans-3-methylenecyclopropane-1,2-dicarboxylic acid (XL), which was submitted to optical resolution with (R)-alpha-methylbenzylamine (XLI) yielding, after crystallization, the corresponding (R,R)-enantiomeric salt (XLII). The decomposition of the salt and esterification of the free acid with trimethyl orthoformate affords (1R-trans)-3-methylenecyclopropane-1,2-dicarboxylic acid dimethyl ester (XLIII), which is reduced with LiAlH4 in THF to (1R-trans)-3-methylenecyclopropane-1,2-dimethanol (XLIV). The esterification of (XLIV) with benzoic anhydride and triethylamine in ethyl acetate affords the corresponding dibenzoate (XLV), which is epoxidized with m-chloroperbenzoic acid (MCPBA) in dichloromethane to afford the oxirane (XLVI). The isomerization of (XLVI) by means of LiI in ethyl acetate gives (2S-trans)-2,3-bis(benzoyloxymethyl)cyclobutanone (IX), which is reduced with lithium trisiamylborohydride in THF yielding [1S-(1alpha,2beta,3beta)]-3-hydroxycyclobutane-1,2-dimethanol 1,2-dibenzoate ester (X). The reaction of (X) with p-toluenesulfonyl chloride in pyridine affords the corresponding tosylate (XI), which is condensed with 6-O-benzylguanine (XII) by means of K2CO3 and 18-crown-6 in DMF yielding the substituted guanine (XIII). Finally, this compound is deprotected by treatment first with sodium methoxide in hot methanol, and then with 3N HCl.
| 【1】 Ireland, C.; Leeson, P.A.; Castaner, J.; Lobucavir. Drugs Fut 1997, 22, 4, 359. |
| 【2】 Godfrey, J.D. Jr.; Mueller, R.H.; Kissick, T.P.; Singh, J. (Bristol-Myers Squibb Co.); Process and intermediates for the preparation of an antiviral agent containing a cyclobutyl group. EP 0535448 . |
| 【3】 Godfrey, J.D. Jr.; Mueller, R.H.; Kissick, T.P.; Singh, J. (Bristol-Myers Squibb Co.); Process for the preparation of an antiviral agent. US 5525726 . |
| 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) | 14380 | [(1S,2S)-2-[(benzoyloxy)methyl]-4-oxocyclobutyl]methyl benzoate | C20H18O5 | 详情 | 详情 | |
| (X) | 14381 | [(1S,2S,4S)-2-[(benzoyloxy)methyl]-4-hydroxycyclobutyl]methyl benzoate | C20H20O5 | 详情 | 详情 | |
| (XI) | 14382 | ((1S,2S,3S)-2-[(benzoyloxy)methyl]-3-[[(4-methylphenyl)sulfonyl]oxy]cyclobutyl)methyl benzoate | C27H26O7S | 详情 | 详情 | |
| (XII) | 14383 | 6-(benzyloxy)-9H-purin-2-ylamine; 6-(benzyloxy)-9H-purin-2-amine | 19916-73-5 | C12H11N5O | 详情 | 详情 |
| (XIII) | 63903 | [(1R,2R,4S)-2-[2-amino-6-(benzyloxy)-9H-purin-9-yl]-4-(hydroxymethyl)cyclobutyl]methanol | C18H21N5O3 | 详情 | 详情 | |
| (XXXIX) | 14410 | ethyl 3-bromo-2-hydroxy-4,6-dimethyl-2H-pyran-5-carboxylate | C10H13BrO4 | 详情 | 详情 | |
| (XL) | 14411 | (1R,2R)-3-methylene-1,2-cyclopropanedicarboxylic acid | 499-02-5 | C6H6O4 | 详情 | 详情 |
| (XLI) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |
| (XLII) | 14412 | (R,R)-3-methylenecyclopropane-1,2-dicarboxylic acid (R)-1-phenylethylamine salt | C14H17NO4 | 详情 | 详情 | |
| (XLIII) | 14413 | dimethyl (1R,2R)-3-methylene-1,2-cyclopropanedicarboxylate | C8H10O4 | 详情 | 详情 | |
| (XLIV) | 14414 | [(1R,2R)-2-(hydroxymethyl)-3-methylenecyclopropyl]methanol | C6H10O2 | 详情 | 详情 | |
| (XLV) | 14415 | [(1R,2R)-2-[(benzoyloxy)methyl]-3-methylenecyclopropyl]methyl benzoate | C20H18O4 | 详情 | 详情 | |
| (XLVI) | 14416 | [(4S,5S)-5-[(benzoyloxy)methyl]-1-oxaspiro[2.2]pent-4-yl]methyl benzoate | C20H18O5 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VI)A new practical asymmetric synthesis of lubocavir has been described: The diastereoselective cycloaddition of (-)-dimenthyl fumarate (I) with ketene dimethylacetal (II) by means of diisobutylaluminum chloride (DIBAC) in toluene gives the cyclobutane (III), which is reduced with LiAlH4 yielding the cyclobutyl dicarbinol (IV). The reaction of (IV) with benzoyl chloride affords the dibenzoate (V), which is deprotected in acidic medium to give the cyclobutanone (VI). The stereoselective reduction of (VI) with DIBAC yields the chiral cyclobutanol (VII), which is treated with triflic anhydride to afford the activated triflate (VIII). The regioselective condensation of (VIII) with 2-amino-6-iodopurine benzyltriethylammonium salt (IX) gives the expected addition product (X), which is debenzoylated with NaOMe in methanol yielding the 2-amino-6-methoxypurine (XI). Finally, this compound is converted to lobucavir by refluxing with aqueous hydrochloric acid.
| 【1】 Singh, J.; Bisacchi, G.S.; Ahmad, S.; et al.; A practical asymmetric synthesis of the antiviral agent lobucavir, BMS-180194. Org Process Res Dev 1998, 2, 6, 393. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10463 | Benzoyl chloride | 98-88-4 | C7H5ClO | 详情 | 详情 | |
| (I) | 34029 | bis[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl] (E)-2-butenedioate | C24H40O4 | 详情 | 详情 | |
| (II) | 34030 | 1-methoxyvinyl methyl ether; 1,1-dimethoxyethylene | C4H8O2 | 详情 | 详情 | |
| (III) | 34031 | bis[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl] (1S,2R)-3,3-dimethoxy-1,2-cyclobutanedicarboxylate | C28H48O6 | 详情 | 详情 | |
| (IV) | 34032 | [(1S,2S)-2-(hydroxymethyl)-3,3-dimethoxycyclobutyl]methanol | C8H16O4 | 详情 | 详情 | |
| (V) | 34033 | [(1S,2S)-2-[(benzoyloxy)methyl]-3,3-dimethoxycyclobutyl]methyl benzoate | C22H24O6 | 详情 | 详情 | |
| (VI) | 14380 | [(1S,2S)-2-[(benzoyloxy)methyl]-4-oxocyclobutyl]methyl benzoate | C20H18O5 | 详情 | 详情 | |
| (VII) | 14381 | [(1S,2S,4S)-2-[(benzoyloxy)methyl]-4-hydroxycyclobutyl]methyl benzoate | C20H20O5 | 详情 | 详情 | |
| (VIII) | 14387 | ((1S,2S,4S)-2-[(benzoyloxy)methyl]-4-[[(trifluoromethyl)sulfonyl]oxy]cyclobutyl)methyl benzoate | C21H19F3O7S | 详情 | 详情 | |
| (IX) | 34036 | 2-Amino-6-iodo-6,9-dihydro-1H-purin-9-ide anion | C5H5IN5 | 详情 | 详情 | |
| (X) | 34034 | [(1R,2R,4S)-2-(2-amino-6-iodo-1,6-dihydro-9H-purin-9-yl)-4-[(benzoyloxy)methyl]cyclobutyl]methyl benzoate | C25H24IN5O4 | 详情 | 详情 | |
| (XI) | 34035 | [(1S,2R,3R)-3-(2-amino-6-methoxy-1,6-dihydro-9H-purin-9-yl)-2-(hydroxymethyl)cyclobutyl]methanol | C12H19N5O3 | 详情 | 详情 |