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【结 构 式】

【分子编号】25254

【品名】2,6-dichloro-9H-purine

【CA登记号】5451-40-1

【 分 子 式 】C5H2Cl2N4

【 分 子 量 】189.00324

【元素组成】C 31.77% H 1.07% Cl 37.52% N 29.64%
与该中间体有关的原料药合成路线共 15 条
合成路线1合成路线2合成路线3合成路线4合成路线5合成路线6合成路线7合成路线8合成路线9合成路线10合成路线11合成路线12合成路线13合成路线14合成路线15

合成路线1

该中间体在本合成路线中的序号：(V)

The reaction of benzonitrile (I) with refluxing ethylene glycol (II) gives ethylene glycol monobenzoate (III), which is chloromethylated with formaldehyde and dry HCl in CH2Cl2 affording 1-benzoyloxy-2-chloromethoxyethane (IV). The condensation of (IV) with 2,6-dichloropurine (V) by means of triethylamine in DMF yields 2,6-dichloro-9-(2-benzoyloxyethoxymethyl)purine (VI), which is aminated and debenzoylated by treatment with NH3 in methanol at 95 C in a pressure vessel giving 2-chloro-9-(2-hydroxyethoxymethyl)adenine (VII). The Sandmeyer reaction of (VII) with NaNO2 in acetic acid affords 2-chloro-9-(2-hydroxyethoxymethyl)hypoxanthine (VIII), which is finally amonolyzed with ammonia in methanol at 125 C in a pressure vessel.

参考文献 中间体
合成目标
【1】 Schaeffer, H.J.; et al.; 9-(2-Hydroxyethoxy)guanine activity aganist viruses of the herpes group. Nature 1978, 272, 583-585.
【2】 Castaner, J.; Hillier, K.; Acycloguanosine. Drugs Fut 1978, 3, 11, 788.
【3】 Schaeffer, H.J. (Glaxo Wellcome plc); Purine derivs.. US 4294831 .
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) 25904 benzonitrile 100-47-0 C7H5N 详情 详情
(II) 11295 Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol 107-21-1 C2H6O2 详情 详情
(III) 39965 2-hydroxyethyl benzoate C9H10O3 详情 详情
(IV) 39966 2-(chloromethoxy)ethyl benzoate C10H11ClO3 详情 详情
(V) 25254 2,6-dichloro-9H-purine 5451-40-1 C5H2Cl2N4 详情 详情
(VI) 39967 2-[(2,6-dichloro-9H-purin-9-yl)methoxy]ethyl benzoate C15H12Cl2N4O3 详情 详情
(VII) 39968 2-[(6-amino-2-chloro-9H-purin-9-yl)methoxy]-1-ethanol C8H10ClN5O2 详情 详情
(VIII) 39969 2-chloro-9-[(2-hydroxyethoxy)methyl]-9H-purin-6-ol C8H9ClN4O3 详情 详情

合成路线2

该中间体在本合成路线中的序号：(XII)

Reaction of 1,2:5,6-di-O-isopropylidene-3-O-tosyl-a-D-allofuranose (I) with KF in acetamide at 210 oC gives 3-deoxy-3-fluoro-1,2:5,6-di-O-isopropylidene-a-D-glucofuranose (II), which is treated with a 1:1 mixture of metha-nol and 0.7% aqueous H2SO4 to yield 3-deoxy-3-fluoro-1,2-isopropylidene-a-D-glucofuranose (III). Selective acylation of the sugar (III) with benzoyl chloride in pyridine affords the 6-O-benzoyl derivative (IV), which is treated with Amberlite IR-100 (H+) ion-exchange resin in hot dioxane to provide 6-O-benzoyl-3-deoxy-3-fluoro-D-glucofuranose (V). The oxidative cleavage of glucofuranose (V) by means of KIO4 in water results in rearrangement to give 5-O-benzoyl-2-deoxy-2-fluoro-3-O-formyl-D- arabinofuranose (VI), which is deformylated by means of NaOMe in methanol to provide 5-O-benzoyl-2-deoxy-2-fluoro-D-arabinofuranose (VII). Acylation of the arabinofuranose (VII) with acetic anhydride in pyridine affords the 1,3-di-O-acetyl derivative (VIII), which is treated with HBr in AcOH/CH2Cl2 to yield 3-O-acetyl-5-O-benzoyl-2-deoxy-2-fluoro-D-arabinofuranosyl bromide (IX) (1). Condensation of compound (IX) with 2-chloroadenine (X) by means of potassium tert-butoxide in different solvents gives the acylated 2-chloroadenosine derivative (XI), which is finally deacylated by means of NaOMe in methanol.

参考文献 中间体
合成目标
【1】 Bauta, W.E.; Schulmeier, B.E.; Cantrell, W.R. Jr.; Lovett, D.; Puente, J. (Ilex Oncology, Inc.); Process for preparing purine nucleosides. US 2003114663; WO 0311877 .
【2】 Clayton, S.D., Montgomery, J.A., Riordan, J.M., Secrist, J.A. III., Shortnacy-Fowler, A.T.; Synthesis and biologic activity of 2'-fluoro-2-halo derivatives of 9-beta-D-arabinofuranosyladenine. J Med Chem 1992, 35 (2): 397
【3】 Castaner, J., Chilman-Blair, K., Mealy, N.E.; Clofarabine. Drugs Fut 2004, 29 (2): 112
【4】 Fox, J.J., Reichman, U., Watanabe, K.A.; A practical synthesis of 2-deoxy-2-fluoro-D-arabinofuranose derivatives. Carbohydr Res 1975, 42 (2): 233
【5】 Montgomery, J.A., Secrist, J.A. III (Southern Research Institute); 2-Halo-9-(2-deoxy-2-fluoro-B-D-arabinofuranosyl) adenine nucleoside derivs.. JP 1993502014, US 5034518, WO 9014352
【6】 Montgomery, J.A., Secrist, J.A. III, Fowler, A.T. (Southern Research Institute); Methods for synthesizing 2-chloro-9-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-9H-purin-6-amine. WO 0160383, CA 2400470, EP 1261350
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
（X） 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
(I) 63931 (3aR,5R,6S,6aR)-5-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-yl 4-methylbenzenesulfonate C19H26O8S 详情 详情
(II) 63932 (3aR,5R,6S,6aS)-5-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-6-fluoro-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole C12H19FO5 详情 详情
(III) 63933 (1S)-1-[(3aR,5R,6S,6aS)-6-fluoro-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl]-1,2-ethanediol C9H15FO5 详情 详情
(IV) 63934 (2S)-2-[(3aR,5R,6S,6aS)-6-fluoro-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl]-2-hydroxyethyl benzoate C16H19FO6 详情 详情
(V) 63935 (2S)-2-[(2R,3R,4S)-3-fluoro-4,5-dihydroxytetrahydro-2-furanyl]-2-hydroxyethyl benzoate C13H15FO6 详情 详情
(VI) 63936 [(2R,3R,4S)-4-fluoro-3-(formyloxy)-5-hydroxytetrahydro-2-furanyl]methyl benzoate C13H13FO6 详情 详情
(VII) 63937 [(2R,3R,4S)-4-fluoro-3,5-dihydroxytetrahydro-2-furanyl]methyl benzoate C12H13FO5 详情 详情
(VIII) 63938 [(2R,3R,4S)-3,5-bis(acetyloxy)-4-fluorotetrahydro-2-furanyl]methyl benzoate C16H17FO7 详情 详情
(IX) 17691 [(2R,3R,4S)-3-(acetoxy)-5-bromo-4-fluorotetrahydro-2-furanyl]methyl benzoate C14H14BrFO5 详情 详情
(XI) 63940 [(2R,3R,4S,5R)-3-(acetyloxy)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluorotetrahydro-2-furanyl]methyl benzoate C19H17ClFN5O5 详情 详情
(XII) 25254 2,6-dichloro-9H-purine 5451-40-1 C5H2Cl2N4 详情 详情
(XIII) 63941 [(2R,3R,4S,5R)-3-(acetyloxy)-5-(2,6-dichloro-9H-purin-9-yl)-4-fluorotetrahydro-2-furanyl]methyl benzoate C19H15Cl2FN4O5 详情 详情
(XIV) 63942 (2R,3R,4S,5R)-5-(2-chloro-6-methoxy-9H-purin-9-yl)-4-fluoro-2-(hydroxymethyl)tetrahydro-3-furanol C11H12ClFN4O4 详情 详情

合成路线3

该中间体在本合成路线中的序号：(I)

The condensation of 2,6-dichloropurine (I) with 4-methoxybenzylamine (II) in butanol at 120 C gives 2-chloro-6-(4-methoxybenzylamino)purine (II), which is treated with isopropyl iodide (IV) and NaH in DMF yielding 2-chloro-9-isopropyl-6-(4-methoxybenzylamino)purine (V). Finally, this compound is condensed with diethanolamine (VI) in DMSO at 160 C.

参考文献 中间体
合成目标
【1】 Schow, S.R.; et al.; Synthesis and activity of 2,6,9-trisubstituted purines. Bioorg Med Chem Lett 1997, 7, 21, 2697.
【2】 Lum, R.T.; Blum, C.L.; Mackman, R.; Wick, M.M.; Schow, S.R. (CV Therapeutics, Inc.); Purine inhibitors of cyclin dependent kinase 2 and IkappaB-alpha. EP 1021186; US 5866702; WO 9805335 .
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) 25254 2,6-dichloro-9H-purine 5451-40-1 C5H2Cl2N4 详情 详情
(II) 15098 4-Methoxybenzylamine; (4-Methoxyphenyl)methanamine 2393-23-9 C8H11NO 详情 详情
(III) 38022 N-(2-chloro-9H-purin-6-yl)-N-(4-methoxybenzyl)amine; 2-chloro-N-(4-methoxybenzyl)-9H-purin-6-amine C13H12ClN5O 详情 详情
(IV) 19369 2-iodopropane 75-30-9 C3H7I 详情 详情
(V) 38023 2-chloro-9-isopropyl-N-(4-methoxybenzyl)-9H-purin-6-amine; N-(2-chloro-9-isopropyl-9H-purin-6-yl)-N-(4-methoxybenzyl)amine C16H18ClN5O 详情 详情
(VI) 24273 2-[(2-hydroxyethyl)amino]-1-ethanol 111-42-2 C4H11NO2 详情 详情

合成路线4

该中间体在本合成路线中的序号：(VII)

The oxidation of 1-O-mehyl 2,3-isopropylidene-D-ribofuranoside (I) gives the corresponding aldehyde (II), which is condensed with methyltriphenylphosphonium bromide by means of butyllithium in THF yielding methyl 5-deoxy-2,3-isopropylidene-5-methylene-D-ribofuranoside (III). Elimination of the isopropylidene protecting group by passing through an Amberlyst resin (acid form) affords the free ribofuranoside (IV), which is benzoylated with benzoyl chloride and triethylamine in dichloromethane to afford the dibenzoyl derivative (V). The methyl ribofuranoside (V) was converted into the 1-O-acetyl derivative (VI) and condensed with 2,6-dichloro-9H-purine (VII) by heating at 150 C to provide the dichloropurine derivative (VIII), which is treated with O-methylhydroxylamine and triethylamine to afford 2',3'-di-O-benzoyl-2-chloro-5'-deoxy-N-methoxy-5'-methyleneadenosine (IX). Finally, this compound is debenzoylated with ammonia in methanol.

参考文献 中间体
合成目标
【1】 Lau, J.; Knutsen, L.J.S. (Novo Nordisk A/S); Chemical cpds., their preparation and use. EP 0719275; JP 1999511436; US 5589467; WO 9507921 .
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
15455 (aminooxy)methane; O-methylhydroxylamine 67-62-9 CH5NO 详情 详情
(I) 10017 [(3aR,4R,6R,6aR)-6-Methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methanol 4099-85-8 C9H16O5 详情 详情
(II) 10018 (3aR,4S,6R,6aR)-6-Methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbaldehyde C9H14O5 详情 详情
(III) 25257 (3aS,4R,6R,6aR)-4-methoxy-2,2-dimethyl-6-vinyltetrahydrofuro[3,4-d][1,3]dioxole; (3aS,4R,6R,6aR)-2,2-dimethyl-6-vinyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl methyl ether C10H16O4 详情 详情
(IV) 25258 (2R,3S,4S,5R)-2-methoxy-5-vinyltetrahydro-3,4-furandiol C7H12O4 详情 详情
(V) 25259 (2R,3R,4R,5R)-4-(benzoyloxy)-2-methoxy-5-vinyltetrahydro-3-furanyl benzoate C21H20O6 详情 详情
(VI) 25260 (2R,3R,4R,5S)-5-(acetoxy)-4-(benzoyloxy)-2-vinyltetrahydro-3-furanyl benzoate C22H20O7 详情 详情
(VII) 25254 2,6-dichloro-9H-purine 5451-40-1 C5H2Cl2N4 详情 详情
(VIII) 25261 (2R,3R,4S,5R)-4-(benzoyloxy)-2-(2,6-dichloro-9H-purin-9-yl)-5-vinyltetrahydro-3-furanyl benzoate C25H18Cl2N4O5 详情 详情
(IX) 25262 (2R,3R,4S,5R)-4-(benzoyloxy)-2-[2-chloro-6-(methoxyamino)-9H-purin-9-yl]-5-vinyltetrahydro-3-furanyl benzoate C26H22ClN5O6 详情 详情

合成路线5

该中间体在本合成路线中的序号：(VII)

The cyclization of ribofuranoside (I) with trimethylsilyl acetylene (II) by means of NBS in DMF gives the trimethylsilylisoxazole (III), which is desilylated with NaOH in methanol yielding the isoxazole (IV). Elimination of the isopropylidene protecting group of (IV) by passing through a Dowex 50 H+ column affords the dihydroxy compound (V), which is benzoylated with benzoyl chloridde and DMAP in pyridine giving the dibenzoyl derivative (VI). The condensation of (VI) with 2,6-dichloro-9H-purine (VII) in refluxing hexamethyldisilazane (HMDA) provides the purine derivative (VIII), which is treated with 0-methylhydroxylamine and triethylamine in refluxing dioxane yielding the adenosine derivative (IX). Finally, this compound is debenzoylated with ammonia in methanol.

参考文献 中间体
合成目标
【1】 Knutsen, L.; Olsen, U.B.; Roberts, S.M.; Varley, D.R.; Bowler, A.N. (Novo Nordisk A/S); Novel N-alkoxyadenine derivs. acting as cytokine inhibitors. WO 9801459 .
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
15455 (aminooxy)methane; O-methylhydroxylamine 67-62-9 CH5NO 详情 详情
(I) 25249 (3aR,4R,6R,6aS)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbaldehyde O-methyloxime C10H17NO5 详情 详情
(II) 23897 ethynyl(trimethyl)silane；trimethylsilyl acetylene 1066-54-2 C5H10Si 详情 详情
(III) 25250 3-[(3aR,4R,6R,6aS)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-5-(trimethylsilyl)isoxazole; (3aS,4R,6R,6aR)-2,2-dimethyl-6-[5-(trimethylsilyl)-3-isoxazolyl]tetrahydrofuro[3,4-d][1,3]dioxol-4-yl methyl ether C14H23NO5Si 详情 详情
(IV) 25251 3-[(3aR,4R,6R,6aS)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]isoxazole; (3aS,4R,6R,6aR)-6-(3-isoxazolyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl methyl ether C11H15NO5 详情 详情
(V) 25252 (2R,3S,4S,5R)-2-(3-isoxazolyl)-5-methoxytetrahydro-3,4-furandiol C8H11NO5 详情 详情
(VI) 25253 (2R,3R,4R,5R)-4-(benzoyloxy)-2-(3-isoxazolyl)-5-methoxytetrahydro-3-furanyl benzoate C22H19NO7 详情 详情
(VII) 25254 2,6-dichloro-9H-purine 5451-40-1 C5H2Cl2N4 详情 详情
(VIII) 25255 (2R,3R,4S,5R)-4-(benzoyloxy)-2-(2,6-dichloro-9H-purin-9-yl)-5-(3-isoxazolyl)tetrahydro-3-furanyl benzoate C26H17Cl2N5O6 详情 详情
(IX) 25256 (2R,3R,4S,5R)-4-(benzoyloxy)-2-[2-chloro-6-(methoxyamino)-9H-purin-9-yl]-5-(3-isoxazolyl)tetrahydro-3-furanyl benzoate C27H21ClN6O7 详情 详情

合成路线6

该中间体在本合成路线中的序号：(I)

Condensation of 2,6-dichloropurine (I) with 3-chloroaniline (II) in hot pentanol yielded the 6-anilino purine (III). This was then alkylated at the N-9 with iodoethane and K2CO3 to afford (IV). Finally, displacement of the 2-chloro of (IV) with cis-1,2-cyclohexanediamine (V) at 150 C furnished the title compound.

参考文献 中间体
合成目标
【1】 Imbach, P.; Capraro, H.G.; Furet, P.; Mett, H.; Meyer, T.; Zimmermann, J.; 2,6,9-Trisubstituted purines: Optimization towards highly potent and selective CDK1 inhibitors. Bioorg Med Chem Lett 1999, 9, 1, 91.
【2】 Capraro, H.-G.; Zimmermann, J.; Furet, P.; Peterli, P. (Novartis AG); Purine derivs. and processes for their preparation. JP 1999514336; WO 9716452 .
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) 25254 2,6-dichloro-9H-purine 5451-40-1 C5H2Cl2N4 详情 详情
(II) 25239 3-chloroaniline; 3-chlorophenylamine 108-42-9 C6H6ClN 详情 详情
(III) 59602 2-chloro-N-(3-chlorophenyl)-9H-purin-6-amine; N-(3-chlorophenyl)-N-(2-chloro-9H-purin-6-yl)amine C11H7Cl2N5 详情 详情
(IV) 59603 2-chloro-N-(3-chlorophenyl)-9-ethyl-9H-purin-6-amine; N-(2-chloro-9-ethyl-9H-purin-6-yl)-N-(3-chlorophenyl)amine C13H11Cl2N5 详情 详情
(V) 37409 (1R,2S)-2-aminocyclohexylamine; (1R,2S)-1,2-cyclohexanediamine 1121-22-8 C6H14N2 详情 详情

合成路线7

该中间体在本合成路线中的序号：(IV)

Adenine (I) was oxidized with hydrogen peroxide in aqueous acetic acid to give adenine 1-N-oxide (II). Diazotization of (II) with sodium nitrite and acetic acid, followed by hydrolysis of the diazonium salt provided hypoxanthine 1-N-oxide (III). 2,6-Dichloropurine (IV) was then obtained by treatment of (III) with phosphoryl chloride in the presence of triethylamine. Displacement of the 6-chlorine atom of (IV) by benzylamine (V) in boiling n-butanol yielded 6-benzylamino-2-chloropurine (VI), which was subsequently alkylated at the 9-N with isopropyl iodide and NaH to give (VII). Finally, the remaining 2-chloro atom of (VII) was displaced by thiomorpholine (VIII) to furnish the title compound.

参考文献 中间体
合成目标
【1】 Woo, E.-R.; Baek, D.J.; Lee, s.-C.; Hong, C.Y.; Lee, K.-S.; Yang, B.-S.; Cho, J.-H.; Oh, C.-H.; Synthesis and biological activities of C-2, N-9 substituted 6-benzylaminopurine derivatives as cyclin-dependent kinase inhibitor. Arch Pharm 1999, 332, 6, 187.
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) 10343 9H-Purin-6-amine; 9H-Purin-6-ylamine; Adenine 73-24-5 C5H5N5 详情 详情
(II) 36313 6-amino-9H-purin-1-ium-1-olate C5H5N5O 详情 详情
(III) 36314 6-hydroxy-9H-purin-1-ium-1-olate C5H4N4O2 详情 详情
(IV) 25254 2,6-dichloro-9H-purine 5451-40-1 C5H2Cl2N4 详情 详情
(V) 15147 Benzylamine; Phenylmethanamine 100-46-9 C7H9N 详情 详情
(VI) 36315 N-benzyl-2-chloro-9H-purin-6-amine; N-benzyl-N-(2-chloro-9H-purin-6-yl)amine C12H10ClN5 详情 详情
(VII) 36316 N-benzyl-2-chloro-9-isopropyl-9H-purin-6-amine; N-benzyl-N-(2-chloro-9-isopropyl-9H-purin-6-yl)amine C15H16ClN5 详情 详情
(VIII) 36317 thiomorpholine 123-90-0 C4H9NS 详情 详情

合成路线8

该中间体在本合成路线中的序号：(VIII)

Alternatively, condensation of 2,6-dichloropurine (VIII) with protected ribose (IX) at 140 C gave the ribofuranosyl purine (X). Subsequent displacement of the 6-chloro of (V) by amine (V), followed by hydrolysis of the benzoate esters afforded the intermediate (VII).

参考文献 中间体
合成目标
【1】 Gregson, M.; Ayres, B.E.; Ewan, G.B.; Ellis, F.; Knight, J. (Glaxo Wellcome plc); 2,6-Diaminopurine derivs.. EP 0680488; JP 1996505864; US 5925624; WO 9417090 .
【2】 Keeling, S.E.; et al.; The discovery and synthesis of highly potent, A2A receptor agonists. Bioorg Med Chem Lett 2000, 10, 4, 403.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VIII) 25254 2,6-dichloro-9H-purine 5451-40-1 C5H2Cl2N4 详情 详情
(IX) 26984 (2R,3R,4R,5S)-5-(acetoxy)-4-(benzoyloxy)-2-[(benzoyloxy)methyl]tetrahydro-3-furanyl benzoate C28H24O9 详情 详情
(X) 32565 (2R,3R,4R,5R)-4-(benzoyloxy)-2-[(benzoyloxy)methyl]-5-(2,6-dichloro-9H-purin-9-yl)tetrahydro-3-furanyl benzoate C31H22Cl2N4O7 详情 详情
(XI) 38962 2,2-diphenylethylamine; 2,2-diphenyl-1-ethanamine 3963-62-0 C14H15N 详情 详情
(XII) 38963 ((2R,3R,4R,5R)-3,4-bis(benzoyloxy)-5-[2-chloro-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl]tetrahydro-2-furanyl)methyl benzoate C45H36ClN5O7 详情 详情
(XIII) 38961 (2R,3R,4S,5R)-2-[2-chloro-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl]-5-(hydroxymethyl)tetrahydro-3,4-furandiol C24H24ClN5O4 详情 详情

合成路线9

该中间体在本合成路线中的序号：(I)

Condensation between dichloropurine (I) and substituted aniline (II) in pentanol affords derivative (III), which is then alkylated with ethyl iodide (IV) by means of Cs2CO3 in DMF to provide purine (V). Finally, the desired compound is obtained by attack of amine (VI) and displacement of the chlorine atom of derivative (V) in diglyme.

参考文献 中间体
合成目标
【1】 Bruggen, J.; Caravatti, G.; Capraro, H.-G.; et al.; Chemistry and biological characterization of CGP79807, a highly selective CDK1/2 inhibitor. 221st ACS Natl Meet (April 1 2001, San Diego) 2001, Abst MEDI 150.
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) 25254 2,6-dichloro-9H-purine 5451-40-1 C5H2Cl2N4 详情 详情
(II) 28662 3-aminobenzonitrile 2237-30-1 C7H6N2 详情 详情
(III) 48922 3-[(2-chloro-9H-purin-6-yl)amino]benzonitrile C12H7ClN6 详情 详情
(IV) 10925 Iodoethane;ethyl iod 75-03-6 C2H5I 详情 详情
(V) 48923 3-[(2-chloro-9-ethyl-9H-purin-6-yl)amino]benzonitrile C14H11ClN6 详情 详情
(VI) 19581 trans-4-Aminocyclohexanol；trans-4-Amino-1-cyclohexanol;trans-4-Amino-1-cyclohexanol; 27489-62-9 C6H13NO 详情 详情

合成路线10

该中间体在本合成路线中的序号：(I)

2,6-Dichloropurine (I) was N-alkylated with benzyl chloride to give a 7:3 mixture of 9-benzyl-2,6-dichloropurine (II) and the 7-benzylated isomer (III). After chromatographic isolation of the desired 9-benzyl purine (II), Stille coupling with the 2-furyltin reagent (IV) in the presence of palladium catalyst furnished the corresponding 6-furylpurine.

参考文献 中间体
合成目标
【1】 Nissen-Meyer, J.; Spilsberg, B.; Gundersen, L.-L.; Synthesis and antimycobacterial activity of 6-arylpurines: The requirements for the N-9 substituent in active antimycobacterial purines. J Med Chem 2002, 45, 6, 1383.
【2】 Langli, G.; et al.; Regiochemistry in Stille couplings of 2,6-dihalopurines. Tetrahedron 1996, 52, 15, 5625.
【3】 Nolsoe, J.M.J.; Langli, F.; Bakkestuen, A.K.; Gundersen, L.-L.; 9-Benzylpurines with inhibitory activity against Mycobacterium tuberculosis. Bioorg Med Chem Lett 2000, 10, 11, 1207.
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) 25254 2,6-dichloro-9H-purine 5451-40-1 C5H2Cl2N4 详情 详情
(II) 44961 9-benzyl-2,6-dichloro-9H-purine C12H8Cl2N4 详情 详情
(III) 44962 7-benzyl-2,6-dichloro-7H-purine C12H8Cl2N4 详情 详情
(IV) 44963 tributyl(2-furyl)stannane C16H30OSn 详情 详情

合成路线11

该中间体在本合成路线中的序号：(I)

2,6-Dichloropurine (I) is condensed with cyclobutylamine (II) in the presence of diisopropylethylamine in hot butanol to produce the 6-cyclobutylamino purine (III). The 2-chloro group of purine (III) is then displaced with 4-amino-N-methylacetanilide (IV) in N-methylpyrrolidone at 145 C to furnish the target diamino purine derivative.

参考文献 中间体
合成目标
【1】 Bammerlin, H.; Le Grand, D.; Hayler, J.; et al.; Novel 2,6-disubstituted purines - The synthesis of potent and selective inhibitors of the protein tyrosine kinase Syk. Drugs Fut 2002, 27, Suppl. A.
【2】 Menear, K.A.; Mattes, H.; Collingwood, S.P.; Walker, C.V.; Hayler, J.; Le Grand, D.M.; Cockcroft, X.-L. (Novartis AG; Novartis-Erfindungen VmbH); Purine derivs. inhibitors of tyrosine protein kinase syk. EP 1200435; WO 0109134 .
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) 25254 2,6-dichloro-9H-purine 5451-40-1 C5H2Cl2N4 详情 详情
(II) 58377 cyclobutylamine; cyclobutanamine; Aminocyclobutane 2516-34-9 C4H9N 详情 详情
(III) 58378 2-chloro-N-cyclobutyl-9H-purin-6-amine; N-(2-chloro-9H-purin-6-yl)-N-cyclobutylamine C9H10ClN5 详情 详情
(IV) 58379 N-(4-aminophenyl)-N-methylacetamide; 4'-amino-N-methylacetanilide C9H12N2O 详情 详情

合成路线12

该中间体在本合成路线中的序号：(I)

Condensation of 2,6-dichloropurine (I) with benzylamine (II) in boiling butanol afforded 6-(benzylamino)-2-chloropurine (III), which was subsequently alkylated at the 9-N with isopropyl bromide (IV), yielding purine (V). The 2-chloro group was finally displaced with (R)-2-amino-1-butanol (VI) in a sealed tube at 160 C to provide the title compound.

参考文献 中间体
合成目标
【1】 Wang, S.; et al.; Synthesis and configuration of the cyclin-dependent kinase inhibitor roscovitine and its enantiomer. Tetrahedron Asymmetry 2001, 12, 20, 2891.
【2】 Havlicek, L.; et al.; Cytokinin-derived cyclin-dependent kinase inhibitors: Synthesis and cdc2 inhibitory activity of olomoucine and related compounds. J Med Chem 1997, 40, 4, 408.
【3】 Meijer, L.; Bisagni, E.; Legraverend, M. (CNRS (Centre National de la Recherche Scientifique)); Novel purine derivs. having, in particular, antiproliferative properties, and biological uses thereof. EP 0874847; FR 2741881; JP 2000501408; US 2002049218; US 6316456; WO 9720842 .
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) 25254 2,6-dichloro-9H-purine 5451-40-1 C5H2Cl2N4 详情 详情
(II) 15147 Benzylamine; Phenylmethanamine 100-46-9 C7H9N 详情 详情
(III) 36315 N-benzyl-2-chloro-9H-purin-6-amine; N-benzyl-N-(2-chloro-9H-purin-6-yl)amine C12H10ClN5 详情 详情
(IV) 32658 2-bromopropane 75-26-3 C3H7Br 详情 详情
(V) 36316 N-benzyl-2-chloro-9-isopropyl-9H-purin-6-amine; N-benzyl-N-(2-chloro-9-isopropyl-9H-purin-6-yl)amine C15H16ClN5 详情 详情
(VI) 48572 (S)-(+)-2-Amino-1-butanol; L-(+)-2-Amino-1-butanol; (S)-2-Amino-1-butanol 5856-62-2 C4H11NO 详情 详情

合成路线13

该中间体在本合成路线中的序号：(II)

　

参考文献 中间体
合成目标
【1】 Montgomery JA,Shortnacy-Fowler AT,et aL 1992.Synthesis and biological activity of 2'-fluoro-2-halo derivatives of 9-β-D-arabinofuranosyladerune.J.MaL Chem.35: 397-- 401.
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) 17691 [(2R,3R,4S)-3-(acetoxy)-5-bromo-4-fluorotetrahydro-2-furanyl]methyl benzoate C14H14BrFO5 详情 详情
(II) 25254 2,6-dichloro-9H-purine 5451-40-1 C5H2Cl2N4 详情 详情
(III) 63941 [(2R,3R,4S,5R)-3-(acetyloxy)-5-(2,6-dichloro-9H-purin-9-yl)-4-fluorotetrahydro-2-furanyl]methyl benzoate C19H15Cl2FN4O5 详情 详情

合成路线14

该中间体在本合成路线中的序号：(II)

　

参考文献 中间体
合成目标
【1】 Montgomery JA,Fowler AT,et al.2001.Improved methods for synthesizing 2-chloro-9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-9H-purin-6-amine. W02001060383
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) 66206 (2R,3R,4S)-5-bromo-4-fluorotetrahydrofuran-2,3-diyl dibenzoate 　 C18H14BrFO5 详情 详情
(II) 25254 2,6-dichloro-9H-purine 5451-40-1 C5H2Cl2N4 详情 详情
(III) 66208 (3R,4S,5S)-5-(2,6-dichloro-9H-purin-9-yl)-4-fluorotetrahydrofuran-2,3-diyl dibenzoate 　 C23H15Cl2FN4O5 详情 详情
(IV) 63942 (2R,3R,4S,5R)-5-(2-chloro-6-methoxy-9H-purin-9-yl)-4-fluoro-2-(hydroxymethyl)tetrahydro-3-furanol C11H12ClFN4O4 详情 详情

合成路线15

该中间体在本合成路线中的序号：(I)

　

参考文献 中间体
合成目标
【1】 Schaeffer HJ, Thomas HJ. 1958. Synthesis of potential anticancer agents XIV. Ribosides of 2,6-disubstituted purines. J Am Chem Soc, 80: 3738～3741.
【2】 Zablocki J, Elzein E. 2007. Process for preparaing an A2A-adenosine receptor agonist and its polymorphs. WO 2007/092372A1 (CV Therapeutics Inc).
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) 25254 2,6-dichloro-9H-purine 5451-40-1 C5H2Cl2N4 详情 详情
(III) 67380 (2R,3R,4R,5R)-2-acetoxy-5-((benzoyloxy)methyl)tetrahydrofuran-3,4-diyl dibenzoate 14215-97-5 C28H24O9 详情 详情
(IV) 67381 (2R,3R,4R,5R)-2-((benzoyloxy)methyl)-5-chlorotetrahydrofuran-3,4-diyl dibenzoate 　 C26H21ClO7 详情 详情
(V) 32565 (2R,3R,4R,5R)-4-(benzoyloxy)-2-[(benzoyloxy)methyl]-5-(2,6-dichloro-9H-purin-9-yl)tetrahydro-3-furanyl benzoate C31H22Cl2N4O7 详情 详情
(VI) 67382 (3R,4R,5R)-2-(2,6-dichloro-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol 13276-52-3 C10H10Cl2N4O4 详情 详情
(VII) 54960 (2R,3R,4S,5R)-2-(6-amino-2-hydrazino-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3,4-furandiol C10H15N7O4 详情 详情
(VIII) 67383 ethyl 1-(9-((3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-6-(((E)-3-ethoxy-2-formyl-3-oxoprop-1-en-1-yl)amino)-9H-purin-2-yl)-1H-pyrazole-4-carboxylate 　 C22H25N7O9 详情 详情
Extended Information