Structure of 6-Chloropurine ribonucleoside
CAS No.: 2004-06-0
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Synonyms: 6-Chloropurine riboside
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Zhou, Jujun ; Deng, Youchao ; Iyamu, Iredia D. ; Horton, John R. ; Yu, Dan ; Hajian, Taraneh , et al.
Abstract: S-Adenosyl-L-methionine (SAM) analogs are adaptable tools for studying and therapeutically inhibiting SAM-dependent methyltransferases (MTases). Some MTases play significant roles in host-pathogen interactions, one of which is Clostridioides difficile-specific DNA adenine MTase (CamA). CamA is needed for efficient sporulation and alters persistence in the colon. To discover potent and selective CamA inhibitors, we explored modifications of the solvent-exposed edge of the SAM adenosine moiety. Starting from the two parental compounds (6e and 7), we designed an adenosine analog (11a) carrying a 3-phenylpropyl moiety at the adenine N6-amino group, and a 3-(cyclohexylmethyl guanidine)-Et moiety at the sulfur atom off the ribose ring. Compound 11a (IC50 = 0.15 μM) is 10x and 5x more potent against CamA than 6e and 7, resp. The structure of the CamA-DNA-inhibitor complex revealed that 11a adopts a U-shaped conformation, with the two branches folded toward each other, and the aliphatic and aromatic rings at the two ends interacting with one another. 11a occupies the entire hydrophobic surface (apparently unique to CamA) next to the adenosine binding site. Our work presents a hybrid knowledge-based and fragment-based approach to generating CamA inhibitors that would be chem. agents to examine the mechanism(s) of action and therapeutic potentials of CamA in C. difficile infection.
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Purchased from AmBeed: 2086772-26-9 ; 29908-03-0 ; 73-24-5 ; 83948-53-2 ; 39684-80-5 ; 58-61-7 ; 2004-06-0 ; 2038-57-5 ; 199915-38-3 ; 2040291-27-6 ; 3218-02-8 ; 1561178-17-3 ; 58944-73-3
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CAS No. : | 2004-06-0 |
Formula : | C10H11ClN4O4 |
M.W : | 286.67 |
SMILES Code : | O[C@H]1C(N2C=NC3=C(Cl)N=CN=C23)O[C@H](CO)[C@H]1O |
Synonyms : |
6-Chloropurine riboside
|
MDL No. : | MFCD26142246 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 19 |
Num. arom. heavy atoms | 9 |
Fraction Csp3 | 0.5 |
Num. rotatable bonds | 2 |
Num. H-bond acceptors | 7.0 |
Num. H-bond donors | 3.0 |
Molar Refractivity | 63.28 |
TPSA ? Topological Polar Surface Area: Calculated from |
113.52 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.31 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
0.26 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
-1.23 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
-2.06 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
-1.01 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
-0.55 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.0 |
Solubility | 2.87 mg/ml ; 0.01 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.2 |
Solubility | 1.79 mg/ml ; 0.00624 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-0.56 |
Solubility | 79.0 mg/ml ; 0.275 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
No |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-7.86 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
0.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
0.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<0.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
3.71 |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With bis(isopropyl)ethylamine; In propan-1-ol; at 80℃; for 6h; | A mixture of <strong>[27757-86-4]3-(aminomethyl)thiophene</strong> (0.25 mL, 2.5 mmol), 6-chloropurine ribofuranoside (143 mg, 0.5 mmol), and diisopropylethylamine (2 mL, 12 mmol) in 1-propanol (25 mL) was heated at 80 C for 6 h. The mixture was concentrated by rotary evaporation, and recrystallized from MeOH to yield the desired product JMF3461 (136 mg, 75% yield). The purity of product was 99% as shown by HPLC on an HC-C18 column (Agilent, 4.6 chi 250 mm, 5 mutaueta) with elution of gradients of 50% aqueous MeOH. C15Hi7504S; yellow powder; mp 134.3-135.1 C; [a]2D= -58.6 (DMSO, c = 1.0); TLC (2-propanol/hexane, (2:3)) R = 0.33; 1H NMR (DMS0-4s, 400 MHz) 6 8.36 (2 H, br s), 8.22 (1 H, s), 7.43 (1 H, dd, J= 3, 5 Hz), 7.28 (1 H, d, J= 1.6 Hz), 7.09 (1 H, d, J= 4.8 Hz), 5.88 (1 H, d, J = 6.4 Hz), 5.43 (1 H, d, J= 6.0 Hz), 5.38 (1 H, q, J= 4.6 Hz), 5.17 (1 H, d, J= 4.4 Hz), 4.69 (2 H, s), 4.63^1.16 (1 H, m), 4.14-4.13 (1 H, m), 3.97-3.95 (1 H, m), 3.69-3.64 (1 H, m), 3.57-3.52 (1 H, m),13C NMR (DMSO-i/<s, 100 MHz) delta 154.4, 152.3, 148.5, 140.8, 139.9, 127.9, 125.1, 120.0, 1 19.8, 87.9, 85.9, 73.5, 70.7, 61.7, 42.9; ESI-MS calcd for CuH^NjC^S: 364.1080, found: m/z 364.1079 [M + H]+. |
75% | With N-ethyl-N,N-diisopropylamine; In propan-1-ol; at 80℃; for 6h; | <strong>[27757-86-4]3-(aminomethyl)thiophene</strong> (0.25 mL, 2.5 mmol) '6-chloropurine nucleofuranoside (143 mg, 0.5 mmol), and diisopropylethylamine (2 mL, 12 mmol) The 1-propanol (25 mL) mixture was heated at 80 C for 6 hours. The mixture was concentrated by rotary evaporation and recrystallized from EtOAc to give the desired product JMF 3461 ( 136 mg, 75% yield). The purity of the product is 99%, |
With triethylamine; In propan-1-ol; at 70℃; for 8h; | First step, hydroxyamine hydrochloride (874 mg) and NaOAc (1.18 g) were added to a solution of 3-thiophenecarbaldehyde (800 mg) in EtOH (50 ml). The reaction mixture was stirred at room temperature for 6 h. EtOH was removed under reduced pressure. H2O (40 ml) was added to the residue, and extracted with EtOAc (3 × 40 ml). The EtOAc of the combined organic layer was removed by rotary evaporation under reduced pressure to yield 3-thiophenecarbaldehyde oxime (722 mg) as a pale yellowish solid. Second step, 3-thiophenecarbaldehyde oxime (722 mg) and zinc dust (2.23 g) in HOAc (5 ml) was stirred at room temperature for 6 h. The reaction solution was filtered to remove the excess zinc dust and ZnOAc residue, and the filtrate was concentrated to yield 3-thiopheneylmethanamine (323 mg) as a yellowish oil. Third step, a mixture of 3-thiopheneylmethanamine (158 mg), 6-chloropurine riboside (200 mg) and triethylamine (3 ml) in PrOH (60ml) was heated to 70C and reacted for 8 h. After evaporation of the reaction mixture, the residue was separated by column chromatography over silica gel and eluted with CHCl3-CH3OH (20 : 1) to yield N6-(3-thiopheneylmethyl)-adenosine(150 mg) as a white solid: positive ESIMS m/z 364[M + H]+, 386[M + Na]+ and 402 [M + K]+; negative ESIMS m/z 362[M - H]-; 1H NMR (300MHz, DMSO-d6): the adenosine moiety delta 8.36 (2H, s, -NH, H-2), 8.22 (1H, s, H-8), 5.88 (1H, d, 6.0Hz, H-1), 5.43 (1H, d, 6.0Hz, -OH), 5.38 (1H, m, -OH), 5.17 (1H, d, 4.5Hz, -OH), 4.60 (1H, m, H-2'), 4.13 (1H, m, H-3'), 3.95 (1H, m, H-4'), 3.70-3.64 (1H, m, H-5a'), 3.58 (1H, m, H-5b'); the 3-thiopheneylmethyl moiety delta 7.43 (1H, dd, 4.8Hz, 3.0Hz, H-5"), 7.28 (1H, brs, H-2"), 7.08 (1H, dd, 4.8Hz, 0.9Hz, H-4"), 4.68 (2H, brs, H-7"); 13C NMR (75MHz, DMSO-d6): the adenosine moiety delta 154.4 (s, C-6), 152.5 (d, C-2), 148.6 (s, C-4), 140.9 (d, C-8), 119.9 (s, C-5), 88.1 (d, C-1), 86.1 (d, C-4'), 73.7 (d, C-2'), 70.8 (d, C-3'), 61.8 (t, C-5'); the 3-thiopheneylmethyl moiety delta 140.1 (s, C-3"), 127.7 (d, C-4"), 126.2 (d, C-5"), 121.8 (d, C-2"), 39.5 (t, C-6)omicron |
150 mg | With triethylamine; In propan-1-ol; at 70℃; for 8h; | Third step, a mixture of 3-thiopheneylmethanamine (158 mg), 6-chloropurine riboside (200 mg) and triethylamine (3 ml) in PrOH (60 ml) was heated to 70 C. and reacted for 8 h. After evaporation of the reaction mixture, the residue was separated by column chromatography over silica gel and eluted with CHCl3-CH3OH (20:1) to yield N6-(3-thiopheneylmethyl)-adenosine (150 mg) as a white solid: positive ESIMS m/z 364[M+H]+, 386[M+Na]+ and 402 [M+K]+; negative ESIMS m/z 362[M-H]-; 1H NMR (300 MHz, DMSO-d6): the adenosine moiety delta 8.36 (2H, s, -NH, H-2), 8.22 (1H, s, H-8), 5.88 (1H, d, 6.0 Hz, H-1'), 5.43 (1H, d, 6.0 Hz, -OH), 5.38 (1H, m, -OH), 5.17 (1H, d, 4.5 Hz, -OH), 4.60 (1H, m, H-2'), 4.13 (1H, m, H-3'), 3.95 (1H, m, H-4'), 3.70-3.64 (1H, m, H-5a'), 3.58 (1H, m, H-5b'); the 3-thiopheneylmethyl moiety delta 7.43 (1H, dd, 4.8 Hz, 3.0 Hz, H-5"), 7.28 (1H, brs, H-2"), 7.08 (1H, dd, 4.8 Hz, 0.9 Hz, H-4"), 4.68 (2H, brs, H-7"); 13C NMR (75 MHz, DMSO-d6): the adenosine moiety delta 154.4 (s, C-6), 152.5 (d, C-2), 148.6 (s, C-4), 140.9 (d, C-8), 119.9 (s, C-5), 88.1 (d, C-1'), 86.1 (d, C-4'), 73.7 (d, C-2'), 70.8 (d, C-3'), 61.8 (t, C-5'); the 3-thiopheneylmethyl moiety delta 140.1 (s, C-3"), 127.7 (d, C-4"), 126.2 (d, C-5"), 121.8 (d, C-2"), 39.5 (t, C-6). |
150 mg | With triethylamine; In propan-1-ol; at 70℃; for 8h; | 158 mg of 3-thiophene methylamine was taken and dissolved in propanol (60 mL). To a solution of 6-chloropurine nucleoside (200 mg) and triethylamine (3 mL)The mixture was heated to 70 C., reacted for 8 hours, and the solvent was recovered with a reaction solution. Chloroform-methanol (20: 1) separated by silica gel column chromatography, To obtain 150 mg of N6-(3-thiophenemethyl)adenosine as a white solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In methanol; at 80℃; for 40h; | [0154] 3. A mixture of 6-chloropurine riboside (0.5 gm, 1.74 mmol), <strong>[88675-24-5]3-aminotetrahydrofuran</strong> (0.325 gm, 2.6 mmol) and triethylamine (0.73 ml, 5.22 mmol) in methanol (10 ml) was heated to 80° C. for 40 hours. The mixture was cooled and concentrated under reduced pressure. The residue was chromatographed on a short column of silica gel, eluting with methylene chloride/methanol/propylamine (90/10/1). The fractions containing the product were combined and concentrated under reduced pressure. The residue was chromatographed on a chromatotron (2 mm plate, 92.5/7.5/1, methylene chloride/methanol/propylamine). The resulting white solid was recrystallized from methanol/ethyl acetate to give 0.27 gm of (4S,2R,3R,5R)-2-hydroxymethyl-5-[6-(tetrahydrofuran-3-ylamino)-purin-9-yl]-tetrahydrofuran-3,4-diol as white crystals (mp 128° C.-130° C.). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In methanol; | Preparation of 6-(<strong>[88675-24-5]3-aminotetrahydrofuran</strong>yl)purine Riboside A mixture of 6-chloropurine riboside (0.5 gm, 1.74 mmol), <strong>[88675-24-5]3-aminotetrahydrofuran</strong> (0.325 gm, 2.6 mmol) and triethylamine (0.73 ml, 5.22 mmol) in methanol (10 ml) was heated to 80° C. for 40 hours. The mixture was cooled, and concentrated. The residue was filtered through a short column of silica gel eluding with 90/10/1 (CH2 Cl2 /MeOH/PrNH2) the fractions containing the product were combined and concentrated. The residue was chromatorgraphed on the chromatotron (2 mm plate, 92.5/7.5/1, CH2 CL2 /MeOH/Pr NH2). The resulting white solid was recrystallized from MeOH/EtOAc to give 0.27 gm of white crystals (mp 128°-130° C.). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In ethanol; water; | EXAMPLE 1 N6 -Fluorenyladenosine 4.0 g of 6-chloropurine riboside, 3.79 g of <strong>[5978-75-6]9-aminofluorene hydrochloride</strong> and 3.52 g of triethylamine are refluxed in 100 ml ethanol under nitrogen for 20 hrs. the solvent is evaporated to dryness and residue is treated with 100 ml of cold water. Precipitated solid is filtered and treated with 50 ml of methanol-chloroform (1:1) affording 3.8 g (63%) of N6 -fluorenyladenosine having a m.p of 210-212 C. Anals. Calcd. for C23 H21 N5 O4. 10 H2 O 0.3HCl C=60.00; H=5.09; N=15.21. Found: C=59.95; H=4.72; N=15.13. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tributyl-amine; In propan-1-ol; ethanol; | EXAMPLE 3 Preparation of N6 -methyl-N6 -(3-carboxypropyl)adenosine A mixture of 10.0 g (34.9 mmole) of 6-chloropurine riboside, 11.0 g (71.6 mmole) of <strong>[6976-17-6]4-(methylamino)butanoic acid hydrochloride</strong>, and 20.0 g (108 mmole) of tributylamine in 300 ml of propanol was heated at reflux for two days. The solution was allowed to cool and concentrated in vacuo to a thick oil. The oil was treated with several portions of diethyl ether to remove soluble organic material. Two crops of crude product were crystallized from ethanol and redissolved in 100 ml of 50percent aqueous ethanol. The resulting solution was decolorized with charcoal, filtered, and the volume was reduced to about 30 ml by boiling. Upon cooling, 4.3 g (11.7) mmole) of N6 -methyl-N6 -(3-carboxypropyl)adenosine was obtained as a fluffy white solid. Anal. Calcd. for C15 H21 N5 O6: C, 49.04; H, 5.76; N, 19.06. Found: C, 48.91; H, 5.83; N, 18.67. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In ethanol; | EXAMPLE 1 N(6)-(2-Indanyl)adenosine Two grams 6-chloropurine riboside, 1.48 grams <strong>[2338-18-3]2-aminoindane hydrochloride</strong> and 1.74 g triethylamine are refluxed in ethanol under nitrogen for 20 hours. Upon cooling, solid material crystallizes. The reaction mixture is diluted with 70 ml ethanol, filtered and washed with ethanol. Solid thus obtained is suspended in approximately 25 to 30 ml methanol, filtered, and washed with methanol and dried affording 1.95 g (73%) N(6)-(2-indanyl)adenosine having a melting point of 166-168 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In propan-1-ol; at 80℃; for 6h; | A mixture of (S)-1-(3-methoxyphenyl)-ethylamine (635 mg) and 6-chloropurine riboside (300 mg) in PrOH (50 ml) was heated to 80C for 6 h. After evaporation of the reaction mixture, the residue was separated by column chromatography over Sephadex LH-20 gel and eluted with ethanol to yield N6-[(S)-1-(3-methoxyphenyl)-ethyl]-adenosine(340 mg) as a white solid: positive ESIMS mlz 402 [M + H]+; negative ESIMS mlz 400 [M - H]-; 1H NMR (300 MHz, DMSO-d6): the adenosine moiety delta 8.40 (1H, s, H-2), 8.28 (1H, brs, -NH), 8.18 (1H, s, H-8), 5.91 (1H, d, J= 6.0 Hz, H-1'), 5.47 (1H, m, -OH), 5.42 (1H, m, -OH), 5.21 (1H, d, J = 3.9 Hz, -OH), 4.62 (1H, m, H-2'), 4.17 (1H, m, H-3'), 3.98 (1H, m, H-4'), 3.66 (1H, m, H-5'a), 3.56 (1H, m, H-5'b); the (S)-1-(3-methoxyphenyl)-ethyl moiety delta 7.19 (1H, t, J = 7.5 Hz, H-5'), 7.02 (1H, brs, H-2'), 7.00 (1H, brd, J = 7.5 Hz, H-6'), 6.74 (1H, d, J = 7.5 Hz, H-4'), 5.49 (1H, m, H-7'), 3.70 (4H, m, H-5a', -OCH3), 1.52 (3H, d, J= 6.9 Hz, H-8'); 13C NMR (75MHz, DMSO-d6): the adenosine moiety delta 153.9 (s, C-6), 152.4 (d, C-2), 148.6 (s, C-4), 139.9 (d, C-8), 119.7 (s, C-5), 88.0 (d, C-1'), 86.0 (d, C-4'), 73.7 (d, C-2'), 70.7 (d, C-3'), 61.7 (t, C-5'); the (S)-1-(3-methoxyphenyl)-ethyl moiety delta 159.3 (s, C-3'), 146.9 (s, C-1'), 129.3 (d, C-5'), 118.5 (d, C-6'), 112.2 (d, C-2'), 111.7 (d, C-4'), 55.0 (q, -OCH3), 48.9 (d, C-7'), 22.6 (q, C-8')o | |
340 mg | In propan-1-ol; at 80℃; for 6h; | A mixture of (S)-1-(3-methoxyphenyl)-ethylamine (635 mg) and 6-chloropurine riboside (300 mg) in PrOH (50 ml) was heated to 80 C. for 6 h.After evaporation of the reaction mixture, the residue was separated by column chromatography over Sephadex LH-20 gel and eluted with ethanol to yield N6-[(S)-1-(3-methoxyphenyl)-ethyl]-adenosine (340 mg) as a white solid: positive ESIMS m/z 402 [M+H]+; negative ESIMS m/z 400 [M-H]-; 1H NMR (300 MHz, DMSO-d6): the adenosine moiety delta 8.40 (1H, s, H-2), 8.28 (1H, brs, -NH), 8.18 (1H, s, H-8), 5.91 (1H, d, J=6.0 Hz, H-1'), 5.47 (1H, m, -OH), 5.42 (1H, m, -OH), 5.21 (1H, d, J=3.9 Hz, -OH), 4.62 (1H, m, H-2'), 4.17 (1H, m, H-3'), 3.98 (1H, m, H-4'), 3.66 (1H, m, H-5'a), 3.56 (1H, m, H-5'b); the (S)-1-(3-methoxyphenyl)-ethyl moiety delta 7.19 (1H, t, J=7.5 Hz, H-5"), 7.02 (1H, brs, H-2"), 7.00 (1H, brd, J=7.5 Hz, H-6"), 6.74 (1H, d, J=7.5 Hz, H-4"), 5.49 (1H, m, H-7"), 3.70 (4H, m, H-5a', -OCH3), 1.52 (3H, d, J=6.9 Hz, H-8"); 13C NMR (75 MHz, DMSO-d6): the adenosine moiety delta 153.9 (s, C-6), 152.4 (d, C-2), 148.6 (s, C-4), 139.9 (d, C-8), 119.7 (s, C-5), 88.0 (d, C-1'), 86.0 (d, C-4'), 73.7 (d, C-2'), 70.7 (d, C-3'), 61.7 (t, C-5'); the (S)-1-(3-methoxyphenyl)-ethyl moiety delta 159.3 (s, C-3"), 146.9 (s, C-1"), 129.3 (d, C-5"), 118.5 (d, C-6"), 112.2 (d, C-2"), 111.7 (d, C-4"), 55.0 (q, -OCH3), 48.9 (d, C-7"), 22.6 (q, C-8"). |
340 mg | In propan-1-ol; at 80℃; for 6h; | (S)-1-(3-methoxyphenyl)-ethylamine (635 mg) was dissolved in normal propyl alcohol (50 mL), 6-chloropurine nucleoside (300 mg) Heat up to 80 C and let it react for 6 h. The solvent was recovered in the reaction solution, chromatographed through a gel column and eluted with ethanol to obtain white solid N6 -[(S)-1-(3-methoxyphenyl)-ethyl]-adenosine(340 mg) It was |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In propan-1-ol; at 80℃; for 8h; | A mixture of L-tyrosine ethyl ester (686 mg, the hydrochloride), 6-chloropurine riboside (200 mg) and triethylamine (3 ml) in PrOH (50 ml) was heated to 80°C for 10 h.After evaporation of the reaction mixture, the residue was separated by column chromatography over silica gel and eluted with CHCl3-CH3OH (8 : 1) to yield preparation of N-(6-adenosine)-(L) -tyrosine ethyl ester (260 mg) as white solid: positive ESIMS m/z 460 [M + H]+; negative ESIMS m/z 458 [M - H]- and 494 [M + Cl]+; 1H NMR (300 MHz, DMSO-d6): the adenosine moiety delta 8.39 (1H, s, H-2), 8.17 (1H, s, H-8), 8.01 (1H, brd, J = 6.9 Hz, -NH), 5.87 (1H, d, J = 6.0 Hz, H-1?), 5.43 (1H, d, J = 6.0 Hz, -OH), 5.29 (1H, m, -OH), 5.16 (1H, d, J = 4.5 Hz, -OH), 4.58 (1H, H-2'), 4.12 (1H, m, H-3'), 3.93 (1H, m, H-4'), 3.65 (1H, m, H-5'a), 3.54 (1H, m, H-5'b); the (L)-tyrosine ethyl ester moiety delta 9.17 (1H, s, -OH), 7.07 (2H, d, J= 8.1 Hz, H-2', H-6'), 6.62 (2H, d, J = 8.1 Hz, H-3', H-5'), 4.84 (1H, m, H-8'), 4.06 (2H, q, J = 7.2 Hz, -OCH2CH3)), 3.10 (2H, m, H-7'), 1.11 (3H, t, J = 7.2 Hz, -OCH2CH3); 13C NMR (75 MHz, DMSO-d6): the adenosine moiety delta 154.2 (d, C-6), 152.2 (d, C-2), 148.8 (s, C-4), 140.4 (d, C-8), 119.9 (s, C-5), 88.1 (d, C-1?), 86.0 (d, C-4'), 73.7 (d, C-2'), 70.8 (d, C-3'), 61.8 (t, C-5'); the (L)-tyrosine ethyl ester moiety delta 172.3 (s, C-9'), 156.1 (s, C-4'), 130.2 (d, C-2', C-6'), 127.9 (s, C-1?), 115.2 (d, C-3', C-5'), 60.7 (t, -OCH2CH3), 55.1 (d, C-8'), 35.7 (t, C-7'), 14.2 (q, -OCH2CH3)omicron | |
260 mg | With triethylamine; In propan-1-ol; at 80℃; for 10h; | A mixture of L-tyrosine ethyl ester (686 mg, the hydrochloride), 6-chloropurine riboside (200 mg) and triethylamine (3 ml) in PrOH (50 ml) was heated to 80° C. for 10 h. After evaporation of the reaction mixture, the residue was separated by column chromatography over silica gel and eluted with CHCl3-CH3OH (8:1) to yield preparation of N-(6-adenosine)-(L)-tyrosine ethyl ester (260 mg) as white solid: positive ESIMS m/z 460 [M+H]+; negative ESIMS m/z 458 [M-H]- and 494 [M+Cl]+; 1H NMR (300 MHz, DMSO-d6): the adenosine moiety delta 8.39 (1H, s, H-2), 8.17 (1H, s, H-8), 8.01 (1H, brd, J=6.9 Hz, -NH), 5.87 (1H, d, J=6.0 Hz, H-1'), 5.43 (1H, d, J=6.0 Hz, -OH), 5.29 (1H, m, -OH), 5.16 (1H, d, J=4.5 Hz, -OH), 4.58 (1H, H-2'), 4.12 (1H, m, H-3'), 3.93 (1H, m, H-4'), 3.65 (1H, m, H-5'a), 3.54 (1H, m, H-5'b); the (L)-tyrosine ethyl ester moiety delta 9.17 (1H, s, -OH), 7.07 (2H, d, J=8.1 Hz, H-2", H-6"), 6.62 (2H, d, J=8.1 Hz, H-3", H-5"), 4.84 (1H, m, H-8"), 4.06 (2H, q, J=7.2 Hz, -OCH2CH3)), 3.10 (2H, m, H-7"), 1.11 (3H, t, J=7.2 Hz, -OCH2CH3); 13C NMR (75 MHz, DMSO-d6): the adenosine moiety delta 154.2 (d, C-6), 152.2 (d, C-2), 148.8 (s, C-4), 140.4 (d, C-8), 119.9 (s, C-5), 88.1 (d, C-1'), 86.0 (d, C-4'), 73.7 (d, C-2'), 70.8 (d, C-3'), 61.8 (t, C-5'); the (L)-tyrosine ethyl ester moiety delta 172.3 (s, C-9"), 156.1 (s, C-4"), 130.2 (d, C-2", C-6"), 127.9 (s, C-1"), 115.2 (d, C-3", C-5"), 60.7 (t, -OCH2CH3), 55.1 (d, C-8"), 35.7 (t, C-7"), 14.2 (q, -OCH2CH3). |
250 mg | With triethylamine; In propan-1-ol; at 80℃; for 10h; | <strong>[4089-07-0]L-<strong>[4089-07-0]tyrosine ethyl ester hydrochloride</strong></strong> (686 mg) was taken and 6-chloropurine nucleoside (200 mg) and triethylamine (3 mL) dissolved in propanol (50 mL) were added and the mixture was heated to 80 ° C. and reacted for 10 hours The solvent is recovered with the reaction solution,Separation by silica gel column chromatography, washing out with chloroform-methanol (8: 1), white solid N-(6-adenosine)-(L)-tyrosine ethyl (260 mg) is obtained |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In propan-1-ol; at 80℃; for 10h; | A mixture of L-tryptophan ethyl ester (752 mg, the hydrochloride), 6-chloropurine riboside (200 mg) and triethylamine (3 ml) in PrOH (50 ml) was heated to 80C for 10 h. After evaporation of the reaction mixture, the residue was separated by column chromatography over silica gel and eluted with CHCl3-CH3OH (8 : 1) to yield preparation of N-(6-adenosine)-(L)- tryptophan ethyl ester (260 mg) as white solid: positive ESIMS m/z 483 [M + H]+ and 521 [M + K]+; negative ESIMS m/z 481 [M - H]-; 1H NMR (300 MHz, DMSO-d6): the adenosine moiety delta 8.38 (1H, s, H-2), 8.17 (1H, s, H-8), 7.97 (1H, d, J= 8.1 Hz, -NH), 5.87 (1H, d, J= 5.7 Hz, H-1?), 5.44 (1H, d, J= 5.7 Hz, -OH), 5.29 (1H, m, -OH), 5.18 (1H, d, J = 4.8 Hz, -OH), 4.57 (1H, m, H-2'), 4.11 (1H, m, H-3'), 4.94 (1H, m, H-4'), 3.65 (1H, m, H-5'a), 3.54 (1H, m, H-5'b); the L-tryptophan ethyl ester moiety delta 10.81 (1H, s, -NH), 7.54 (1H, d, J = 7.5 Hz, H-7'), 7.31 (1H, d, J = 7.5 Hz, H-4'), 7.20 (1H, s, H-2'), 7.05 (1H, t, J = 7.5 Hz, H-5'), 6.97 (1H, t, J= 7.5 Hz, H-6'), 4.96 (1H, m, H-9'), 4.06 (2H, q, J= 7.5 Hz, -OCH2CH3), 3.35 (2H, m, H-8'), 1.10 (3H, t, J= 7.5 Hz, -OCH2CH3); 13C NMR (75 MHz, DMSO-d6): the adenosine moiety delta 154.2 (s, C-6), 152.2 (d, C-2), 148.8 (s, C-4), 140.4 (d, C-8), 119.9 (s, C-5), 88.1 (d, C-1?), 86.0 (d, C-4'), 73.7 (d, C-2'), 70.7 (d, C-3'), 61.7 (t, C-5'); the L-tryptophan ethyl ester moiety delta 172.5 (s, C-10'), 136.3 (d, C-2'), 127.2 (s, C-7'a), 124.0 (d, C-3'a), 121.1 (d, C-4'), 118.6 (d, C-5'), 118.2 (d, C-7'), 111.6 (s, C-3'), 110.0 (d, C-6'), 60.7 (t, -OCH2CH3), 54.2 (d, C-9'), 26.8 (t, C-8'), 14.1 (q, -OCH2CH3)omicron | |
260 mg | With triethylamine; In propan-1-ol; at 80℃; for 10h; | A mixture of L-tryptophan ethyl ester (752 mg, the hydrochloride), 6-chloropurine riboside (200 mg) and triethylamine (3 ml) in PrOH (50 ml) was heated to 80 C. for 10 h. After evaporation of the reaction mixture, the residue was separated by column chromatography over silica gel and eluted with CHCl3-CH3OH (8:1) to yield preparation of N-(6-adenosine)-(L)-tryptophan ethyl ester (260 mg) as white solid: positive ESIMS m/z 483 [M+H]+ and 521 [M+K]+: negative ESIMS m/z 481 [M-H]-; 1H NMR (300 MHz, DMSO-d6): the adenosine moiety delta 8.38 (1H, s, H-2), 8.17 (1H, s, H-8), 7.97 (1H, d, J=8.1 Hz, -NH), 5.87 (1H, d, J=5.7 Hz, H-1'), 5.44 (1H, d, J=5.7 Hz, -OH), 5.29 (1H, m, -OH), 5.18 (1H, d, J=4.8 Hz, -OH), 4.57 (1H, m, H-2'), 4.11 (1H, m, H-3'), 4.94 (1H, m, H-4'), 3.65 (1H, m, H-5'a), 3.54 (1H, m, H-5'b); the L-tryptophan ethyl ester moiety delta 10.81 (1H, s, -NH), 7.54 (1H, d, J=7.5 Hz, H-7"), 7.31 (1H, d, J=7.5 Hz, H-4"), 7.20 (1H, s, H-2"), 7.05 (1H, t, J=7.5 Hz, H-5"), 6.97 (1H, t, J=7.5 Hz, H-6"), 4.96 (1H, m, H-9"), 4.06 (2H, q, J=7.5 Hz, -OCH2CH3), 3.35 (2H, m, H-8"), 1.10 (3H, t, J=7.5 Hz, -OCH2CH3); 13C NMR (75 MHz, DMSO-d6): the adenosine moiety delta 154.2 (s, C-6), 152.2 (d, C-2), 148.8 (s, C-4), 140.4 (d, C-8), 119.9 (s, C-5), 88.1 (d, C-1'), 86.0 (d, C-4'), 73.7 (d, C-2'), 70.7 (d, C-3'), 61.7 (t, C-5'); the L-tryptophan ethyl ester moiety delta 172.5 (s, C-10"), 136.3 (d, C-2"), 127.2 (s, C-7"a), 124.0 (d, C-3"a), 121.1 (d, C-4"), 118.6 (d, C-5"), 118.2 (d, C-7"), 111.6 (s, C-3"), 110.0 (d, C-6"), 60.7 (t, -OCH2CH3), 54.2 (d, C-9"), 26.8 (t, C-8"), 14.1 (q, -OCH2CH3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol; for 12h;Reflux; | A mixture of L-isoleucinol (492 mg) and 6-chloropurine riboside (300 mg) in EtOH (50 ml) was refluxed for 12 h.After evaporation of the reaction mixture, the residue was separated by column chromatography over Sephadex LH-20 gel and eluted with EtOH to yield N6-[(L)-2-(1-hydroxy-3 -methyl)-pentyl]-adenosine(315 mg) as a white solid: positive ESIMS m/z 368 [M + H]+ and 390 [M + Na]+; negative ESIMS m/z 366 [M - H]-; 1H NMR (300 MHz, DMSO-d6): the adenosine moiety delta 8.33 (1H, s, H-2), 8.17 (1H, s, H-8), 7.28 (1H, brd, J = 9.3 Hz, -NH), 5.86 (1H, d, J = 6.3 Hz, H-1?), 5.44 (2H, m, 2*-OH), 5.17 (1H, d, J = 4.8 Hz, -OH), 4.62 (1H, m, H-2'), 4.13 (1H, m, H-3'), 3.95 (1H, m, H-4'), 3.66 (1H, m, H-5'a), 3.53 (1H, m, H-5'b); the (L)-2-(1-hydroxy-3-methyl)-pentyl moiety delta 4.59 (1H, m, -OH), 4.21 (1H, m, H-2'), 3.53 (2H, m, H-1?), 1.75 (1H, m, H-3'), 1.49 (1H, m, H-4a'), 1.09 (1H, m, 4b'), 0.89 (3H, d, J= 6.6 Hz, -CH3), 0.82 (3H, t, J= 7.2 Hz, C-5'); 13C NMR (75 MHz, DMSO-d6): the adenosine moiety delta 155.1 (s, C-6), 152.4 (d, C-2), 148.3 (s, C-4), 139.9 (d, C-8), 119.8 (s, C-5), 88.3 (d, C-1?), 86.1 (d, C-4'), 73.6 (d, C-2'), 70.9 (d, C-3'), 61.9 (t, C-5');thethe (L)-2-(1-hydroxy-3-methyl)-pentyl moiety delta 61.3 (t, C-1?), 55.7 (d, C-2'), 35.3 (t, C-3'), 25.3 (d, C-4'), 15.6 (q, C-5'), 11.4 (q, -CH3)omicron | |
315 mg | In ethanol; for 12h;Reflux; | A mixture of L-isoleucinol (492 mg) and 6-chloropurine riboside (300 mg) in EtOH (50 ml) was refluxed for 12 h. After evaporation of the reaction mixture, the residue was separated by column chromatography over Sephadex LH-20 gel and eluted with EtOH to yield N6-[(L)-2-(1-hydroxy-3-methyl)-pentyl]-adenosine (315 mg) as a white solid: positive ESIMS m/z 368 [M+H]+ and 390 [M+Na]+; negative ESIMS m/z 366 [M-H]-; 1H NMR (300 MHz, DMSO-d6): the adenosine moiety delta 8.33 (1H, s, H-2), 8.17 (1H, s, H-8), 7.28 (1H, brd, J=9.3 Hz, -NH), 5.86 (1H, d, J=6.3 Hz, H-1'), 5.44 (2H, m, 2*-OH), 5.17 (1H, d, J=4.8 Hz, -OH), 4.62 (1H, m, H-2'), 4.13 (1H, m, H-3'), 3.95 (1H, m, H-4'), 3.66 (1H, m, H-5'a), 3.53 (1H, m, H-5'b); the (L)-2-(1-hydroxy-3-methyl)-pentyl moiety delta 4.59 (1H, m, -OH), 4.21 (1H, m, H-2"), 3.53 (2H, m, H-1"), 1.75 (1H, m, H-3"), 1.49 (1H, m, H-4-a"), 1.09 (1H, m, 4b"), 0.89 (3H, d, J=6.6 Hz, -CH3), 0.82 (3H, t, J=7.2 Hz, C-5"); 13C NMR (75 MHz, DMSO-d6): the adenosine moiety delta 155.1 (s, C-6), 152.4 (d, C-2), 148.3 (s, C-4), 139.9 (d, C-8), 119.8 (s, C-5), 88.3 (d, C-1'), 86.1 (d, C-4'), 73.6 (d, C-2'), 70.9 (d, C-3'), 61.9 (t, C-5'); the (L)-2-(1-hydroxy-3-methyl)-pentyl moiety delta 61.3 (t, C-1"), 55.7 (d, C-2"), 35.3 (t, C-3"), 25.3 (d, C-4"), 15.6 (q, C-5"), 11.4 (q, -CH3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In propan-1-ol; at 70℃; for 8.0h; | First step, hydroxyamine hydrochloride (1.29 g) and NaOAc (1.67 g) were added to a solution of 4-methoxy-3-hydroxybenzaldehyde (1.55 g) in EtOH (80 ml). The reaction mixture was stirred at room temperature for 6 h. EtOH was removed under reduced pressure. H2O (40 ml) was added to the residue, and extracted with EtOAc (3 × 40 ml). The EtOAc of the combined organic layer was removed by rotary evaporation under reduced pressure to yield 4-methoxy-3-hydroxybenzaldehyde oxime (1.45 g) as a pale yellowish solid. Second step, a solution of 4-methoxy-3-hydroxybenzaldehyde oxime (1.45 g) and concentrated HCl (1 ml) in EtOH (40 ml) was subjected to hydrogenation at atmospheric pressure in the presence of 10% Pd/C (85 mg). The reaction solution was filtered and the filtrate was concentrated to yield 4-methoxy-3-hydroxybenzylamine hydrochloride (1.59 g) as a white solid. Third step, a mixture of 4-methoxy-3-hydroxybenzylamine (469 mg, the hydrochloride), 6-chloropurine riboside (143 mg) and N, N-diisopropylethylamine (2 ml) in PrOH (40 ml) was heated to 70C and reacted for 8 h. After evaporation of the reaction mixture, the residue was separated by column chromatography over silica gel and eluted with CHCl3-CH3OH (30 : 1) to yield N6-(4-methoxy-3-hydroxybenzyl)-adenosine(164 mg) as a white solid: positive ESIMS 404 [M + H]+; negative ESIMS m/z 402 [M - H]- and 438 [M + Cl]-; 1H NMR (400 MHz, DMSO-d6): the adenosine moiety δ 8.35 (1H, s, H-2), 8.32 (1H, brs, -NH), 8.19 (1H, brs, H-8), 5.87 (1H, d, J= 6.0 Hz, H-1), 5.41 (1H, d, J=6.4 Hz, -OH), 5.37 (1H, m, -OH), 5.18 (1H, d, J= 4.8Hz, -OH), 4.60 (1H, m, H-2'), 4.13 (1H, m, H-3'), 3.95 (1H, m, H-4'), 3.66 (1H, m, H-5'a), 3.54 (1H, m, H-5'b); the 4-methoxy-3-hydroxybenzyl moiety δ 8.82 (1H, s, -OH), 6.80 (1H, d, J = 8.4 Hz, H-5"), 6.76 (1H, brs, H-2"), 6.70 (1H, brd, J = 8.4Hz, H-6"), 4.60 (2H, m, H-7"), 3.71 (3H, s, -OCH3); 13C NMR (125 MHz, DMSO-d6): the adenosine moiety δ 154.4 (C-6), 152.3 (C-2), 148.4 (C-4), 139.8 (C-8), 119.8 (C-5), 87.9 (C-1), 85.9 (C-4'), 73.4 (C-2'), 70.6 (C-3'), 61.6 (C-5'); the 4-methoxy-3-hydroxybenzyl moiety δ 146.5 (C-4"), 146.3 (C-3"), 132.6 (C-1), 117.8 (C-6"), 114.6 (C-2"), 112.1 (C-5"), 55.7 (-OCH3), 42.4 (C-7")o | |
164 mg | With N-ethyl-N,N-diisopropylamine; In propan-1-ol; at 70℃; for 8.0h; | Third step, a mixture of 4-methoxy-3-hydroxybenzylamine (469 mg, the hydrochloride), 6-chloropurine riboside (143 mg) and N,N-diisopropylethylamine (2 ml) in PrOH (40 ml) was heated to 70 C. and reacted for 8 h. After evaporation of the reaction mixture, the residue was separated by column chromatography over silica gel and eluted with CHCl3-CH3OH (30:1) to yield N6-(4-methoxy-3-hydroxybenzyl)-adenosine (164 mg) as a white solid: positive ESIMS 404 [M+H]+; negative ESIMS m/z 402 [M-H]- and 438 [M+Cl]-; 1H NMR (400 MHz, DMSO-d6): the adenosine moiety δ 8.35 (1H, s, H-2), 8.32 (1H, brs, -NH), 8.19 (1H, brs, H-8), 5.87 (1H, d, J=6.0 Hz, H-1'), 5.41 (1H, d, J=6.4 Hz, -OH), 5.37 (1H, m, -OH), 5.18 (1H, d, J=4.8 Hz, -OH), 4.60 (1H, m, H-2'), 4.13 (1H, m, H-3'), 3.95 (1H, m, H-4'), 3.66 (1H, m, H-5'a), 3.54 (1H, m, H-5'b); the 4-methoxy-3-hydroxybenzyl moiety δ 8.82 (1H, s, -OH), 6.80 (1H, d, J=8.4 Hz, H-5"), 6.76 (1H, brs, H-2"), 6.70 (1H, brd, J=8.4 Hz, H-6"), 4.60 (2H, m, H-7"), 3.71 (3H, s, -OCH3); 13C NMR (125 MHz, DMSO-d6): the adenosine moiety δ 154.4 (C-6), 152.3 (C-2), 148.4 (C-4), 139.8 (C-8), 119.8 (C-5), 87.9 (C-1'), 85.9 (C-4'), 73.4 (C-2'), 70.6 (C-3'), 61.6 (C-5'); the 4-methoxy-3-hydroxybenzyl moiety δ 146.5 (C-4"), 146.3 (C-3"), 132.6 (C-1"), 117.8 (C-6"), 114.6 (C-2"), 112.1 (C-5"), 55.7 (-OCH3), 42.4 (C-7"). |
164 mg | With N-ethyl-N,N-diisopropylamine; In propan-1-ol; at 70℃; for 8.0h; | 9 mg of 4-methoxy-3-hydroxymethylamine hydrochloride was taken and 6-chloropurine nucleoside (143 mg) and N,N-diisopropylethylamine base (2 ml) were added to dissolve in propanol (40 mL) , Heated to 70 C., reacted for 8 hours, solvent was recovered with the reaction solution, separated by silica gel column chromatography, washing off with chloroform-methanol (15: 1) to obtain a white solid164 mg of N6-(4-methoxy-3-hydroxy-benzyl)adenosine are obtained |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In propan-1-ol; at 70℃; for 8.0h; | First step, hydroxyamine hydrochloride (5.07 g) and NaOAc (12.05 g) were added to a solution of 4-hydroxyacetophenone (5 g) in EtOH (80 ml). The reaction mixture was stirred at 60C for 6 h. EtOH was removed under reduced pressure. H2O (40 ml) was added to the residue, and extracted with EtOAc (3 × 40 ml). The EtOAc of the combined organic layer was removed by rotary evaporation under reduced pressure to yield 4-hydroxyacetophenone oxime (4.53 g) as a pale yellowish solid. Second step, a solution of 4-hydroxyacetophenone oxime (4.53 g) in EtOH (50 ml) was subjected to hydrogenation at atmospheric pressure in the presence of 10% Pd/C (502 mg). The reaction solution was filtered and the filtrate was concentrated to yield the 1-(4-hydroxyphenyl)-ethylamine (5.2 g) as a white solid. Third step, a mixture of 1-(4-hydroxyphenyl)-ethylamine (288 mg), 6-chloropurine riboside (200 mg) and triethylamine (3 ml) in PrOH (60 ml) was heated to 70C for 8h. After evaporation of the reaction mixture, the residue was separated by column chromatography over silica gel and eluted with CHCl3-CH3OH (20 : 1) to yield N6-[(+/-)-1-(4-hydroxyphenyl)-ethyl] -adenosine(220 mg) as a white solid: positive ESIMS m/z 388 [M + H]+[Show Image] 410 [M + Na]+; negative ESIMS m/z 386 [M - H]-; 1H NMR (300 MHz, DMSO-d6): the adenosine moiety delta 8.36 (1H, s, H-2), 8.17 (1H, s, H-8), 8.12 (1H, d, J= 8.4 Hz, -NH), 5.88 (1H, d, J= 5.7 Hz, H-1), 5.45 (2H, m, 2×-OH), 5.19 (1H, d, J = 4.5 Hz, -OH), 4.60 (1H, m, H-2'), 4.15 (1H, m, H-3'), 3.97 (1H, m, H-4'), 3.66 (1H, m, H-5a'), 3.55 (1H, m, H-5'b); the (+/-)-1-(4-hydroxyphenyl)-ethyl moiety delta 9.27 (1H, s, -OH), 7.23 (1H, d, J = 8.1 Hz, H-2", H-6"), 6.67 (1H, d, J = 8.1 Hz, H-3", H-5"), 5.42 (1H, m, H-7"), 1.49 (1H, d, J= 6.9 Hz, H-8"); 13C NMR (75 MHz, DMSO-d6): the adenosine moiety delta 153.8 (s, C-6), 152.3 (d, C-2), 148.5 (s, C-4), 139.8 (d, C-8), 119.7 (s, C-5), 88.0 (d, C-1), 86.0 (d, C-4'), 73.6 (d, C-2'), 70.7 (d, C-3'), 61.8 (t, C-5'); the (+/-)-1-(4-hydroxyphenyl)-ethyl moiety delta 156.1 (s, C-4"), 135.3 (s, C-1), 127.3 (d, C-2", C-6"), 114.9 (d, C-3", C-5"), 48.3 (d, C-7"), 22.5 (q, C-8")o | |
220 mg | With triethylamine; In propan-1-ol; at 70℃; for 8.0h; | Third step, a mixture of 1-(4-hydroxyphenyl)-ethylamine (288 mg), 6-chloropurine riboside (200 mg) and triethylamine (3 ml) in PrOH (60 ml) was heated to 70 C. for 8 h. After evaporation of the reaction mixture, the residue was separated by column chromatography over silica gel and eluted with CHCl3-CH3OH (20:1) to yield N6-[(+/-)-1-(4-hydroxyphenyl)-ethyl]-adenosine (220 mg) as a white solid: positive ESIMS m/z 388 [M+H]+ 410 [M+Na]+; negative ESIMS m/z 386 [M-H]-; 1H NMR (300 MHz, DMSO-d6): the adenosine moiety delta 8.36 (1H, s, H-2), 8.17 (1H, s, H-8), 8.12 (1H, d, J=8.4 Hz, -NH), 5.88 (1H, d, J=5.7 Hz, H-1'), 5.45 (2H, m, 2*-OH), 5.19 (1H, d, J=4.5 Hz, -OH), 4.60 (1H, m, H-2'), 4.15 (1H, m, H-3'), 3.97 (1H, m, H-4'), 3.66 (1H, m, H-5a'), 3.55 (1H, m, H-5'b); the (+-)-1-(4-hydroxyphenyl)-ethyl moiety delta 9.27 (1H, s, -OH), 7.23 (1H, d, J=8.1 Hz, H-2", H-6"), 6.67 (1H, d, J=8.1 Hz, H-3", H-5"), 5.42 (1H, m, H-7"), 1.49 (1H, d, J=6.9 Hz, H-8"); 13C NMR (75 MHz, DMSO-d6): the adenosine moiety delta 153.8 (s, C-6), 152.3 (d, C-2), 148.5 (s, C-4), 139.8 (d, C-8), 119.7 (s, C-5), 88.0 (d, C-1'), 86.0 (d, C-4'), 73.6 (d, C-2'), 70.7 (d, C-3'), 61.8 (t, C-5'); the (+-)-1-(4-hydroxyphenyl)-ethyl moiety delta 156.1 (s, C-4"), 135.3 (s, C-1"), 127.3 (d, C-2", C-6"), 114.9 (d, C-3", C-5"), 48.3 (d, C-7"), 22.5 (q, C-8"). |
220 mg | With triethylamine; In propan-1-ol; at 70℃; for 8.0h; | 4-hydroxybenzene(288 mg) was dissolved in n-propyl alcohol (60 mL), 6-chloropurine nucleoside (200 mg) and triethylamine (3 ml) were added, heated to 70 C. and reacted for 8 h. The solvent was evaporated with the reaction solution, chromatographed through a silica gel column and eluted with chloroform-methanol (20: 1) to give a white solidWas obtained to obtain N6-[1-(4-hydroxycyclohexylphenyl ketone)-ethyl]-adenosine (220 mg) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In propan-1-ol; at 70℃; for 8h; | First step, 9-fluorenone oxime (400 mg) and concentrated HCl (0.86 ml) in EtOH (50 ml) was subjected to hydrogenation at atmospheric pressure in the presence of 10% Pd/C (33 mg). The reaction solution was filtered and the filtrate was concentrated. The residue was suspended in EtOAc, and the suspension was filtered to yield fluorenamine hydrochloride (240 mg) as a white solid. Second step, a mixture of fluorenamine (304 mg, the hydrochloride), 6-chloropurine riboside (200 mg) and triethylamine (3 ml) in PrOH (60ml) was heated to 70C and reacted for 8 h. After evaporation of the reaction mixture, the residue was separated by column chromatography over silica gel and eluted with CHCl3-CH3OH (20 : 1) to yield N6-(fluorene-9-yl)-adenosine(208 mg) as a white solid: positive ESIMS m/z 432 [M + H]+ and 454 [M + Na]+; negative ESIMS m/z 430 [M - H]- and 466 [M + Cl]-; 1H NMR (300 MHz, DMSO-d6): the adenosine moiety delta 8.46. (1H, d, J = 8.1 Hz, -NH), 8.38 (2H, s, H-2, H-8), 5.94 (1H, d, J = 5.4 Hz, H-1), 5.52 (1H, d, J = 5.7 Hz, -OH), 5.44 (1H, m, -OH), 5.25 (1H, d, J = 4.8 Hz, -OH), 4.66 (1H, m, H-2'), 4.19 (1H, m, H-3'), 4.01 (1H, m, H-4'), 3.67 (1H, m, H-5'a), 3.56 (1H, m, H-5'b); the 9-fluorene moiety delta 7.86 (2H, d, J = 7.5 Hz, H-4", H-5"), 7.46 (2H, d, J = 7.5 Hz, H-1, H-8), 7.40 (2H, t, J= 7.5 Hz, H-2", H-7"), 7.26 (2H, t, J= 7.5 Hz, H-3", H-6), 6.69 (1H, d, J = 8.1 Hz, H-9"); 13C NMR (75 MHz, DMSO-d6): the adenosine moiety delta 155.1 (s, C-6), 152.4 (d, C-2), 148.8 (s, C-4), 140.3 (d, C-8), 120.2 (s, C-5), 88.1 (d, C-1), 86.0 (d, C-4'), 73.6 (d, C-2'), 70.7 (d, C-3'), 61.7 (t, C-5'); the 9-fluorene moiety delta 145.0 (s, C-8"a, C-9"a), 140.3 (s, C-4"a, C-5a ), 128.3 (d, C-1, C-8"), 127.5 (d, C-3", C-6"), 124.8 (d, C-2", C-7"), 120.2 (d, C-4", C-5"), 54.9 (d, C-9")o | |
208 mg | With triethylamine; In propan-1-ol; at 70℃; for 8h; | Second step, a mixture of fluorenamine (304 mg, the hydrochloride), 6-chloropurine riboside (200 mg) and triethylamine (3 ml) in PrOH (60 ml) was heated to 70 C. and reacted for 8 h. After evaporation of the reaction mixture, the residue was separated by column chromatography over silica gel and eluted with CHCl3-CH3OH (20:1) to yield N6-(fluorene-9-yl)-adenosine (208 mg) as a white solid: positive ESIMS m/z 432 [M+H]+and 454 [M+Na]+; negative ESIMS m/z 430 [M-H]- and 466 [M+Cl]-; 1H NMR (300 MHz, DMSO-d6): the adenosine moiety delta 8.46 (1H, d, J=8.1 Hz, -NH), 8.38 (2H, s, H-2, H-8), 5.94 (1H, d, J=5.4 Hz, H-1'), 5.52 (1H, d, J=5.7 Hz, -OH), 5.44 (1H, m, -OH), 5.25 (1H, d, J=4.8 Hz, -OH), 4.66 (1H, m, H-2'), 4.19 (1H, m, H-3'), 4.01 (1H, m, H-4'), 3.67 (1H, m, H-5'a), 3.56 (1H, m, H-5'b); the 9-fluorene moiety delta 7.86 (2H, d, J=7.5 Hz, H-4", H-5"), 7.46 (2H, d, J=7.5 Hz, H-1", H-8'"), 7.40 (2H, t, J=7.5 Hz, H-2", H-7"), 7.26 (2H, t, J=7.5 Hz, H-3", H-6'"), 6.69 (1H, d, J=8.1 Hz, H-9"); 13C NMR (75 MHz, DMSO-d6): the adenosine moiety delta 155.1 (s, C-6), 152.4 (d, C-2), 148.8 (s, C-4), 140.3 (d, C-8), 120.2 (s, C-5), 88.1 (d, C-1'), 86.0 (d, C-4'), 73.6 (d, C-2'), 70.7 (d, C-3'), 61.7 (t, C-5'); the 9-fluorene moiety delta 145.0 (s, C-8"a, C-9"a), 140.3 (s, C-4"a, C-5"a), 128.3 (d, C-1", C-8"), 127.5 (d, C-3", C-6"), 124.8 (d, C-2", C-7"), 120.2 (d, C-4", C-5"), 54.9 (d, C-9"). |
208 mg | With triethylamine; In propan-1-ol; at 70℃; for 8h; | 6-Chloropurine nucleoside (200 mg) and triethylamine (3 mL) were added to a solution of 9-fluorene hydrochloride (304 mg) and dissolved in propanol (60 mL)The mixture was heated to 70 C., reacted for 8 hours, and the solvent was recovered with a reaction solution. The residue was separated by silica gel column chromatography and washed with chloroform-methanol (20: 1) to obtain a white solid N6-(fluoren-9-yl)-adenosine (208 mg) is obtained |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
240 mg | With triethylamine; In propan-1-ol; at 70℃; for 8h; | Third step, a mixture of 1-(naphthalene-2-yl)-ethylamine (436 mg, the hydrochloride), 6-chloropurine riboside (200 mg) and triethylamine (3 ml) in PrOH (60 ml) was heated to 70 C. and reacted for 8 h. After evaporation of the reaction mixture, the residue was separated by column chromatography over silica gel and eluted with CHCl3-CH3OH (20:1) to yield N6-[(+/-)-1-(naphthalene-2-yl)-ethyl]-adenosine (240 mg) as a white solid: positive ESIMS m/z 422 [M+H]+, 444 [M+Na]+ and 460[M+K]+; 1H NMR (300 MHz, DMSO-d6): the adenosine moiety δ 8.43 (1H, m, -NH), 8.41 (1H, m, H-2), 8.19 (1H, s, H-8), 5.91 (1H, d, J=6.0 Hz, H-1'), 5.46 (2H, m, 2*-OH), 5.23 (1H, d, J=4.2 Hz, -OH), 4.63 (1H, m, H-2'), 4.17 (1H, m, H-3'), 4.00 (1H, m, H-4'), 3.69 (1H, m, H-5'a), 3.56 (1H, m, H-5'b); the (+-)-1-(naphthalene-2-yl)-ethyl moiety δ 7.90 (1H, brs, H-1"), 7.84 (3H, m, H-4", H-5", H-8"), 7.64 (1H, d, J=8.4 Hz, H-3"), 7.43 (2H, m, H-6", H-7"), 5.68 (1H, m, H-9"), 1.63 (3H, d, J=7.2 Hz, H-10"); 13C NMR (75 MHz, DMSO-d6): the adenosine moiety δ 154.0 (s, C-6), 152.4 (d, C-2), 148.7 (s, C-4), 139.9 (d, C-8), 119.9 (s, C-5), 88.1 (d, C-1'), 86.0 (d, C-4'), 73.6 (d, C-2'), 70.7 (d, C-3'), 61.7 (d, C-5'); the (+/-)-1-(naphthalene-2-yl)-ethyl moiety δ 142.8 (s, C-2"), 132.9 (s, C-4"a), 132.1 (s, C-8"a), 127.9 (d, C-4"), 127.7 (s, C-7"), 127.5 (d, C-6"), 126.2 (d, C-5"), 125.6 (d, C-8"), 125.2 (d, C-3"), 124.2 (d, C-1"), 49.1 (d, C-9"), 22.5 (q, C-10"). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With triethylamine; In neat (no solvent); at 210℃; under 12929.0 Torr; for 0.0166667h;Irradiation; | General procedure: Synthesis of (2R, 3R, 4S, 5R)-2-(6-(benzylamino)-9H-purin-9-yl)-5-(hydroxymethyl) tetrahydrofuran-3,4-diol, 2. In a 7 mL MW vessel, 6-chloropurinoriboside 3 (20 mg, 0.07 mmol), benzylamine 4 (7.5 mg,0.07 mmol, 7.7 muL) and triethylamine (7.08 mg, 0.07 mmol, 9.8 muL)were mixed. The solid mixture was stirred in CEM Explorer. MWMethod: T = 210 C, Power: 300 W, Hold Time: 1 min, P = 250 PSI,Power Max activated. After cooling, the solvent was removed in vacuoand the crude was dissolved in methanol and then purified on PTLC(DCM/MeOH 9:1) to afford compound 2 as white solid (24 mg, 94%).C17H20N5O4: 358.1510; Found 358.1515. Rt: 8.92 min. |
Tags: 2004-06-0 synthesis path| 2004-06-0 SDS| 2004-06-0 COA| 2004-06-0 purity| 2004-06-0 application| 2004-06-0 NMR| 2004-06-0 COA| 2004-06-0 structure
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