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CAS No. : | 4291-63-8 | MDL No. : | |
Formula : | C10H12ClN5O3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | PTOAARAWEBMLNO-KVQBGUIXSA-N |
M.W : | 285.69 | Pubchem ID : | 20279 |
Synonyms : |
2-Chloro-2′-deoxyadenosine;CldAdo;* 2chlorodeoxyadenosine.;2CdA. Code name: RWJ26251. Chemical structure names: * 2chloro2deoxyadenosine;Leustatine. Abbreviations: 2CDA;Cladribina. US brand name: Leustatin. Foreign brand names: Leustat;NSC 105014;Jk 6251;2-Chlorodeoxyadenosine;RWJ 26251;2CdA
|
Chemical Name : | (2R,3S,5R)-5-(6-Amino-2-chloro-9H-purin-9-yl)-2-(hydroxymethyl)tetrahydrofuran-3-ol |
Num. heavy atoms : | 19 |
Num. arom. heavy atoms : | 9 |
Fraction Csp3 : | 0.5 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 6.0 |
Num. H-bond donors : | 3.0 |
Molar Refractivity : | 66.52 |
TPSA : | 119.31 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -8.03 cm/s |
Log Po/w (iLOGP) : | 1.15 |
Log Po/w (XLOGP3) : | 0.02 |
Log Po/w (WLOGP) : | -0.61 |
Log Po/w (MLOGP) : | -1.79 |
Log Po/w (SILICOS-IT) : | -0.84 |
Consensus Log Po/w : | -0.41 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.84 |
Solubility : | 4.11 mg/ml ; 0.0144 mol/l |
Class : | Very soluble |
Log S (Ali) : | -2.08 |
Solubility : | 2.39 mg/ml ; 0.00837 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -1.01 |
Solubility : | 28.2 mg/ml ; 0.0986 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 0.0 |
Synthetic accessibility : | 3.65 |
Signal Word: | Danger | Class: | 6.1 |
Precautionary Statements: | P201-P202-P260-P264-P270-P280-P301+P310+P330-P308+P313-P405-P501 | UN#: | 2811 |
Hazard Statements: | H301-H341-H361-H372 | Packing Group: | Ⅲ |
GHS Pictogram: |
* 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 |
---|---|---|
59% | With ammonia; In methanol; at 60℃; | Preparation of 6-amino-2-chloiO-9-(2-deoxy-beta-D-eryf/?rc>- pentofuranosyPpurine (2-chloro-2'-deoxyadenosine') f cladribine).Treatment of 3-benzyl-l-{2-chloro-9-[2-deoxy-3,5-di-6>-0-toluoyl)-beta-D- e/>tf/m>pentofuranosyl]purin~6-yl}-2-prorhoylimidazolium iodide (0.83 g, crude) with NH3MeOH (26%, 50 mL) at 60 C followed by ion exchange chromatography (Dowex 1 x 2 [OHT], H2OZMeOH) by method 3 gave cladribine (0.31 g, quantitative). Recrystallization from EtOH gave a white solid (0.153 g, 54%), and the residue from the mother liquor was recrystallized from H2O to give a second crop (0.015 g, 59% total): mp > 300 C; UV (MeOH) max 212, 265 nm (epsilon 24 000, 14 600), min 229 nm (epsilon 2000); 1H NMR (500 MHz, DMSO-J6) delta 8.36 (s, IH), 7.83 (br, 2H), 6.26 (t, J= 6.7 Hz, IH), 5.32 (d, J- 4.3 Hz, IH), 4.97 (t, J= 5.5 Hz, IH), 4.38 (S, IH), 3.85 (s, IH), 3.57-3.61 (m, IH), 3.48-3.53 (m, IH), 2.62-2.67 (m, IH), 2.25-2.29 (m, IH); 13C NMR (125 MHz, DMSO-J6) delta 157.5, 153.6, 150.8, 140.5, 118.8, 88.6, 84.2, 71.4, 62.3, 38.0; HRMS m/z 285.0615 (M+ [C10H12ClN5O3] = 285.0629). Anal. Calcd for CI0HI2CIN5O3: C, 42.04; H, 4.23; N, 24.51. Found: C, 41.87; H, 4.50; N, 24.39. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With sodium methylate; In methanol; at 10 - 50℃; for 1.33333h;Heating / reflux; | [0042] b. To a suspension of 2-chloro-6-heptanoylamido-9-pentofuranosyl purine (product of 2a, 3.60 g; 5.68 mmol) in anhydrous methanol (30 ml) at 50 C. under nitrogen atmosphere was added 25% CH3ONaCH3OH (1.0 ml; 4.375 mmol) all at once. The mixture immediately afforded a clear solution and the solution was warmed at reflux temperature for 20 minutes followed by stirring at room temperature for 30 minutes. The mixture was further stirred at 10 C. for 30 minutes and the separated solid was collected by filtration; washed with cold methanol (1?10 ml) and air-dried. This material was crystallized from 1% aqueous ethanol to yield pure 10b (1.16 g; 72%); m.p. 217-20 C. (softens), solidifies and does not melt below 290 C. [lit. m.p. 210-15 C. (softens) and then solidifies and turns brown]. 1H NMR (DMSO-d6): ? 8.33 (S, 1H, C8H), 7.76 (S, 2H, D2O-exchangeable, NH2), 6.25 (t, 1H, peak width 14.0 Hz, C?1H). Analysis calculated for C10H12ClN5O3 (285.69): C, 42.04; H, 4.23; N, 24.51; Cl, 12.41. Found: C, 42.01; H, 4.27; N, 24.42 and Cl, 12.49. |
72% | With sodium methylate; In methanol; at 20 - 50℃; for 0.333333h; | [0073] The blocked nucleoside 5 (3.60 g, 5.68 mmol) was suspended in anhydrous methanol (30 mL) and the mixture was warmed with stirring to 50 C. (internal temp). Sodium methoxide was added to the stirred suspension (25 wt % solution in methanol, 1.0 mL, 4.375 mmol; pH ca. 10.5) and the resulting clear solution became cloudy after stirring at room temperature for 20 min. The solution was stirred under nitrogen atmosphere in an ice cold bath (5-10 C.) for an additional 30 min. The solid was collected by filtration, washed with cold methanol (1?10 mL) and air dried to give 1.28 g. [0074] The material was triturated with boiling ethanol (20 mL) and the mixture was stirred at room temperature for 15 min. The solid was collected by filtration and dried at 70 C./0.3 mm Hg for 3 h to give 2-chloro-2?-deoxyadenosine 6, 1.164 g (72%), mp 220 C. (softens at 210-215 C.). Rf0.31 (20% methanol-methylene chloride). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With pyridine; di-isopropyl azodicarboxylate; triphenylphosphine; at 20℃; for 1.58333h; | 5'-O-[4-bis(2-chloroethyl)-p-aminobenzenebutyryl]-<strong>[4291-63-8]2-chloro-2'-deoxyadenosine</strong> (2- CdA - CLB). In the 50 ml flask, 428 mg (1.5 mmol) of <strong>[4291-63-8]2-chloro-2'-deoxyadenosine</strong>, 456 mg (1.5 mmol) of 4- bis(2-chloroethylo)-p-aminobenzenebutanoic acid and 10 ml of dry pyridine were placed. The solvent was evaporated to remove water from the sample. This action was repeated with a new portion of pyridine - 10 ml. Then, 12 ml of pyridine was added and stirred at room temperature for about 5 min. Triphenylphosphine (525 mg, 2 mmol) and diisopropyl azodicarboxylate (405 mg, 2 mmol) were then added portionwise and the sample was stirred for another 90 min. Then, the sample was evaporated to oil. To remove the remaining pyridine the sample was thrice evaporated with toluene (3 x 15 ml). The residue was applied onto a silica gel column (3 x 25 cm, silica gel 60, Merck) and chromatographed with chloride methylene chloride ( 400 ml) and, then, with the mixture of methylene chloride - methanol (95: 5). The fractions containing the product were evaporated to a solid foam. 420 mg of the compound was obtained. Yield .49%. TLC: Rf (MeOHI CHCl3) : 0.49. 1H NMR (D6Me2SO, No. (ppm)): 1.73-2.72 (2m, H-2' and H-2" and -CH2-CH2-CH2-), 3.68 (bs, N-CH2-CH2-), 4.00 (m, H-4'), 4.16 and 4.23 (2m, H-5' and H-5"), 4.46 (m, H- 3'), 5.50 (bs, OH-3'), 6.36 (t, H-1'), 6.99 and 6.64 (2d, H-phenyl), 7.83 (bs, NH2), 8.31 (s, H-8). ESI-TOF mass of C25H31Cl3N6O4 (M+H+) - Calculated: 571.1389. Found: 571.1376. Elemental analysis: calculated for C25H31Cl3N6O4 (571.90): C,50.41; H, 5.11; N, 14.69. Found: C, 50.29; H, 5.15; N, 14.52. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2% | With 1-methyl-1H-imidazole; In tetrahydrofuran; at -78 - 20℃; | Synthesis of 2-chloro-2 ' -deoxyadenosine-5 ' -[phenyl-(methoxy-L-alaninyl)] -phosphate (CPF203); . EPO <DP n="19"/>N-Methylimidazole (NMI) (0.29 g, 3.50mmol, 0.29 mL) was added to a stirring suspension of <strong>[4291-63-8]2-chloro-2'-deoxyadenosine</strong> (0.200 g, 0.70 mmol) in dry THF (10 mL). 1-Phenyl- (methoxy-L-alaninyl)-phosphorochloridate (0.58 g, 2.10 mmol) in dry THF was added dropwise at -780C. After 15 min the reaction was let to rise to room temperature. The reaction was followed by TLC (DCM/MeOH 95/5), after 4 hours further 1-Phenyl- (methoxy-L-alaninyl)-phospho chloridate (0.28 g, 1.0 mmol) was added and the reaction was left stirring overnight. MeOH was added to quench the reaction, volatiles were evaporated and the residue was purified by flash chromatography (DCM/MeOH 100/0 to 95/5) and preparative TLC (DCM/MeOH 96/4) to give the product as white foam (0.008 g, 2% yield; Cladribine recovered 0.15 g). 31P-NMR (CDCl3, 121 MHz): delta 4.56,4.21. 1H- NMR (CDCl3, 300 MHz): delta 8.14,8.07 (IH, 2s, H-8), 7.52-7.29 (5H, m, Ph), 656-6.50 (IH, m, H-I'), 6.18-6.01 (IH, bs, NH2), 4.90-4.77 (IH, m, H-3'), 4.46-4.56 (2H, m, H-5'), 4.32- 4.26 (IH, m, H-4'), 4.22-4.02 (IH, m, CHNH), 3.85,3.83 (3H, 2s, CH3O)5 2.92-2.61 (2H, m, H-2'), 1.56-1.44 (3H, m, CH3CH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4% | With 1-methyl-1H-imidazole; In tetrahydrofuran; at -78 - 20℃; | Synthesis of 2-chloro-2 ' -deoxyadenosine-5 ' - [phenyl-(benzoxy-L-alaninyl)] -phosphate(CPF204).NMI (0.29 g, 3.50 mmol, 0.29 mL) was added to a stirring suspension of 2-chloro-2'- deoxyadenosine (0.200 g, 0.70 mmol) in dry THF (10 mL). l-Phenyl-(benzoxy-L- alaninyl)-phosphorochloridate (0.74 g, 2.10 mmol) in dry THF was added dropwise at - 780C. After 15 min the reaction was let to rise to room temperature and the reaction was left stirring overnight. MeOH was added to quench the reaction, volatiles were evaporated. The residue was purified by flash chromatography (DCM/MeOH 100/0 to 95/5) and preparative TLC (DCM/MeOH 96/4) to give the product as white foam (0.015 g, 4%yield). 31P-NMR (MeOH, 121 MHz): delta 5.11,4.81. 1H-NMR (MeOH, 300 MHz): delta8.12,8.10 (IH, 2s, H-8), 7.23-7.04 (1OH, m, PhO, PACH2), 6.30-6.24 (IH, m, H-I'), 5.04- 5.00 (2H, m, PhCH2), 4.52-4.48 (IH, m, H-3'), 4.29-4.15 (2H, m, H-5'), 4.08-4.04 (IH, m, H-4'), 3.91-3.81 (IH, m, CHNH), 2.63-2.54 (IH, m, one of H-2'), 2.41-2.33 (IH, m, one EPO <DP n="20"/>of R-T), 1.24-1.17 (3H, m, CRCH3). 13C-NMR (MeOD; 75 MHz): delta 20.6,20.8 (CH3), 41.2(C-2'), 52.0,52.1 (CHCH3), 67.7,68.1,68.2,68.3 (C-5 CH2Ph), 72.6 (C-3'), 86.2,86.4 (C- 1 '), 87.2,87.3 (C-4'X 121.7,121.8,126.5,129.6,129.7,129.9,131.1,137.6,141.5 (C-5,C- 8,PhCR2,PhO,"ipso" PhCR2), 151.8,151.9 (C-6), 152.4,152.5 ("ipso" PhO), 155.7,155.8 (C-2), 158.4 (C-4), 175.0,175.2 (COOCH2Ph). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1-methyl-1H-imidazole; In tetrahydrofuran; at -78 - 20℃; | Synthesis of <strong>[4291-63-8]2-chloro-2'-deoxyadenosine</strong>-5'-[l-naphthyl-(methoxy-L-alaninyl)]- phosphate.NMI (0.29 g, 3.50 mmol, 0.29 mL) was added to a stirring suspension of 2-chloro-2'- deoxyadenosine (0.200 g, 0.70 mmol) in dry THF (6 mL). l-Naphthyl-(benzoxy-L- alaninyl)-phosphochloridate (0.85 g, 2.10 mmol) in dry THF (4 mL) was added dropwise at -78 0C. After 15 min the reaction was allowed to rise to room temperature and left stirring overnight. MeOH was added to quench the reaction, volatiles were evaporated. The residue was purified by flash chromatography (DCM/MeOH 100/0 to 95/5) and by preparative HPLC (H2O/CH3CN 60/40) to give the product as white foam (mixed. 26 mg, fast eluting. llmg, slow eluting. 8 mg). MIXED (CPF210)31P-NMR (CDCl3, 202 MHz): delta 3.64,3.23 (int.: 1.00,0.97).HPLC: Rt 8.92, 9.59 min. 1H-NMR (CDCl3, 500 MHz): delta 8.00-7.98 (IH, m, H-8 Naph),7.86 (0.5 H, s, one of H-8 of one diastereoisomer), 7.77 (IH, d, H-5 Naph, 3J=7.4 Hz), 7.75 (0.5 H, s, one of H-8 of one diastereoisomer), 7.56 (IH, d, H-4 Naph, 3J=8.3 Hz), 7.44- 7.40 (3H, m, H-2 Naph, H-6 Naph, H-7 Naph), 7.31-7.15 (6H, m, H-3 Naph, Ph), 6.25- 6.21 (IH, m, H-I'), 5.73 (2H, bs, NH2), 5.04 (IH, s, CH2Ph of one diastereoisomer), 4.97 (0.5Eta, d, 2J=12.2 Hz, one CH2Ph of one diastereoisomer), 4.94 (0.5Eta, d, 2J=12.2 Hz, one CH2Ph of one diastereoisomer), 4.57-4.54 (0.5Eta, m, H-3 'of one diastereoisomer), 4.49- EPO <DP n="21"/>4.46 (0.5H, m, H-3'of one diastereoisomer), 4.34-4.23 (2H, m, H-5'), 4.11-4.00 (2H, m, H- 4', CHNH), 3.91 (0.5H, CHiVJf of one diastereoisomer), 3.90 (0.5H, CHNH of one diastereoisomer), 3.13 (0.5Eta, OH of one diastereoisomer), 3.01 (0.5H, OH of one diastereoisomer), 2.56-2.51 (0.5H, m, one H-2'of one diastereoisomer), 2.43-2.29 (1.5H, m, three H-2'), 1.27-1.24 (3H, 2d, CHCH3).13C-NMR (CDCl3; 125 MHz): delta 19.7,19.8 (CH3), 38.8 (C-2'), 49.4,49.5 (CHCH3),64.8,66.2,66.3 (0-5',CH2Ph), 69.8 (C-3'), 83.0 (C-I'), 83.9,84.0 (C-4'), 113.9,114.0 (C-2 Naph), 117.6,120.2,120.3,123.9,124.5,125.2,125.4,125.5,125.7,126.8,127.1,127.4,127.5, 127.6 (C-5, C-8, PZzCH2, C-5a Naph, C-3 Naph, C-4 Naph, C-5 Naph, C-6 Naph, C-7 Naph, C-8 Naph, C-8a Naph), 133.6,133.7,134.1 ("ipso" PZJCH2, C-4a Naph), 145.3 (C-I Naph), 149.3 (C-6), 153.0 (C-2), 155.13 (C-4), 172.4 (COOCH2Ph). FAST ELUTING (cpOll)31P-NMR (CDCl3, 202 MHz): delta 3.60,3.22 (int.: 4,87,1.00). HPLC: Rt 7.59, 8.92 min. 1H-NMR (CDCl3, 500 MHz): delta 8.03 (IH, d, 3J=7.5 Hz, H-8 Naph), 7.92 (0.2H, s, one of H-8of minor diastereoisomer), 7.80 (0.8H, s, H-8), 7.79 (IH, d, 3J=7.4 Hz, H-5 Naph), 7.61 (IH, d, H-4 Naph, 3J=8.3 Hz), 7.47-7.44 (3H, m, H-2 Naph, H-6 Naph, H-7 Naph), 7.35- 7.12 (6H, m, H-3 Naph, Ph), 6.29-6.26 (IH, m, H-I'), 5.88 (2H, bs, NH2), 5.08 (0.4H, s, CH2Ph of minor diastereoisomer), 5.05,4.97 (1.6Eta, 2d, 2J=12.2 Hz, CH2Ph), 4.61-4.58 (0.2H, m, H-3' of minor diastereoisomer), 4.54-4.51 (0.8H, m, H-3'), 4.36-4.32 (2H, m, H- 5'), 4.12-4.06 (2.2H, m, H-4', CHNH, CHNH of minor diastereoisomer), 3.82 (0.8Eta, CHNH), 3.32 (0.2Eta, OH of minor diastereoisomer), 3.25 (0.8H, OH), 2.58-2.53 (0.2H, m, one H-2'of minor diastereoisomer), 2.46-2.42 (0.2H, m, one H-2'of minor diastereoisomer), 2.41-2.33 (1.6H, m, H-2'), 1.31-1.29 (3H, 2d, CHCH3).SLOW ELUTINuG (cpf212) 31P-NMR (CDCl3, 202 MHz): delta 3.64,3.25 (int.: 1.00.28.15).HPLC: Rt 9.59, 10.92 min. 1H-NMR (CDCl3, 500 MHz): delta 7.99-7.97 (IH, dd, H-8 Naph), EPO <DP n="22"/>7.87 (IH, s, H-8), 7.77-7.74 (IH, m, H-5 Naph), 7.57 (IH, d, H-4 Naph, 3J=8.3 Hz), 7.44- 7.40 (3H, m, H-2 Naph, H-6 Naph, H-7 Naph), 7.29-7.20 (6H, m, H-3 Naph, Ph), 6.23 (IH, m, H-I'), 5.81 (2H, bs, NH2), 5.03 (2H, s, CJf2Ph)5 5.00,4.92 (d, 2J=12.3 Hz, CH2Ph of minor diastereoisomer), 4.58-4.55 (IH, m, H-3'), 4.49,4.48 (m, H-3' of minor diastereoisomer), 4.34-4.23 (2H, m, H-5'), 4.08-3.99 (3H, m, H-4', CJfNH, CUNH), 3.78 (CHNJf of minor diastereoisomer), 3.31 (IH, bs, OH), 2.56-2.50 (IH, m, one H-2'), 2.42- 2.38 (IH, m, one H-2'), 2.37-2.31 (m, H-2' of minor diastereoisomer), 1.26 (3H, 2d, CHCJf3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3% | With 1-methyl-1H-imidazole; In tetrahydrofuran; at -78 - 20℃; | Synthesis of <strong>[4291-63-8]2-chloro-2'-deoxyadenosine</strong>-5'-[4-chloro-l-naphthyl-(benzoxy-L-alaninyl)]- rhohosphate(CPF218).NMI (0.26 g, 3.20 mmol, 0.25 mL) was added to a stirring suspension of 2-chloro-2'- deoxyadenosine (0.183 g, 0.64 mmol) in dry THF (6 mL). 4-Chloro-l-naphthyl-(benzoxy-L-alaninyl)-phosphochloridate (0.87 g, 1.92 mmol) in dry THF (4 mL) was added dropwise at -78 0C. After 15 min the reaction was allowed to rise to room temperature and left stirring overnight.MeOH was added to quench the reaction, volatiles were evaporated. The residue was purified by flash chromatography (DCM/MeOH 100/0 to 95/5) and by preparative HPLC (H2O/CH3CN 60/40) to give the product as white foam(15 mg, 3%). 31P-NMR (CDCl3,202 MHz): delta 3.45,3.26. HPLC: Rt 7.92, 10.20 min.1H-NMR (CDCl3, 500 MHz): delta 8.14-8.10 (IH, m, H-5 Naph), 7.99-7.96 (IH, m, H-8Naph), 7.88 (0.5 H, s, one of H-8 of one diastereoisomer), 7.82 (0.5 H, s, one of H-8 of one diastereoisomer), 7.54-7.49 (IH, m, H-6 Naph), 7.47-7.40 (IH, m, H-7 Naph), 7.32-7.14 (7H, m, H-2 Naph, H-3 Naph, Ph), 6.25-6.22 (IH, m, H-I'), 6.04 (2H, bs, NH2), 5.00 (IH, s, CJf2Ph of one diastereoisomer), 4.97 (0.5H, d, 2J=12.2 Hz, one CJf2Ph of one EPO <DP n="23"/>diastereoisomer), 4.90 (0.5H, d, 2J=12.2 Hz, one CH2Ph of one diastereoisomer), 4.59-4.54 (IH, m, H-3'), 4.33-4.19 (2.5H, m, H-5 CHMf of one diastereoisomer), 4.08-3.96 (2.5H, m, H-4', CHNH, CHiVH of one diastereoisomer), 3.61,3.57 (1Eta, 2 bs, OEta-3'), 3.01 (0.5H, OH of one diastereoisomer), 2.59-2.34 (2H, m, H-2'), 1.25-1.23 (3H, m, CHCH3). 13C-NMR (CDCl3; 125 MHz): delta 20.8 (CH3), 39.7 (C-2'), 50.5 (CHCH3), 66.2,66.3 (C-55), 67.4(CH2Ph), 71.0 (C-3'X 84.1 (C-I'), 84.9,85.0,85.1 (C-4'),114.8,114.9,115.1,118.8,121.8,124.7,125.5,127.2,127.8,128.1,128.3,128.5,128.6,128.7 (C- 2 Naph, C-3 Naph, C-4 Naph, C-5 Naph, C-6 Naph, C-7 Naph, C-8 Naph, C-8aNaph, Ph), 131.6 (C-4a), 135.0 ("ipso" PZzCH2), 139.3,139.4 (C-8), 145.3,145.4 (C-I Naph), 150.4 (C- 6), 154.1 (C-2), 156.1 (C-4), 173.3 (COOCH2Ph). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
8.74 g (84.0%) | In methanol; CH3; dichloromethane; N,N-dimethyl-formamide; | A. 2-Chloro-2'-deoxy-5'-O-[(1,1-dimethylethyl)dimethylsilyl]-adenosine. To a solution of 7.43 g (0.026 m) of <strong>[4291-63-8]2-chloro-2'-deoxyadenosine</strong> in 150 mL of DMF, cooled by an ice-bath, was added 3.94 g (0.0578 m) of imidazole followed by 4.31 g (0.0286 m) of t-butyldimethylsilyl chloride. The solution was stirred cold 1.5 hours, then for 2 hours with the ice-bath removed. To the cooled solution was added another 0.79 g (0.012 m) of imidazole followed by 0.86 g (0.0057 m) of t-butyldimethylsilyl chloride. The solution was stirred for 1 hour, then treated with 150 mL of MeOH. The solution was concentrated at 50 C. at oil pump pressure. The resulting residue was partitioned between H2 O and EtOAc. The EtOAc layer was dried (MgSO4) and concentrated to give 10.94 g of a solid. This material was dissolved in CH3 OH/CH2 Cl2 and the solution was treated with 75 g of flash silica gel. The solvents were evaporated and the powder was applied to a column of 900 g of flash silica gel packed in CH2 Cl2 /MeOH (100:1). Elution was initially performed using CH2 Cl2 /MeOH (100:1), then 50:1, then 20:1. Appropriate fractions were pooled and concentrated to give 8.74 g (84.0%) of the product as a white solid. This material had the same tlc characteristics as a previously, similarly synthesised and characterized sample, and was itself not further characterized (tlc: SiO2 (CH2 Cl2 /MeOH, 20:1, Rf?0.3. The physical characteristics of the previously characterized sample follow: mp 195-196 C., with resolidification at 198 C. Anal. for C16 H26 N5 O3 ClSi: Calcd.: C, 48.05; H, 6.55, N, 17.51; Cl, 8.86.Found: C, 48.17; H, 6.31; N, 17.60, Cl, 8.77. IR (KBr)gamma=2930, 2859, 1643, 1594, 1314, 838 cm-1. NMR (DMSO, 100 MHz)delta=0.0 (s, 6, Si(CH3 s)2), 0.8 (s, 9, C(CH3)3), 4.4 (m, 1, H-3'), 6.3 (t, J=6.5 Hz, 1, H-1'), 7.8 (s, 2, NH2), 8.3 (s, 1, H-8). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With ammonia; In methanol; at 80℃; for 13h; | Preparation of 6-amino-2-chloro-9-(2-deoxy-beta-D-eryfLambdaro- pentofuranosyDpurine (2-chloro~2>-deoxyadenosine) (cladribine) .A solution of 2-chloro-9-[2-deoxy~3,5-di-0-(p-toluoyl)-beta-D-eryt/zr°- pentofuranosyl]-6-(2-pentylimidazol-l-yl)purine (0.35 g, 0.55 mmol) in methanolic ammonia (14%) was stirred at 80 C for 13 h. Volatiles were evaporated, and the oily residue was extracted with CH2Cl2 (10 mL) to remove lipophilic by-products. The semi-solid residue was dissolved in acetone (with additions of small amounts of MeOH - if necessary), volatiles were evaporated, and the semi-solid was allowed to crystallize (~1 h). This material was extracted with CH2Cl2 (10 mL) and dried. The resulting 2-chloro-2'-deoxyadenosine (white powder; 113 mg, 70%) was pure by 1H NMR analysis. Additional amounts of cladribine (-24 mg, 15%; containing traces of the alpha-anomer) were recovered from the concentrated extracts by chromatography (EtOAc -» EtOAc/MeOH, 10:1) followed by a similar extraction sequence. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With sodium methylate; In methanol; at 20 - 30℃; for 6h; | To the above prepared mixture of2-chloro-6-trimethylsilylamino-9-[3,5-di-0-(4-chlorobenzoyl)-2-deoxy-beta-D-ribofurano syl]- purine (IVa) and2-chloro-6-amino-9-[3,5-di-O-(4-chlorobenzoyl)-2'-deoxy-beta-D-ribofuranosyl]-purine (IVb) (179 g, >95.4% HPLC purity) in MeOH (895 ml_, 5 P) was added 29%MeONa/MeOH solution (5.25 g, 0.1 eq.) at 20-300C. The mixture was stirred at 20-300C for 6 hours, the solid was filtered, washed with MeOH (60 ml_, 0.34 P) and then dried in vacuo at 5O0C for 6 hour to give 72 g white to off-white crude cladribine with 98.9% HPLC purity in ca. 93% yield.EXAMPLE 4Recrystallisation[0055] Crude cladribine (70 g), H2O (350 mL, 5 P), MeOH (350 mL, 5 P) and 29% MeONa/MeOH solution (0.17 g) were stirred and heated under reflux until the mixture turned clear. The mixture was stirred for 3 hour and was then filtered to remove the precipitates at 74-780C. The mixture was stirred and heated under reflux until the mixture turned clear and was then cooled. Crystals started to form at ca. 450C. The slurry was stirred for 2 hour at the cloudy point. The slurry was cooled slowly at a rate of 5C/0.5 hour. The slurry was stirred at 10-200C for 4-8 hours and then filtered. The filter cake was washed three times with MeOH (50 mL each) and dried at 5O0C in vacuo for 6 hours to give 62.7 g of 99.9% HPLC pure cladribine in ca. 90% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With sodium carbonate; In methanol; at 20℃; for 2h;pH 8 - 9; | Compounde 7 (0.074 g, 0.20 mmol) was dissolved in MeOH (2 mL) andthe pH value was adjusted to 8-9 with Na2CO3. The mixture was stirred atroom temperature for 2 hours and concentrated under reduced pressure.The crude product was purified by flash column chromatography on silicagel using CHCl3/MeOH (1/1) as eluent to give 2, yield 93%.White solid, m.p. 306-310C (dec.). 1H NMR (400 MHz, DMSO-d6): delta8.34 (s, 1H), 7.34 (brs, 2H), 6.36-6.33 (m, 1H), 5.34 (s, 1H), 5.29 (s, 1H),4.11 (t, J = 2.4 Hz, 1H), 3.90-3.87 (m, 1H), 3.64 (dd, J 1 = 11.6 Hz, J 2 =39.2 Hz, 2H), 2.76-2.69 (m, 1H), 2.28-2.21 (m, 1H); 13C NMR (100 MHz, DMSO-d6) delta 155.9, 153.7, 148.7, 139.4, 119.0, 87.8, 83.8, 70.8, 61.7, 42.0;HRMS calcd for C10H13ClN5O3 [M+H+] 286.0701, found 286.0703. |
Tags: 4291-63-8 synthesis path| 4291-63-8 SDS| 4291-63-8 COA| 4291-63-8 purity| 4291-63-8 application| 4291-63-8 NMR| 4291-63-8 COA| 4291-63-8 structure
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