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CAS No. : | 20724-73-6 | MDL No. : | MFCD02682947 |
Formula : | C10H15N3O5 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | PPUDLEUZKVJXSZ-VPCXQMTMSA-N |
M.W : | 257.24 | Pubchem ID : | 500902 |
Synonyms : |
2'-C-Methylcytidine;2CMC;mCyd ;2'-C-MeC
|
Num. heavy atoms : | 18 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.6 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 6.0 |
Num. H-bond donors : | 4.0 |
Molar Refractivity : | 60.69 |
TPSA : | 130.83 Ų |
GI absorption : | Low |
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) : | -9.6 cm/s |
Log Po/w (iLOGP) : | 0.68 |
Log Po/w (XLOGP3) : | -2.44 |
Log Po/w (WLOGP) : | -2.49 |
Log Po/w (MLOGP) : | -1.58 |
Log Po/w (SILICOS-IT) : | -1.81 |
Consensus Log Po/w : | -1.53 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -0.01 |
Solubility : | 250.0 mg/ml ; 0.972 mol/l |
Class : | Very soluble |
Log S (Ali) : | 0.23 |
Solubility : | 440.0 mg/ml ; 1.71 mol/l |
Class : | Highly soluble |
Log S (SILICOS-IT) : | 0.41 |
Solubility : | 655.0 mg/ml ; 2.55 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 0.0 |
Synthetic accessibility : | 3.99 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
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 |
---|---|---|
80% | With ammonia In methanol at 20℃; | Example 2: Synthesis of 2'-C-methylcytidine (4) Saturated NH3 in methanol (250 mL) was added to the compound of example 1 (5.4 g, 8.0 mmol) and was stirred overnight at room temperature. The reaction mixture was evaporated with silica gel and chromatographed on a silica gel column eluting with CH2Cl2/MeOH/NH3 (8.3: 1 .5:0.2) to obtain the title compound as white solid (80percent). TLC (CH2CI2/MeOH/NH3, 8.3: 1 .5:0.2): Rf = 0.13. Yield = 80percent. 1 H NMR (500 MHz, MeOD) δ: 8.13 (d, 1 H, J6, 5 = 7.5 Hz, H-6), 6.02 (s, 1 H , H-1 '), 5.89 (d, 1 H, J5, 6 = 7.5 Hz, H-5), 3.99-3.96 (dd, J = 1 .9 Hz, 12.45 Hz, 1 H, H-5'), 3.93-3.91 (m, 1 H, H-4'), 3.82- 3.77 (m, 2H, H-3' & H-5"), 1 .10 (s, 3H, -CH3). (0314) 13C NMR (125 MHz, MeOD) δ: 167.5 (C-4), 158.5 (C-2), 143.1 (C-6), 95.9 (C-5), 93.9 (C-1 '), 83.8 (C-4'), 80.2 (C-2'), 73.7 (C-3'), 60.8 (C-5'), 20.5 (-CH3). HRMS (ESI+) calcd for Ci0H15N3O5Na [M+Na]+ 280.0904, found 280.0901 . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
solution of N- (tert-butoxycarbonyl)-L-valine (46.50 g, 214 mmol.), CARBONYLDIIMIDAZOLE (34.70 G, 214 MMOL. ), AND ANHYDROUS TETRAHYDROFURAN (1000 ML) IN a 2 L round bottom flask, was stirred at 25 C under argon for 1.5 hours and then at 40- 50 C for 20 minutes. In a separate 5 L 5-necked round bottom flask, equipped with an overhead stirrer, cooling tower, temperature probe, addition funnel, and an argon line WAS ADDED 4-AMINO-L- (3, 4-DIHYDROXY-5-HYDROXYMETHYL-3-METHYL-TETRAHYDRO-FURAN-2-YL) - 1H-PYRIMIDINE-2-ONE (50.0 g, 195 MMOL.) and anhydrous N, N-DIMETHYLFORMAMIDE (1000 mL). This mixture was heated at 100 C for 20 minutes until all of the pyrimidine-2-one derivative compound went into solution, and then triethylamine (500 mL) and 4- dimethylaminopyridine (2.38 g, 19 mmol) were added to the solution. The mixture was next heated at 97 C for 20 minutes and the tetrahydrofuran solution was added slowly through an addition funnel over a period of 2 hours, maintaining the temperature no lower than 82 C. The reaction mixture was heated at 82 C for 1 hour and monitored by HPLC (product = 68%, SM = 11%, and impurity at about 12 min = 17%, excluding DIMETHYLAMINOPYRIDINE). The reaction mixture was cooled to room temperature and then triethylamine and tetrahydrofuran were removed under vacuum at 30 C. The solution was then neutralized with acetic acid to a pH of 7.69. N, N-DIMETHYLFORMAMIDINE was removed under vacuum at 35 C and chased with ethyl acetate (2 x 200 ML). The crude product was stirred with ethyl acetate (500 mL) and water (300 mL). The two layers were separated and the aqueous layer was extracted with ethyl acetate (500 mL). The combined organic layers were washed with an aqueous saturated brine solution (500 mL). Next the organic layer was extracted with an aqueous solution of malonic acid (4 x 400 mL, 10WT. %). The organic layer was checked by TLC (silica, 20% methanol in dichloromethane) to make sure that all the desired product was removed from the organic layer. The acidic aqueous extracts were combined and cooled in an ice bath and neutralized with triethylamine to a pH of 7.40 so that the solids fell out of solution. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19% | With 1-methyl-1H-imidazole; In dichloromethane; at -20 - 20℃; for 10h; | A solution of (2-C-methyl-beta-D-ribofuranosyl)cytosine (0.066g, 0.257mmol) in anhydrous dichloromethane (1.5ml) at -1O0C under argon was added slowly a solution of 4-Chlorophenyl methoxydimethylglycmylphosphorochloridate (1.2ml, 0.769mmol) and 1-methylimidazole (0.12ml, 1.54mmol) in anhydrous dichloromethane (0.5ml). The EPO <DP n="22"/>reaction mixture was stirred at -10C/-20C for 2 hours then gradually stirred at room temperature for 8 hours. The mixture was evaporated under reduced pressure, and the crude was purified by silica gel chromatography in a gradient of 8% methanol in chloroform to afford the product as a yellow paste (28mg, 0.05mmol, 19%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60.1% | EXAMPLE 1 Propionic acid (2R,3R,4R,5R)-5-(4-amino-2-oxo-2H-pyrimidin-1-yl)-4-hydroxy-4-methyl-3-propionyloxy-tetrahydro-furan-2-ylmethyl ester; hydrochloride salt (I-1) To a solution of I-4 (1.0 g, 3.89 mmol) in THF (15 mL) and H2O (7 mL) was added TEA (4.72 g, 33.87 mol) and the reaction mixture was cooled to 5 C. Propionyl chloride (1.44 g, 15.45 mmol) was added slowly while maintaining the temperature of the reaction mixture below 0 C. The reaction was monitored by hplc and after the initial addition was complete monopropionate ester was still present and additional propionyl chloride (0.72 g, 7.77 mmol) was added and the reaction stirred overnight at RT. The reaction mixture was cooled to 0 C. and the pH was adjusted to ca. 6.5 with con HCl. The mixture was partitioned between EtOAc (30 mL) and H2O (15 mL) and the phases separated. The aqueous phase was extracted with EtOAc (2*25 mL) and the combined organic extracts were washed with dilute brine (2*20 mL), dried (Na2SO4), filtered and concentrated in vacuo to afford the free base as an oil. The oil was dissolved in IPA (5 mL) and treated with HCl in IPA (1 mL of ca. 4 N HCl) and concentrated in vacuo. The residue was recrystallized from IPA/MTBE/iso-propyl acetate (1:3:15) and the resulting crystals filtered and washed with iso-propyl acetate and dried in vacuo at 80 C. to afford 0.95 g (60.1%) of 1-1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72.6% | EXAMPLE 2 Iso-butyric acid (2R,3R,4R,5R)-5-(4-amino-2-oxo-2H-pyrimidin-1-yl)-4-hydroxy-3-isobutyryloxy-4-methyl-tetrahydro-furan-2-ylmethyl ester; hydrochloride salt (I-2) To a solution of I-4 (0.50 g, 1.94 mmol), DMAP (0.026 g, 0.21 mmol), THF (8 mL) and H2O (4 mL) was added TEA (2.36 g, 16.93 mmol) and the reaction mixture was cooled to ca. -5 C. Iso-butyryl chloride (0.93 mL, 8.75 mmol) was added dropwise ant a rate which allowed the reaction temperature to be maintained below 0 C. The reaction was monitored by HPLC-MS. Additional aliquots of 0.41 g and 0.21 g of iso-butyryl chloride (total of 1.55 g, 14.58 mmol) were added to eliminate monoacylated byproduct (determined by hplc). The reaction was stirred overnight at RT, cooled to 0 C. and the pH was adjusted to pH 6.5 with con HCl. The mixture was partitioned between EtOAc (30 mL) and H2O (15 mL) and the phases separated. The aqueous phase was extracted with EtOAc (2*15 mL) and the combined organic extracts were washed sequentially with dilute brine (20 mL), dilute NaHCO3 (20 mL), dilute brine (15 mL) dried (Na2SO4), filtered and concentrated in vacuo to afford the free base as an oil. The oil was dissolved in EPA (5 mL) and treated with HCl in IPA (1 mL of ca. 4 N HCl) and concentrated in vacuo. The residue was recrystallized from IPA/MTBE (1:10) and the resulting crystals filtered and washed with MTBE and dried in vacuo at 80 C. to afford 0.61 g (72.6%) of 1-2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55.7% | EXAMPLE 3 Pentanoic acid (2R,3R,4R,5R)-5-(4-amino-2-oxo-2H-pyrimidin-1-yl)-4-hydroxy-4-methyl-3-pentanoyloxy-tetrahydro-furan-2-ylmethyl ester; hydrochloride salt (I-3) To a solution of I-4 (0.490 g, 1.90 mmol), DMAP (0.026 g, 0.21 mmol), THF (7 mL) and H2O (3 mL) was added TEA (2.31 g, 16.59 mmol) and the reaction mixture was cooled to ca. 0 C. Valeric anhydride (1.6 g, 2.57 mmol) was added dropwise at a rate which allowed the reaction temperature to be maintained below 5 C. The reaction was monitored by HPLC-MS. Two 0.32 g aliquots of valeric anhydride (2.24 g, 11.99 mmol total) were added to eliminate monoacylated byproduct. The reaction mixture was cooled to 0 C. and the pH was adjusted to pH 6.8 with con HCl. The mixture was partitioned between EtOAc (30 mL) and H2O (15 mL) and the phases separated. The aqueous phase was extracted with EtOAc (2*15 mL) and the combined organic extracts were washed sequentially with dilute NaHCO3 (2*20 mL) and water (1*20 mL), dried (Na2SO4), filtered and concentrated in vacuo to afford the free base as an oil. The oil was dissolved in IPA (5 mL) and treated with HCl in IPA (0.8 mL of ca. 4 N HCl) and concentrated in vacuo. The residue was recrystallized from IPA/MTBE/heptane (1:0.5:10; 15 mL) and the resulting crystals filtered and washed with heptane and dried in vacuo at 80 C. under N2 to afford 0.88 g (55.7%) of 1-3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2'-C-Methylcytidine was diluted with THF (0.09 M). The resulting slurry was cooled to-78C, and ter/-butylmagnesium chloride (as 1.0 M solution in THF, 2.2 eq.) was added. The mixture was immediately warmed to 0C, stirred for 30 min and again cooled to -78 C, then (2S)-2-[ [chloro(l-phenoxy)phosphoryl] amino] propyl pivalate (as 1.0 M solution in THF, 2.0 eq.) was added dropwise. The reaction was allowed to reach RT overnight, and then was quenched by the addition of water. The aqueous phase was extracted three times with EtOAc, the combined organic phases were washed with brine and dried over Na2SO4. The crude product was purified by column chromatography on silica gel eluting with 92:8 DCM/MeOH, and the resulting white solid was dissolved in DMSO and purified by RP-HPLC. Fractions containing the pure diastereoisomers were combined and freeze-dried to afford the title compounds as their white TFA salts. First-Eluting Diastereoisomer: lH NMR (300 MHz, CD3OD) delta 7.98 (d, J = 7.95 Hz, IH), 7.43-7.20 (m, 5H), 6.02-5.99 (m, 2H), 4.58-4.51 (m, IH), 4.46-4.37 (m, IH), 4.22-4.15 (m, IH), 4.08 (dd, J = 10.84, 5.75 Hz, IH), 3.93 (dd, J = 10.72, 6.52 Hz, IH), 3.77 (d, J = 9.29 Hz, IH), 3.64-3.53 (m, IH), 1.22 (s, 9H), 1.23- 1.17 (m, 6H), NH2, NH, 2 x OH not visible, 3 Ip NMR: (300 MHz CD3OD) delta: 5.56; MS (ES+) m/z 556 (M+H)+ Second-Eluting Diastereoisomer: lH NMR (300 MHz, CD3OD): delta 8.02 (d, J = 7.59 Hz, IH), 7.44-7.22 (m, 5H), 6.03-6.00 (m,2H), 4.58-4.53 (m, IH), 4.43-4.36 (m, IH), 4.22-4.15 (m, IH), 4.04 (dd, J = 10.94, 5.64 Hz, IH), 3.91-3.81 (m, 2H), 3.63-3.54 (m, IH), 1.23-1.17 (m, 15H), NH2, NH, 2 x OH not visible, 3 Ip NMR: (300 MHz CD3OD) delta: 5.68; MS (ES+) m/z 556 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2'-C-Methylcytidine was diluted with acetone (0.04M) and/7-toluensulfonic acid and 2,2-dimethoxypropane were added. The resulting slurry was stirred for 24h at RT. The solvent was evaporated, the residue was dissolved in MeOH and Amberlite A-26 (previously washed with 2N NaOH and H2O) was added. The resulting mixture was stirred for 2 h. The Amberlite was filtered off and the solution was evaporated. The crude product was purified by column chromatography on silica gel (DCM/MeOH=9:l) to give the desired product as a white powder. lH NMR (300 MHz, CD3OD) delta 7.96 (d, J = 7.56 Hz, IH), 6.18 (s, IH), 5.90 (d, J = 7.56 Hz, IH), 4.51-4.48 (m, IH), 4.28-4.23 (m, IH), 3.86 (dd, J = 3.04 and 12.12 Hz, IH), 3.78 (dd, J = 3.52 and 12.12 Hz, IH), 1.59 (s, 3H), 1.43 (s, 3H), 1.25 (s, 3H); MS (ES+) m/z 298 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step 2: H-Butyl (2S)-2-[[(2R, 3R, 4R, 5R)-5-(4-amino-2-oxopyrimidin-l(2 H)-yl)-3,4- dihydroxy-4-methyltetrahydrofuran-2-yl] -methoxy } -(4- chlorophenoxy)phosphoryl] - amino }propanoate2'-C-Methylcytidine (evaporated twice from toluene) was diluted with THF (0.097M). The resulting slurry was cooled to -78 0C, then tert-butylmagnesium chloride (as 1.0M solution in THF, 2.0 eq.) was added. The mixture was immediately warmed to 0 0C, stirred for thirty min and again cooled to -78 0C, then «-butyl iV-[chloro(4-chlorophenoxy)phosphoryl]-L- alaninate (as 1.0 M solution in THF, 2.0 eq.) was added dropwise. The reaction was allowed to reach room temperature overnight, and quenched by the addition of water. The aqueous phase was extracted three times with EtOAc, the combined organic phases were washed with brine and dried over Na2SO4. The crude was purified by column chromatography on silica gel (DCM/MeOH gradient from 90/10 to 80/20), the resulting off white solid was redissolved in DMSO and purified by RP-HPLC (stationary phase: column Symmetry C 18, 7 mum, 19 x 300 mm. Mobile phase: acetonitrile/H2O buffered with 0.1% TFA). Fractions containing the pure compounds were combined and freeze-dried to afford the title compounds as TFA-salts as a 1.07:1* mixture (First Eluting: Second Eluting). lH NMR (300 MHz, OMSO-d6 ) delta 8.05 and 8.04* (d, J = 7.74 Hz and J* = 7.96 Hz, IH), 7.46- 7.38 (m, 2H), 7.34-7.25 (m, 2H), 6.10* and 6.08 (d, , J* = 7.96 and J = 7.74 Hz, IH), 6.02* and 6.01 (s, IH), 4.67-4.53 (m, IH), 4.53-4.37 (m, IH), 4.25-4.08 (m, 3H), 4.07-3.93 (m, IH), 3.84* and 3.81 (d, J = 4.64 Hz and J* = 4.64 Hz, IH), 1.71-1.56 (m, 2H), 1.48-1.35 (m, 5H), 1.22 (s, 3H), 0.97 (t, J = 7.19 Hz, 3H); 31p NMR: (300 MHz CD3OD ) delta: 5.16, 5.09* ppm; MS (ES+) m/z 575 (M+ H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Reference Example 1 (R6=Et)Step 1:; 5'-O-[[[(1S)-2-ethoxy-1-methyl-2-oxo ethyl]amino](9H-fluoren-9-ylmethoxy)phosphinyl]-<strong>[20724-73-6]2'-C-methylcytidine</strong>Bisphenyl phosphite was dissolved in pyridine (0.3 M) and a solution of fluorenylmethyl alcohol in pyridine (0.3 M) was added. The mixture was stirred at 0 C. for 20 min. Then a solution of 2'-C-methyl-cytidine in pyridine (0.3M) was added at 0 C. The resulting solution was warmed to 40 C. and stirred for 1 h at this temperature. The solvent was evaporated and the residue dissolved in DMA (0.19M). The resulting solution was added to a solution of L-alanine-ethylester hydrochloride (1.2 eq.) and Et3N (2.0 eq.) in iPrOH:CCl4 (0.24 M, 10:1). The mixture was stirred for 10 min at 0 C. and then the solvent was evaporated. The residue was dissolved in EtOAc and water. The aqueous phase was extracted three times with EtOAc, the combined organic phases were washed with brine and dried over Na2SO4. The crude product was purified by RP-HPLC (stationary phase: column XTerra C18, 5 mum, 19×150 mm. Mobile phase: MeCN/H2O 5 mM AMBIC). Fractions containing the pure compound were freeze-dried to afford the title compound as white powder and as a mixture of diastereoisomers 1:1. MS (ES+) m/z 615 (M+H)- |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 2(R6=2PrPen); Step 1: 2'-C-methyl-2',3'-O-(1-methylethylidene)-cytidine2'-C-Methylcytidine was diluted with acetone (0.04M) and p-toluensulfonic acid and 2,2-dimethoxypropane were added. The resulting slurry was stirred for 24 h at RT. The solvent was evaporated, the residue was dissolved in MeOH and Amberlite A-26 (previously washed with 2N NaOH and H2O) was added. The resulting mixture was stirred for 2 h. The Amberlite was filtered off and the solution was evaporated. The crude product was purified by column chromatography on silica gel (DCM:MeOH=9:1) to give the desired product as a white powder. 1H NMR (300 MHz, CD3OD) delta 7.96 (d, J 7.56, 1H), 6.18 (s, 1H), 5.90 (d, J 7.56, 1H), 4.51-4.48 (m, 1H), 4.28-4.23 (m, 1H), 3.86 (dd, J 12.12, 3.04, 1H), 3.78 (dd, J 12.12, 3.52, 1H), 1,59 (s, 3H), 1.43 (s, 3H), 1.25 (s, 3H); MS (ES+) m/z 298 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step 3: 5'-O-[[[(1S)-2-n-butoxy-1-methyl-2-oxoethyl]amino](1-naphthalenyloxy)phosphinyl]-<strong>[20724-73-6]2'-C-methylcytidine</strong>; 2'-C-Methylcytidine was diluted with THF (0.097 M). The resulting slurry was cooled to -78 C., then tert-butylmagnesium chloride (as 1.0 M solution in THF, 2.2 eq.) was added. The mixture was immediately warmed to 0 C., stirred for thirty min and again cooled to -78 C., then butyl N-[chloro(1-naphthyloxy)phosphoryl]-L-alaninate (as 1.0 M solution in THF, 2.2 eq.) was added dropwise. The reaction was allowed to reach RT overnight, and then was quenched by the addition of water. The aqueous phase was extracted three times with EtOAc, the combined organic phases were washed with brine and dried over Na2SO4. The crude was purified by column chromatography on silica gel (DCM/MeOH gradient from 90:10 to 80:20), and the resulting off white solid was dissolved in DMSO and purified by RP-HPLC. Fractions containing the pure diastereoisomers were combined and freeze-dried to afford the title compounds as their white TFA salts. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tert-butylmagnesium chloride; In tetrahydrofuran; at -78℃; | Step 3: 5'-O-[[[(1S)-2-[2-(hexyloxy)ethoxy]-1-methyl-2-oxoethyl]amino]phenoxy-phosphinyl]-<strong>[20724-73-6]2'-C-methylcytidine</strong>; 2'-C-Methylcytidine (evaporated twice from toluene) in THF (0.097 M) was cooled to '78 C., tert-butylmagnesium chloride (as 1.0M solution in THF, 2.2 eq.) was added followed by the addition of 2-(hexyloxy)ethyl N-[chloro(phenoxy)phosphoryl]-L-alaninate. The crude product was purified by column chromatography on silica gel (DCM/MeOH gradient from 90/10 to 80/20), the resulting off white solid was dissolved in DMSO and purified by RP-HPLC (stationary phase: column Symmetry C18, 7 mum, 19×300 mm. Mobile phase: acetonitrile/H2O buffered with 0.1% TFA). Fractions containing the pure compounds were combined and freeze dried to afford the title compounds as a white powder. A 1:1.8* mixture was observed by 31P NMR.1H NMR (300 MHz, CD3OD) delta: 7.85 and 7.82* (d, J=7.92 Hz and J*=7.92 Hz, 1H), 7.24-7.18 (M, 2H), 7.11-7.02 (m, 3H), 5.87 and 5.83* (d, J=7.83 Hz and J*=7.92 Hz, 1H), 5.81 and 5.80* (s, 1H), 4.45-4.33 (m, 1H), 4.30-4.18 (m, 1H), 4.11-3.94 (m, 3H), 3.87-3.76 (m, 1H), 3.62 and 3.59* (d, J=8.34 Hz and J*=9.30 Hz, 1H), 3.46 (qt, J=4.53 Hz , 2H), 3.28 (t, J=6.60 Hz, 2H), 1.41-1.32 (m, 2H), 1.20-1.13 (m, 9H), 0.99 (s, 3H), 0.74-0.70 (m, 3H). 31P NMR: (300 MHz, CD3OD) delta: 3.86 and 3.63* (s, 1P); MS (ES+) m/z 613 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step 3: 5'-O-[[[(1S)-1-methyl-2-oxo-2-[(propylpentyl)oxy]ethyl]amino]phenoxyphosphinyl]-<strong>[20724-73-6]2'-C-methylcytidine</strong>; 2'-C-Methylcytidine was diluted with THF (0.097 M). The resulting slurry was cooled to -78 C., then tert-butylmagnesium chloride (as 1.0 M solution in THF, 2.2 eq.) was added. The mixture was immediately warmed to 0 C., stirred for 30 min and again cooled to -78 C., then propylpentyl N-[chloro(phenyloxy)phosphoryl]-L-alaninate (as 1.0 M solution in THF, 2.2 eq.) was added dropwise. The reaction was allowed to reach RT overnight, and then was quenched by the addition of water. The aqueous phase was extracted three times with EtOAc, the combined organic phases were dried over Na2SO4. The crude product was purified by column chromatography on silica gel (DCM/MeOH 92:8), and the resulting off white solid was dissolved in DMSO and purified by RP-HPLC (stationary phase: column Symmetry C18, 7 mum, 19×300 mm. Mobile phase: acetonitrile/H2O, water buffered with 5 mM AMBIC). Fractions containing the pure diastereoisomers were combined and freeze-dried to afford the title compounds as a white solid.First-Eluting Diastereoisomer:1H NMR (400 MHz, CD3OD) delta 7.70 (d, J=7.46 Hz, 1H), 7.45-7.30 (m, 2H), 7.30-7.13 (m, 3H), 6.06 (s, 1H), 5.83 (d, J=7.46 Hz, 1H), 4.63-4.51 (m, 1H), 4.48-4.35 (m, 1H), 4.17-3.87 (m, 4H), 3.73 (d, J=9.1 Hz, 1H), 1.67 (bs, 1H), 1.47-1.17 (m, 11H), 1.08 (s, 3H), 0.89 (bs, 6H). NMR: (400 MHz, CD3OD) delta: 3.95; MS (ES+) m/z 597 (M+H)+ Second-Eluting Diastereoisomer:1H NMR (400 MHz, CD3OD) delta 7.68 (d, J=7.33 Hz, 1H), 7.43-7.32 (m, 2H), 7.31-7.16 (m, 3H), 6.04 (s, 1H), 5.83 (d, J=7.33 Hz, 1H), 4.55-4.45 (m, 1H), 4.42-4.31 (m, 1H), 4.14-3.90 (m, 4H), 3.72 (d, J=9.09 Hz, 1H), 1.72-1.59 (m, 1H), 1.43-1.20 (m, 11H), 1.09 (s, 3H), 0.89 (t, J=6.32 Hz, 6H). 31P NMR: (400 MHz, CD3OD) delta: 3.79; MS (ES+) m/z 597 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step 6: 5'-O-[[[1-[((1,1-dimethylethoxy)carbonyl]-1H-indol-5-yl]oxy][[(1S)-2-ethoxy-1-methyl-2-oxoethyl]amino]phosphinyl]-<strong>[20724-73-6]2'-C-methylcytidine</strong>; <strong>[20724-73-6]2'-C-methylcytidine</strong> (evaporated twice from toluene) was diluted with THE (0.097 M). The resulting slurry was cooled to -78 C., then tert-butylmagnesium chloride (as 1.0M solution in THF, 2.2 eq.) was added. The mixture was immediately warmed to 0 C., stirred for thirty mM and again cooled to -78 C., then 1H-indole-1-carboxylic acid 5-[[chloro[[(1S)-2-ethoxy-1-methyl-2-oxoethyl]amino]phosphinyl]oxy]-1,1-dimethylethyl ester (as 1.0 M solution in THF, 1.6 eq.) was added dropwise. The reaction was allowed to reach room temperature overnight, and quenched by the addition of water. The aqueous phase was extracted three times with EtOAc, the combined organic phases were washed with brine and dried over Na2SO4. The crude was dissolved in DMSO and purified by RP-HPLC (stationary phase: column Phenomenex Luna C18(2) 5 mum, 250×21.20 mm. Mobile phase: acetonitrile/H2O buffered with 5 mM AMBIC). Fractions containing the pure compounds were combined and freeze-dried to afford the title compounds as a white powder.First-Eluting Diastereoisomer:1H NMR (300 MHz, DMSO-d6) delta 8.02 (d, J=8.91 Hz, 1H), 7.72 (d, J=3.63 Hz, 1H), 7.56 (d, J=7.45 Hz, 1H), 7.45 (s, 1H), 7.17(d, J=9.06 Hz, 1H), 7.16 (br s, 1H), 7.10 (br s, 1H), 6.71 (d, J=3.60 Hz, 1H), 6.07 (dd, J=10.17 and 12.66 Hz, 1H), 5.95 (s, 1H), 5.70 (d, J=7.44 Hz, 1H), 5.28 (d, J=6.93 Hz, 1H), 5.08 (s, 1H), 4.47-4.35 (m, 1H), 4.32-4.21 (m, 1H), 4.13-3.96 (m, 3H), 3.89-3.75 (m, 1H), 3.58 (t, J=6.96 Hz, 1H), 1.64 (s, 9H), 1.23 (d, J=6.96 Hz, 3H), 1.13 (t, J=7.05 Hz, 3H), 0.92 (s, 3H); 31P NMR: 300 MHz, DMSO-d6) delta: 4.05; MS (ES+) m/z 653 (M+H)+ Second-Eluting Diastereoisomer:1H NMR (300 MHz, DMSO-d6) delta: 8.02 (d, J=8.91 Hz, 1H), 7.72 (d, J=3.63 Hz, 1H), 7.57 (d, J=7.54 Hz, 1H), 7.49 (s, 1H), 7.20 (d, J=7.60 Hz, 1H), 7.18 (br s, 1H), 7.10 (br s, 1H), 6.71 (d, J=3.63 Hz, 1H), 6.00 (dd, J=10.42 and 12.34 Hz, 1H), 5.94 (s, 1H), 5.70 (d, J=7.44 Hz, 1H), 5.23 (d, J=7.05 Hz, 1H), 5.09 (s, 1H), 4.43-4.32 (m, 1H), 4.30-4.18 (m, 1H), 4.13-3.93 (m, 3H), 3.92-3.80 (m, 1H), 3.62 (t, J=7.02 Hz, 1H), 1.65 (s, 9H), 1.25 (d, J=7.02 Hz, 3H), 1.13 (t, J=7.11 Hz, 3H), 0.96 (s, 3H); 31P NMR (300 MHz, DMSO-d6) delta: 4.16; MS (ES+) m/z 653 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | 1-[(2R,3R,4R,5R)-3,4-dihydroxy-5-(hydroxymethyl)-3-methyl-tetrahydrofuran-2-yl]-4-[[(4-methoxyphenyl)-diphenyl-methyl]amino]pyrimidin-2-one (E-5) 2'-C-Methylcytidine (38.9 mmol) was dissolved in pyridine (270 mL) and the reaction mixture was cooled down to 0 C. TMSCl (233.4 mmol) was added and the mixture was stirred at room temperature during 4 hours. DMAP (38.9 mmol) and mMTrCl (77.25 mmol) were added and the reaction mixture was stirred at 50 C. during 2 days. The reaction was cooled down to room temperature and a saturated solution of NaHCO3 was added slowly. The mixture was extracted with CH2Cl2 and the organic layer was dried over Na2SO4, filtered and concentrated. Co-evaporations with toluene and CH2Cl2 were done. The crude was dissolved in CH3OH (500 mL) and NH4F (194.5 mmol) was added. The reaction mixture was heated at reflux and stirred during 1 hour. The reaction mixture was cooled down to room temperature and concentrated. The crude was purified by chromatography on a silica gel column (eluent: CH2Cl2/CH3OH 0 to 10%) to give the expected compound as a yellow powder in 89% yield. 1H NMR (CDCl3, 400 MHz) delta (ppm) 1.08 (s, 3H), 3.71-3.84 (m, 2H), 3.81 (s, 3H), 3.90-3.94 (m, 1H), 3.99-4.03 (m, 1H), 5.14 (d, J=7.63 Hz, 1H), 5.31 (s, 1H), 5.79 (brs, 1H), 6.84 (d, J=8.65 Hz, 2H), 7.13 (d, J=8.69 Hz, 2H), 7.21 (d, J=7.35 Hz, 4H), 7.27-7.34 (m, 8H), 7.51 (brs, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With hydroxylamine hydrochloride; In water; at 50℃; for 40h; | To a solution of 36 (0.175 g, 0.68 mmol) in 2 mL of H20 was added hydroxylamine hydrochloride (0.24 g, 3.4 mmol). The reaction mixture was stirred at50 C and monitored by TLC and/or LC/MS. After 16 h, hydroxylamine hydrochloride (0.24 g, 3.4 mmol) was added and the reaction mixture was stirred 50C for an extra 24 h. After complete consumption of the starting material, the aqueous solution was extracted with AcOEt (3 x 5 mL). The combined organic layer were dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH2Cl2:MeOH = 95:5 to 90: 10 v/v) to give 37 (0.83 g, 0.30 mmol) in 45% yield. LCMS (ESI) Calcd for CioH15N306 273.2, observed (M + 1) 274.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | In water; at 50℃; for 40h; | To a solution of 36 (0.175 g, 0.68 mmol) in 2 mL of H20 was added O- benzylhydroxylamine hydrochloride (0.70 g, 4.38 mmol). The reaction mixture was stirred at 50 C and monitored by TLC and/or LC/MS. After 16 h, O- benzylhydroxylamine hydrochloride (0.30 g, 1.88 mmol) was added and the reaction mixture was stirred 50 C for an extra 24 h. After complete consumption of the starting material, the aqueous solution was extracted with AcOEt (3 x 5 mL). The combined organic layer were dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH2Cl2:MeOH = 95:5 to 90: 10 v/v) to give 41 (0.12 g, 0.33 mmol) in 49% yield. LCMS (ESI) Calcd for C17H2iN306 363.4, observed (M + 1) 364.3 |
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H311 | Toxic in contact with skin |
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Environmental hazards | |
Code | Phrase |
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H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
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