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CAS No. : | 14470-28-1 | MDL No. : | MFCD00000814 |
Formula : | C20H17ClO | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | OBOHMJWDFPBPKD-UHFFFAOYSA-N |
M.W : | 308.80 | Pubchem ID : | 84462 |
Synonyms : |
|
Num. heavy atoms : | 22 |
Num. arom. heavy atoms : | 18 |
Fraction Csp3 : | 0.1 |
Num. rotatable bonds : | 4 |
Num. H-bond acceptors : | 1.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 91.55 |
TPSA : | 9.23 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | Yes |
CYP2C9 inhibitor : | Yes |
CYP2D6 inhibitor : | Yes |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -4.48 cm/s |
Log Po/w (iLOGP) : | 3.48 |
Log Po/w (XLOGP3) : | 5.22 |
Log Po/w (WLOGP) : | 5.12 |
Log Po/w (MLOGP) : | 5.04 |
Log Po/w (SILICOS-IT) : | 5.55 |
Consensus Log Po/w : | 4.88 |
Lipinski : | 1.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -5.38 |
Solubility : | 0.00127 mg/ml ; 0.00000412 mol/l |
Class : | Moderately soluble |
Log S (Ali) : | -5.16 |
Solubility : | 0.00213 mg/ml ; 0.00000689 mol/l |
Class : | Moderately soluble |
Log S (SILICOS-IT) : | -8.21 |
Solubility : | 0.00000191 mg/ml ; 0.0000000062 mol/l |
Class : | Poorly soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.94 |
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 |
---|---|---|
82% | With pyridine at 20℃; for 94h; | |
With pyridine | ||
With pyridine for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With pyridine Ambient temperature; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With pyridine for 20h; Ambient temperature; | |
With pyridine at 25℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With pyridine for 5h; Ambient temperature; | |
87% | In pyridine at 50℃; for 14h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine Yield given; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 3.5h; Inert atmosphere; | |
With dmap; triethylamine In dichloromethane; ethyl acetate 1.) 0 deg C, 30 min, 2.) RT, 15 h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine In tetrahydrofuran for 2h; Ambient temperature; | ||
With pyridine In tetrahydrofuran for 18h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrachloromethane for 576h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59.4% | With triethylamine; In dimethyl sulfoxide; at 20℃; | Ganciclovir (2) (510 mg, 2 mmol) was dissolved in DMSO (3 mL)and triethylamine (1.67 mL, 12 mmol) was added to it followed bymonomethoxytrityl chloride (1.85 g, 6 mmol). After stirring the reactionmixture at room temperature overnight brine (40 mL) was added toit. A solid that precipitated was collected on Celite 521 (Aldrich) byfiltration. The filter cake was washed with water (30 mL) and stirredwith CH2Cl2 (50 mL). The CH2Cl2 solution was filtered, dried over anhydrousNa2SO4 and evaporated at reduced pressure to give the crudeproduct. The crude product was purified by flash chromatography onsilica gel (80 g), eluted with CH2Cl2/MeOH gradient (0-5% MeOH), togive the product 8 as a beige solid (950 mg, 59.4% yield). 1H NMR(600 MHz, DMSO-d6): delta 2.59 (d, J = 9.1 Hz, 1H, CH2OMMTr), 2.93(dd, J= 9.1 and 6.6 Hz, 1H, CH2OMMTr), 2.91 and 3.06 (m, 2H,CH2OH), 3.41 (m, 1H, CH), 3.62 (s, 3H, OCH3 of N-MMTr), 3.76 (s, 3H,OCH3 of O-MMTr), 4.49 (t, J =5.3 Hz, 1H, OH), 4.95 and 5.06 (d,J = 11.2 Hz, 2H, NCH2O), 6.73 (d, J = 8.9 Hz, 2H, H-3?/H-5? ofCH3OPh-C-N), 6.89 (d, J = 8.9 Hz, 2H, H-3?/H-5? of CH3OPh-C-O),7.03-7.31 (m, 24H, Ar-H), 7.71 (s, 1H, N2-H), 7.80 (s, 1H, H-8), 10.73(s, 1H, N1-H); 13C NMR (150 MHz, DMSO-d6): delta 54.88 (OCH3 of NMMTr),54.98 (OCH3 of O-MMTr), 60.88 (CH2OMMTr), 63.28(CH2OH), 69.65 (tC of N-MMTr), 70.62 (NCH2), 78.90 (CH), 85.04 (tCof O-MMTr), 112.79 (C3?/C5? of CH3OPh-C-N), 113.05 (C3?/C5? ofCH3OPh-C-O), 116.68 (C5), 126.33, 126.61, 126.34, 127.47, 127.50,127.65, 127.67, 127.87, 127.97, 128.39, 128.44 (Ph-C), 130.21 (C2?/C6? of CH3OPh-C-N and CH3OPh-C-O), 135.20 (C1? of CH3OPh-C-O),136.68 (C1? of CH3OPh-C-N), 137.88 (C8), 144.16 and 144.41 (C1? ofPh-C-O), 144.78 and 144.83 (C1? of Ph-C-N), 150.97 (C2), 156.70 (C6),157.62 (C4? of CH3OPh-C-N), 158.08 (C4? of CH3OPh-C-O); HRMSCalcd for C49H46N5O6: 799.3370; Found: 800.3448 (M + H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87.7% | With triethylamine In tetrahydrofuran; dichloromethane for 43h; Ambient temperature; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89.3% | With pyridine for 18h; Ambient temperature; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With pyridine at 50℃; | |
79% | With pyridine for 22h; Ambient temperature; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine In tetrahydrofuran at 25℃; for 14h; | ||
With dmap; triethylamine In dichloromethane at 20℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With pyridine for 20h; | |
85% | With pyridine for 20h; Ambient temperature; | |
85% | With pyridine |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With pyridine; triethylamine; at 40℃; | Prepared by a method known in the art. A mixture of cytosin (20 g, 0. 18 mol) and monomethoxytrityl chloride (70 g, 0. 23 mol) was suspended in dry pyridine (750 mL). Triethylamine (25 mL, 0. 18 mol) was added to the mixture in one portion. The mixture was heated gently (40 C) and stirred overnight. Water (150 mL) was added to the stirred suspension, followed by dichloromethane (150 mL). The resulting precipitate was collected by vacuum filtration (8 g). The filtrate was evaporated and the residue was triturated with a mixture of water and dichloromethane. A second crop of product (35 g) was obtained. The total yield was 43 g (62%), m. p. 264-265C decomp., m. p. lit. 255-258 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With pyridine; | 5'-O-(4-Methoxytrityl)<strong>[36791-04-5]ribavirin</strong> (8). <strong>[36791-04-5]Ribavirin</strong> (compound 7; 8.31 mmol; 2.03 g) was dried by repeated coevaporations from dry pyridine and dissolved in the same solvent (15 mL). 4-Methoxytrityl chloride (8.32 mmol; 2.57 g) was added and the reaction was allowed to proceed overnight. The mixture was evaporated to dryness and the residue was equilibrated between chloroform and water. The organic phase was dried on Na2SO4. The crude product was purified by silica gel chromatography using gradient elution from 5 to 10% MeOH in DCM. Yield 68%. 1H NMR (CDCl3) delta 8.45 (s, 1H, H5), 7.39-741 (m, 4H, MMTr), 7.27-7.30 (m, 2H, MMTr), 7.21-7.24 (m, 4H, MMTr), 7.15-7.18 (m, 2H, MMTr), 7.09 (br s, 1H, NH), 6.78-6.80 (m, 2H, MMTr), 6.43 (br s, 1H, NH), 5.98 (d, J=3.5 Hz, 1H, H1'), 4.79 (dd, J=3.5 and 4.7 Hz, 1H, H2'), 4.48 (dd, J=4.7 and 5.1, 1H, H3'), 4.31 (m, 1H, H4'), 3.73 (s, 3H, MeO-MMTr), 3.43 (dd, J=10.6 and 2.8 Hz; 1H, H5'), 3.31 (dd, 10.6 and 4.3 Hz, 1H, H5"). 13C NMR (CDCl3) delta 161.3 (C=O), 158.6 (MMTr), 156.5 (C3), 144.6 (MMTr), 144.0 (C5), 136.3 (MMTr), 130.4 (MMTr), 128.3 (MMTr), 127.9 (MMTr), 127.0 (MMTr), 113.2 (MMTr), 92.9 (C1'), 86.7 (MMTr), 84.6 (C4'), 75.3 (C2'), 71.1 (C3'), 63.5 (C5'), 55.2 (MMTr). |
68% | With pyridine; | <strong>[36791-04-5]Ribavirin</strong> (compound 8a; 8.31 mmol; 2.03 g) was dried by repeated coevaporations from dry pyridine and dissolved in the same solvent (15 mL). 4-Methoxytrityl chloride (8.32 mmol; 2.57 g) was added and the reaction was allowed to proceed overnight. The mixture was evaporated to dryness and the residue was equilibrated between chloroform and water. The organic phase was dried on Na2SO4. The crude product was purified by silica gel chromatography using gradient elution from 5 to 10% MeOH in DCM. Yield 68%. 1H NMR (CDCl3) delta 8.45 (s, 1H, H5), 7.39-741 (m, 4H, MMTr), 7.27-7.30 (m, 2H, MMTr), 7.21-7.24 (m, 4H, MMTr), 7.15-7.18 (m, 2H, MMTr), 7.09 (br s, 1H, NH), 6.78-6.80 (m, 2H, MMTr), 6.43 (br s, 1H, NH), 5.98 (d, J=3.5 Hz, 1H, H1'), 4.79 (dd, J=3.5 and 4.7 Hz, 1H, H2'), 4.48 (dd, J=4.7 and 5.1, 1H, H3'), 4.31 (m, 1H, H4'), 3.73 (s, 3H, MeO-MMTr), 3.43 (dd, J=10.6 and 2.8 Hz; 1H, H5'), 3.31 (dd, 10.6 and 4.3 Hz, 1H, H5). 13C NMR (CDCl3) delta 161.3 (CO), 158.6 (MMTr), 156.5 (C3), 144.6 (MMTr), 144.0 (C5), 136.3 (MMTr), 130.4 (MMTr), 128.3 (MMTr), 127.9 (MMTr), 127.0 (MMTr), 113.2 (MMTr), 92.9 (C1'), 86.7 (MMTr), 84.6 (C4'), 75.3 (C2'), 71.1 (C3'), 63.5 (C5'), 55.2 (MMTr). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multistep reaction. Title compound not separated from byproducts; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With triethylamine In pyridine for 3.5h; Ambient temperature; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at 0 - 20℃; for 23h;ice-sodium chloride bath; | [0086] 20 ml, (200 mmol) of (2-hydroxyethyl) ethylene diamine (HEED) (3) and (30 ml, 0.2 mmol) of triethylamine (ITA) were dissolved in 100 ml of dichloromethane. The mixture was cooled in ice-sodium chloride bath to 0 C. While vigorously stirred, (15 g, 48.57 mmol) of MT-Cl in 50 ml CH2Cl2(DCM) were added drop wisely over one hour. The mixture was stirred for more 2 hrs at 0 C. then allowed to elevate to room temperature and stirred for further 20 hrs. To eliminate the excess of the BEED the organic layer was washed with 3×100 ml water. The organic phase was dried over anhydrous Na2SO4, the solid was filtered off and the solvents were evaporated to dryness. The yellowish oil was used with no further purification. [0087] 1H-NMR (CDCl3) delta: [0088] 7.49-7.15(m, 12H, MMT); 7.14-6.79(dd, 2H, MMT); 3.76(s, 3H, -OCH3); 3.61-3.58(t, 2H, HO-CH2-); 2.75-2.68(m, 4H, -(CH2)2-NH) 2.3-2.26 (t, 2H, -CH2-NH-MMT); [0089] The above product was dissolved in 100 ml of dichloromethane and (7 ml, 50 mmol) of triethylamine was added. The mixture was cooled to 0 C. and (8.57 ml, 58 mmol) of tert-butyl bromoacetate in 20 ml CH2Cl2 were added drop wisely. The mixture was stirred at r.t. for 24 hrs. The organic phase was washed with 3×100 ml water and dried over Na2SO4. After filtering off the solid the solvents were evaporated to dryness under reduced pressure. The yellowish viscous product was purified on silica gel column chromatography. The desired product was obtained as colorless viscous oil. Eluting solvents: 30-50% ether in petroleum ether. [0090] 1H-NMR (CDCl3): [0091] 7.48-7.45 (dd, J1-3=8.4, J1-4=1.2 Hz, 2H, MMT); 7.38-7.36(d, J=7.8 Hz, 2H, MMD, 7.30-7.14(m, 8H, MMT); 6.85-6.79(dd, JI-3=15.3 Hz, J1-4=2.1 Hz, 2H. NW); 3.77(s, 3H, H3CO-); 3.59-3.56(t, J=5.1 Hz, 2H, HO-CH2-); 3.13(s, 2H, N-CH2-COO-); 2.79-2.71(m, 4H, N(CH2)2-); 2.22-2.18(t, J=6 Hz, 2H, -CH2-NH-MMT); 1.41(s, 9H, tert-But). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | The compound was synthesized according to literature procedure[51,52]. Acyclovir (1.0 g, 4.44 mmol, 1.0 equiv.) was suspended inanhydrous pyridine (25 mL) and the suspension was cooled to 0 C.Chlorotrimethylsilane (3.4 mL, 26.6 mmol, 6.0 equiv.) were addeddropwise and the suspension was left to stir for 15 min. Then, DMAP(0.1 g, 0.9 mmol, 0.2 equiv.) and 4-methoxytrityl chloride (1.65 g,5.3 mmol, 1.2 equiv.) were added in one scoop. The reaction was left to stir at r.t. overnight. The reaction mixture is cooled to 0C, water(10 mL) and a 25% NH4OH solution (10 mL) is added and the mixtureis left to stir for 30 min. The crude mixture is filtered, and the solvent isremoved under reduced pressure. The crude product is purified viacolumn chromatography over silica gel with CH2Cl2:MeOH (100:00 to100:07) and isolated as colorless solid (1.3 g, 2.6 mmol, 59%). Thespectral data matches the reported. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With pyridine for 20h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine In dichloromethane; N,N-dimethyl-formamide at 20℃; for 1h; | ||
With trifluoroacetic acid for 0.5h; | I; I-6 Mmt-chloride (1 eq) and mercaptopropionic acid (1.1 eq) were taken up in TFA and incubated for 30 min. TFA was removed under nitrogen flow. The product was dissolved in pyridine, diluted in water, acidified by acetic acid and extracted in ether. The ether phase was separated and dried over Na2SO4. Solvent was removed and product 8 was purified by RP-HPLC. Compound 8 and DMAP (2.5 eq) were dissolved in dry DCM and 2 eq of EDC HCl were added at 0 °C. The solution was stirred for 14 hat RT and washed with sodium acetate buffer (0.25 M, pH 4.5). The organic phase was dried over Na2SO4, concentrated and compound 9 was purified by silica gel column chromatography using heptane/acetic acid ester (1/1) as mobile phase. MS (MW calculated) 9: 479 g/mol (479.7 g/mol) Compound 9, 4-hydroxy-3-methoxy benzylalcohol (7 eq) and DMAP (7 eq) were refluxed in DCM for 2 h under nitrogen atmosphere. After neutralization with acetic acid, the solution was concentrated and compound 10 was purified by RP-HPLC: MS [M+Na]+ (MW+Na calculated) 10: 537 g/mol (537,6 g/mol) Compound 10, chloroformic acid-4-nitrophenyl ester (10 eq), and DIEA (20 eq) were stirred in dry dioxane for 3 h at 40 °C under nitrogen atmosphere. After addition of acetic acid (25 eq) the mixture was concentrated and compound 11 purified by RP-HPLC: MS [M+Na]+ (MW+Na calculated) 11: 702 g/mol (702.7 g/mol) | |
With trifluoroacetic acid for 0.5h; | Mmt-chloride (1 eq) and mercaptopropionic acid (1.1 eq) were dissolved in TFA and incubated for 30 min. The solvent was removed under reduced pressure. The product was dissolved in pyridine, diluted in water, acidified by acetic acid and extracted in ether. The ether phase was separated and dried over Na2SO4. Solvent was removed under reduced pressure and product 2 was purified by RP-HPLC. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine In dichloromethane; N,N-dimethyl-formamide at 20℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
400 mg | Stage #1: L-Ser-Gly With chloro-trimethyl-silane; diisopropylamine In N,N-dimethyl-formamide at 40℃; for 4h; Stage #2: mono-4-methoxytrityl chloride With diisopropylamine In N,N-dimethyl-formamide at 20℃; for 48h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With pyridine at 20℃; for 15h; | 3 Pseudouridine (0.61 g, 2.5 mmol) was dehydrated through co-boiling twice with pyridine (5 mL) which had been dried with Molecular Sieves 4A and suspended in pyridine (9.8 mL). Under stirring at room temperature, 4-methoxytrityl chloride (0.926 g, 3 mmol) was added to the suspension. The mixture was placed in a vessel closed with a ground glass stopper and stirred at room temperature for 15 hours. Water (1 mL) was added to the reaction mixture at room temperature, and the mixture was concentrated under reduced pressure. Ethyl acetate (15 mL) was added to the residue, and the mixture was washed twice with water (4 mL) and once with aqueous saturated sodium bicarbonate (4 mL). The organic layer was dried over sodium sulfate anhydrate, followed by concentration under reduced pressure. The residue was co-boiled once with ethyl acetate (7.7 mL). The residue was dissolved in ethyl acetate (15 mL) with heating. The solution was allowed to stand at 25°C for two hours, and the precipitated crystals were recovered through filtration by means of a glass filter. The crystals recovered through filtration were washed once with ethyl acetate, and co-boiled once with ethanol (10.4 mL). The residue was dissolved in ethanol (10.4 mL) with heating, and the solution was allowed to stand at 25°C for 18 hours. The precipitated crystals were recovered through filtration by means of a funnel (product of Kiriyama Glass Co.). The crystals were washed once with ethyl acetate and dried under reduced pressure (5 mmHg) at 90°C for three hours, to thereby yield 0.582 g of white crystals (first crystals) (45%). The filtrate from which the first crystals had been separated was concentrated under reduced pressure, and the residue was co-boiled once with ethanol (5 mL). The residue was dissolved in ethanol (5 mL) with heating. The solution was allowed to stand at 25°C for one day. Similar to recovery of the first crystals, second crystals were recovered through filtration, followed by drying, to thereby yield 0.169 g of white crystals (second crystals) (13%). Through powder X-ray diffractometry, the thus-yielded crystals (first crystals) exhibited characteristic peaks at the diffraction angles (2θ) of 4.60, 9.76, 12.20, 12.94, 16.60, 17.84, 18.52, 19.04, 20.66, 21.24, 21.70, and 24.60 (see Fig. 4). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N,N-dimethyl-formamide at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56.8% | With triethylamine; In dimethyl sulfoxide; at 20℃; | To a suspension of penciclovir (1) (251 mg, 0.99 mmol) in DMSO(1.5 mL) was first added triethylamine (0.84 mL, 6 mmol) and then panisyldiphenylmethylchloride (862 mg, 2.8 mmol). The reaction mixturewas stirred at room temperature overnight. This resulted in a thickbrown mixture to which brine (30 mL) was added. The solid that separatedwas collected on Celite 521 (Aldrich) by filtration. The solidwas washed with water (30 mL) and then stirred with CH2Cl2 (30 mL).The CH2Cl2 solution was filtered and dried over anhydrous Na2SO4.Evaporation of the solvent at reduced pressure gave the crude productas a yellow foam (1.32 g). The crude product was purified by flashchromatography on silica gel (40 g), eluted with CH2Cl2/MeOH gradient(0-10% MeOH), to give the product 7 (453 mg, 56.8% yield) as abeige solid. 1H NMR (600 MHz, DMSO-d6): delta 1.20 (m, 2H, CH2), 1.40(m, 1H, CH), 2.71 (dd, J = 9.2 and 6.9 Hz, 1H, CH2OMMTr), 2.80 (dd,J = 9.2 and 5.3 Hz, 1H, CH2OMMTr), 3.14 and 3.29 (m, 2H, CH2OH),3.39 (m, 2H, NCH2), 3.64 (s, 3H, OCH3 of N-MMTr), 3.73 (s, 3H, OCH3of O-MMTr), 4.36 (t, J = 4.9 Hz, 1H, OH), 6.75 (d, J= 8.9 Hz, 2H, H-3?/H-5? of CH3OPh-C-N), 6.89 (d, J =9.0 Hz, 2H, H-3?/H-5? of CH3OPh-C-O), 7.07-7.33 (m, 24H, Ar-H), 7.44 (s, 1H, H-8), 10.48 (s, 1H, N1-H);13C NMR (150 MHz, DMSO-d6): delta 28.50 (CH2), 35.30 (CH), 41.27(NCH2), 54.92 (OCH3 of N-MMTr), 55.02 (OCH3 of O-MMTr), 61.14(CH2OMMTr), 63.19 (CH2OH), 69.60 (N-tC), 85.48 (O-tC), 112.77 (C3?/C5? of CH3OPh-C-N), 113.11 (C3?/C5? of CH3OPh-C-O), 116.97 (C5),126.32, 126.73, 127.37, 127.42, 127.75, 127.89, 128.34, 128.43 (Ph-C), 129.78 (C2?/C6? of CH3OPh-C-N), 129.87 (C2?/C6? of CH3OPh-C-O), 135.41 (C1? of CH3OPh-C-O), 136.87 (C1? of CH3OPh-C-N), 137.41(C8), 144.58 (C1? of Ph-C-O), 144.74 and 144.91 (C1? of Ph-C-N),149.46 (C4), 150.36 (C2), 156.56 (C6), 157.62 (C4? of CH3OPh-C-N),158.10 (C4? of CH3OPh-C-O); HRMS Calcd for C50H48N5O5 (M + H):798.3655; Found: 798.3670. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With pyridine for 2h; Heating / reflux; | 1-(4-Hydroxy-5-trityloxymethyltetrahydrofuran-2-yl)-1H-pyrimidine-2,4-dione (32) A solution of 2'-deoxyuridine (10.0 g, 43.9 mmol) and para-anisylchlorodiphenylmethane (16.3 g, 52.6 mmol) in dry pyridine (235 mL) is refluxed for 2 hours. After cooling at room temperature (rt), pyridine is evaporated under reduced pressure, then dichloromethane (400 mL) is added and the solution is washed with water (50 mL x 3), dried over MgSO4, filtered through a fritted glass funnel and concentrated under reduced pressure to afford the crude product, which is submitted to a flash silica gel column chromatography (eluent: hexanes/EtOAc: 5/5 to EtOAc/MeOH: 9/1) to give the pure protected nucleoside 32 (21.9 g, 99 %) as a white solid. The physico-chemical data of the compound are fully related with those previously published. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
14.4 g (73%) | With triethanolamine; N-ethyl-N,N-diisopropylamine; | 1b N-Fluorenylmethoxycarbonyl-2-amino-1-(4-methoxytriphenylmethoxy)ethane 10 g (35.3 mmol) of N-fluorenylmethoxycarbonyl-2-aminoethanol (from Example 1a), dissolved in 100 ml of absol. N,N-dimethylformamide (DMF), were treated at 0 C. with 5.93 g (45.93 mmol) of diisopropylethylamine (DIPEA) and 10.91 g (35.3 mmol) of 4-methoxytriphenylmethyl chloride and stirred first at 0 C. for 1 h, then at room temperature for 1 h. The reaction mixture was evaporated and partitioned between DCM and a saturated aqueous NaHCO3 solution. The organic phase was washed with H2 O and dried over Na2 SO4, and the solvent was evaporated in vacuo. To purify the product, it was chromatographed on silica gel (first n-heptane/ethyl acetate (EA)/triethylamine (TEA) 70:29:1; then EA/TEA 99:1). The yield was 14.4 g (73%). MS (FAB): 562.3 (M+Li)+; 1 H-NMR (200 MHz, DMSO, TMS): delta=2.95 (t, 2H, CH2 O-MMTr); 3.21 (dd, 2H, N-CH2); 3.75 (s, 3H, OCH3); 4.25 (m, 3H, Ar--CH--CH2); 4.61 (t, 1H, OH); 6.80-7.96 (m, 23H, Ar--H, NH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; pyridine; chloroform; toluene; Petroleum ether | 17 1-(Hexadecyloxy)-3-((4-methoxyphenyl)diphenylmethoxy)-2-propanol EXAMPLE 17 1-(Hexadecyloxy)-3-((4-methoxyphenyl)diphenylmethoxy)-2-propanol To a mixture of 84.5 g of 3-(hexadecyloxy)-1,2-propanediol in 265 ml of dry pyridine, stirred in an ice bath under nitrogen, was added in a steady stream a solution of 115.5 g of 4-methoxytrityl chloride in 150 ml of dry tetrahydrofuran. This mixture was stirred in the ice bath for 30 minutes, then at room temperature for 2 hours, then refrigerated at 0° C. overnight. The mixture was concentrated to remove the volatile solvents. The residual solution was dissolved in 400 ml of chloroform, washed twice with 200 ml portions of 10% aqueous sodium bicarbonate and twice with 200 ml portions of water, dried and evaporated. The residue was evaporated twice from toluene, taken up in ether, chilled and filtered. The filtrate was taken to dryness, giving a syrup. A 30 g portion of this syrup was dissolved in petroleum ether and chromatographed on a silica gel column eluding with 20% ether in petroleum ether. The product fractions 6-20 (200 ml each) were combined and evaporated, giving 21 g of the desired compound. | |
In tetrahydrofuran; pyridine; chloroform; toluene; Petroleum ether | 17 1-(Hexadecyloxy)-3-[(4-methoxyphenyl)diphenylmethoxy]-2-propanol EXAMPLE 17 1-(Hexadecyloxy)-3-[(4-methoxyphenyl)diphenylmethoxy]-2-propanol To a mixture of 84.5 g of 3-(hexadecyloxy)-1,2-propanediol in 265 ml of dry pyridine, stirred in an ice bath under nitrogen, was added in a steady stream a solution of 115.5 g of 4-methoxytrityl chloride in 150 ml of dry tetrahydrofuran. This mixture was stirred in the ice bath for 30 minutes, then at room temperature for 2 hours, then refrigerated at 0° C. overnight. The mixture was concentrated to remove the volatile solvents. The residual solution was dissolved in 400 ml of chloroform, washed twice with 200 ml portions of 10% aqueous sodium bicarbonate and twice with 200 ml portions of water, dried and evaporated. The residue was evaporated twice from toluene, taken up in ether, chilled and filtered. The filtrate was taken to dryness, giving a syrup. A 30 g portion of this syrup was dissolved in petroleum ether and chromatographed on a silica gel column eluding with 20% ether in petroleum ether. The product fractions 6-20 (200 ml each) were combined and evaporated, giving 21 g of the desired compound. |
Yield | Reaction Conditions | Operation in experiment |
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To a stirred suspension of Fmoc-Lys (5.1067 g, 13.8618 mmol, 1.0 eq) in methylene chloride (75 ml) at room temperature was added trimethylsilyl chloride (3.8 ml, 29.7312 mmol, 2.14 eq). The mixture was refluxed at 50 C. for 1 hr and the appearance of the solid in the reaction mixture changed. After being cooled in an ice bath, DIEA (7.5 ml, 43.0561 mmol, 3.11 eq) was added, the mixture became homogeneous, and followed by p-anisyldiphenylmethyl chloride (4.4955 g, 14.5580 mmol, 1.05 eq). The orange-red solution was stirred at room temperature overnight (20 hrs). After removal of solvent, the residue was partitioned between ethyl acetate (200 ml) and pH5 buffer (0.05M phthalic acid, adjusted with 10N KOH to pH 5.0). The organic phase was washed with more pH5 buffer (50 ml×2), water (50 ml×1), brine (50 ml×2), dried over magnesium sulfate. After removal of solvent and being dried in vacuo, 9.7336 g of pale yellow foam was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With pyridine; at 20℃; | 3-(4-Methoxytrityloxymethyl)benzonitrile (43a). <strong>[874-97-5]3-(hydroxymethyl)benzonitrile</strong> (2 g, 15 mmol) was dissolved in dry pyridine (120 ml). 4- methoxytrityl chloride (6 g, 19.5 mmol) was added and the mixture was stirred over night at room temperature (r.t.). The reaction was quenched with ethanol (EtOH), evaporated on rotavapor and the residue partitioned between dichloromethane (DCM) and saturated aqueous sodium bicarbonate. The organic phase was dried by sodium sulfate and evaporated. Silica gel column chromatography (gradient 30%DCM / hexane - DCM) gave the title compound (5.98 g,98%).1H-NMR (400MHz, CDCl3): delta 7.70-7.25 (m, 16H), 6.85 (d, 2H), 4.23 (s, 2H), 3.81 (s, 3H). |
98% | With pyridine; at 20℃; | 3-(4-Methoxytrityloxymethyl)benzonitrile (IQa); <n="50"/><strong>[874-97-5]3-(hydroxymethyl)benzonitrile</strong> (2 g, 15 mmol) was dissolved in dry pyridine (120 ml). 4- methoxytrityl chloride (6 g, 19.5 mmol) was added and the mixture was stirred over night at room temperature (r.t.). The reaction was quenched with ethanol (EtOH), evaporated on rotavapor and the residue partitioned between dichloromethane (DCM) and saturated aqueous sodium bicarbonate. The organic phase was dried by sodium sulfate and evaporated. Silica gel column chromatography (gradient 30%DCM / hexane - DCM) gave the title compound (5.98 g, 98%). 1H-NMR (400MHz, CDCl3): delta 7.70-7.25 (m, 16H), 6.85 (d, 2H), 4.23 (s, 2H), 3.81 (s, 3H). |
98% | With pyridine; at 20℃; | Step e <n="49"/>3-(4-MethoxytrityloxymethvObenzonitrile (Ie")3-(Hydroxymethyl)benzonitrile (2 g, 15 mmol) was dissolved in dry pyridine (120 ml). 4- methoxytrityl chloride (6 g, 19.5 mmol) was added and the mixture was stirred over night at room temperature (r.t.). The reaction was quenched with ethanol (EtOH), evaporated on rotavapor and the residue partitioned between dichloromethane (DCM) and saturated aqueous sodium bicarbonate. The organic phase was dried by sodium sulphate and evaporated. Silica gel column chromatography (gradient 30%DCM / hexane - DCM) gave the title compound (5.98 g,98%).1H-NMR (400MHz, CDCl3): delta 7.70-7.25 (m, 16H), 6.85 (d, 2H), 4.23 (s, 2H), 3.81 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; triethylamine at 20℃; for 0.75h; | 2 Example 2Synthesis of Intermediate Compound ssMeO-am (Compound 11) (FIG. 2)(S)-3-methoxy-1-(monomethoxytrityl)aminopropane-2-ol (compound 9)Under an argon atmosphere, 0.90 ml (10.0 mmol) of (R)-(-)-glycidylmethylether (compound 8) was dissolved in 40 ml of dimethylformamide. 1.95 g (3.0 equivalent) of sodium azide and 2.14 g (4.0 equivalent) of ammonium chloride were added to the solution, followed by 3 hours of heating and agitation at 80° C. The reaction solution was cooled to room temperature and then 230 ml of ethyl acetate was added to the solution. The resultant was washed 4 times with 60 ml of water, and then washed once with 60 ml of saturated saline. The organic layer was dried using sodium sulfate. The solution was concentrated under reduced pressure. The thus obtained oily substance was dissolved in 100 ml of ethanol. 600 mg of palladium on carbon (10%) was added to the solution, followed by 13 hours of agitation at room temperature under a hydrogen atmosphere at normal pressures. The palladium catalyst was removed by celite filtration and then the solution was concentrated under reduced pressure. The resultant was further subjected twice to azeotropy with 15 ml of pyridine. Under an argon atmosphere, the thus obtained oily substance was dissolved in 100 ml of pyridine. 4.18 ml (3.0 equivalent) of triethylamine and 3.70 g (1.2 equivalent) of monomethoxytrityl chloride were added to the solution, followed by 45 minutes of agitation at room temperature. 10 ml of ethanol was added to the solution to stop the reaction. The solvent was distilled off under reduced pressure. The residue was dissolved in 240 ml of ethyl acetate. The resultant was washed once with 80 ml of water, washed once with 80 ml of saturated sodium hydrogencarbonate aqueous solution, washed once with 80 ml of water, and then washed once with 80 ml of saturated saline. The organic layer was dried using sodium sulfate. The solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate-hexane). Thus, 1.97 g (yield 52%) of the subject compound (compound 9) was obtained as a pale yellow syrupy substance.1H NMR (270 MHz, DMSO-d6) δ: 7.41-7.38 (m, 4H), 7.30-7.25 (m, 6H), 7.19-7.14 (m, 2H), 6.87-6.83 (m, 2H), 4.78 (d, 1H, J=5.0 Hz), 3.75 (ddddd, 1H, J=4.6, 5.0, 5.3, 5.8, 6.6 Hz), 3.71 (s, 3H), 3.33 (dd, 1H, J=5.3, 9.6 Hz), 3.28 (dd, 1H, J=5.8, 9.6 Hz), 3.23 (s, 3H), 2.42 (dd, 1H, J=6.7, 8.9 Hz), 2.14 (ddd, 1H, J=4.6, 8.9, 11.5 Hz), 1.96 (ddd, 1H, J=6.7, 6.9, 11.5 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 72% 2: 19% | With pyridine; silver nitrate In tetrahydrofuran at 20℃; for 12h; | Uridine (1.0 g, 4.09 mmol), suspended in anhydrous THF (120 mL), was treated with pyridine (3.3 mL, 40.9 mmol), AgNO3 (1.95 g, 11.5 mmol) and MMTrCl (3.55 g, 11.5 mmol). The mixture was stirred at room temperature for 12 h, then the suspension was filtered and concentrated under reduced pressure. The crude was then diluted with CH2Cl2, transferred into a separatory funnel and washed twice with an aq. solution of NaHCO3 5% p.p. The collected organic phases were dried over anhydrous Na2SO4, concentrated under reduced pressure and purified on a silica gel column, eluted with n-hexane/AcOEt (1:1, v/v), added with 1% TEA. Nucleoside 3 was recovered in 72% yield (2.33 g, 2.95 mmol), while the 5',3'-bis-monomethoxytritylated regioisomer was obtained in 19% yield (614 mg, 0.778 mmol). Nucleoside 3: white, amorphous solid; Rf = 0.8 [n-hexane/AcOEt (2:3, v/v)]. 1H NMR (C6D6, 200 MHz): δ 10.86 (1H, bs, N-H); 7.70 (1H, d, J = 8.2 Hz, H-6); 7.64-6.64 (28H, overlapped signals, aromatic protons of MMTr); 6.61 (1H, d, J = 7.2 Hz, H-1'); 5.22 (1H, d, J = 8.4 Hz, H-5); 4.73-4.67 (1H, dd, J = 7.2 and 4.6 Hz, H-2'); 4.03 (1H, bs, H-3'); 3.33 and 3.29 (3H each, s's, 2x OCH3); 3.13-2.92 (3H, overlapped signals, H-5'a, H-5'b and H-4'). 13C NMR (C6D6, 50 MHz): δ 163.3 (C-4); 159.7, 159.4, 149.5, 144.9, 144.3, 143.9, 135.9, 135.2, 131.0, 130.6, 128.7, 128.5, 128.2, 128.0, 127.5, 123.6, 114.1, 113.6 (aromatic carbons of MMTr); 151.8 (C-2); 140.8 (C-6); 103.2 (C-5); 88.0 and 87.8 (quaternary carbons of MMTr); 87.1 (C-1'); 84.7 (C-4'); 78.2 (C-3'); 71.3 (C-2'); 64.7 (C-5'); 54.9 (OCH3). ESI-MS (positive ions): for C49H44N2O8, calcd. 788.3098; found m/z: 811.97 [M + Na+]; 827.84 [M + K+]. HRMS (MALDI-TOF): calcd. forC49H44N2O8Na = 811.2995; found m/z: 811.3021 [M + Na+]. 5’,3’-di(monomethoxytrityl)uridine: white, amorphous solid; Rf = 0.6 [n-hexane/AcOEt (2:3, v/v)]. 1H-NMR (C6D6, 200 MHz): δ 7.78-6.69 (29H, overlapped signals, H-6 and aromatic protons of MMTr); 6.35 (1H, d, J = 4.6 Hz, H-1′); 5.27 (1H, d, J = 8.6 Hz, H-5); 5.02 (1H, d, J = 7.2 Hz, OH-2′, exchangeable proton); 4.60 (1H, dd, J = 7.2 and 4.6 Hz, H-2′); 4.14 (2H, bs, overlapped H-3′ and H-4′); 3.52-3.46 (1H, m, H-5′a); 3.35 and 3.33 (3H each, s's, 2x OCH3); 3.18-3.12 (1H, m, H-5′b). 13C-NMR (C6D6, 50 MHz): δ 163.3 (C-4); 159.5, 145.2, 144.5, 135.8, 135.4, 131.4, 130.9, 129.3, 129.0, 128.2, 128.0, 127.0, 113.6 (aromatic carbons of MMTr); 151.4 (C-2); 140.2 (C-6); 102.7 (C-5); 90.2 (C-1′); 88.2 and 87.7 (quaternary carbons of MMTr); 83.3 (C-4′); 75.2 (C-3′); 73.8 (C-2′); 63.2 (C-5′); 54.8 (OCH3). ESI-MS (positive ions): for C49H44N2O8, calcd. 788.3098; found m/z: 811.94 [M + Na+]; 827.79 [M + K+]. |
Yield | Reaction Conditions | Operation in experiment |
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92% | With pyridine; at 50℃; for 20h;Inert atmosphere; | 2-C-Methyluridine (0.79 g; 3.05 mmol) wasdissolved in dry pyridine (20 mL) under argon. 4-Methoxytrityl chloride (1.03 g; 3.36 mmol)was added and the mixture was stirred at 50 C for 20 hours. The reaction was quenched withsaturated aq NaHCO3 (50 mL) and subjected to DCM (3 × 100 mL) workup. The organic phasewas dried over Na2SO4 and evaporated to dryness. The residue was purified by Silica gelchromatography using DCM containing 5% MeOH as eluent. Compound 7 was obtained as solidin 92% yield (1.50 g). 1H-NMR (500 MHz, CDCl3) : 8.16 (d, 1H, J = 8.0 Hz, H6), 7.41 (m, 4H,MMTr), 7.26 (m, 6H, MMTr), 7.19 (m, 2H, MMTr), 6.86 (d, 2H, J = 9.0 Hz, MMTr), 6.09 (s,1H, H1), 5.23 (d, 1H, J = 8.0 Hz, H5), 4.05-4.17 (m, 2H, H3&H4), 3.81-3.84 (m, 4H, MeOMMTr& H5), 3.61 (br s, 2H, 2-&3-OH); 3.23 (d, 1H, J =12.5 Hz , H5), 1.36 (s, 3H, CH3).13C-NMR (100 MHz, CD3OD) : 164.64 (C4), 158.76 (MMTr), 151.02 (C2), 144.52 (MMTr),141.12 (C6), 135.35 (MMTr), 130.18, 128.10, 127.34, 126.46 and 112.64 (MMTr), 102.94 (C5),91.67 (C1), 87.66 (MMTr), 82.44 (C2), 78.66 (C4), 71.94 (C3), 59.05 (C5), 54.32 (OMe),18.80 (Me). HR-ESI-MS: [M+Na]+ obsd. 553.1921, calcd. 553.1945. |
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 |
---|---|---|
99% | In diethyl ether; dichloromethane; for 2h; | A solution of p-monomethoxytrityl chloride (1.54 g, 5 mmol) in DCM (10 mL) was slowlyadded with stirring to a solution of 3-(methylamino)propylamine (4.4 g, 50 mmol) in DCM(10 mL). After 2 h diethyl ether (166 mL) was added. Brine (100 mL) was mixed with NaOH(4 M, 80 jiL) and the reaction washed with this mixture (3x33 mL). The organic layer waswashed with brine (30 mL), dried with MgSO4 and concentrated in vacuo. Yield (14a): 1.79 g (4.95 mmol, 99 %). |
Yield | Reaction Conditions | Operation in experiment |
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63% | With pyridine; In N,N-dimethyl-formamide; at 20.0℃; for 48.0h; | The deprotected compound (4.8 g, 15.4 mmol) was dried by evaporation of added dry DMF (2×), suspended in a 1:1 mixture of DMF and Py (150 mL) whereupon monomethoxytrityl chloride was added (1.1 eq, 16.9 mmol, 5.2 g). The reaction was left stirring at room temperature for 48 h. Water was added to the reaction mixture and the product was extracted with dichloromethane. The organic layer was separated, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. DMF was removed by co-evaporation with toluene, and finally with dichloromethane. The product 5?-monometoxytrityl <strong>[2140-67-2]N,N-dimethylguanosine</strong> was purified on column chromatography using a linear gradient of MeOH in dichloromethane (0-20%). Yield 5.6 g, 63%. 1H NMR (CDCl3/CD3OD) delta 2.99 (6H, s, NMe2), 3.28 (2H, m, 5?-CH2), 3.70 (6H, s, OMe×2), 4.17 (1H, q, J=4.1 Hz, H4?), 4.28 (1H, t, J=5.3 Hz, H3?), 4.59 (1H, t, J=4.9 Hz, H2?), 5.79 (1H, d, J=5.4 Hz, H1?), 7.11-7.31 (14H, m, MMTr), 7.6 (1H, s, H8), 13C NMR delta 46.2 (NMe2), 64.0 (OMe), 72.2 (5?-CH2), 79.1 (C3?), 82.2 (C2?), 92.1 (C4?), 95.5 (C1?), 120.0, 127.0, 128.3, 130.4, 144 (C8), 210.0, 227.0, 229.0. MS (ES-TOF) m/z calculated: 582.24. found: 582.12. |
Yield | Reaction Conditions | Operation in experiment |
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84% | In N,N-dimethyl-formamide; at 20℃; for 1h; | Preparation 1885-bromo- 1 -[(4-methoxyphenyl) (diphenyl)methyll- 1 H-im idazole (Chloro(4-methoxyphenyl)methylene)dibenzene (24 g, 78 mmol) was added portion-wise to a solution of <strong>[2302-25-2]4-bromo-1 H-imidazole</strong> (10 g, 68 mmol) in DMF (100 mL) and the reaction was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (3 x 400 mL),extracted with dichloromethane (400 mL), dried over MgSO4 and concentrated in vacuo. Theresidue was triturated with mixture of TBDME and heptanes (1:4) to afford the title compound asoff white solid (24.04 g, 84%).1H NMR (400 MHz, DMSO-d6): O ppm 3.75 (5, 3H), 6.94-7.00(m, 5H), 7.06-7.08 (m, 4H), 7.35-7.42 (m, 7H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With triethylamine In N,N-dimethyl-formamide at 20℃; for 2h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
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64% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; N,N-dimethyl-formamide; at 20℃; for 2h; | <strong>[69839-68-5]16-Mercaptohexadecanoic acid</strong> (FA-SH, 3) (366 mg, 1.27 mmol) and Mmt-Cl (392 mg, 1 eq) was dissolved in DCM-DMF (1:1, 6 mL). Diisopropylethylamine (DIPEA, 0.5 mL, 2.3 eq) was added to the mixture. Stirred at RT for 2 h. TLC (1:1 heptane-EtOAc) then showed full conversion. Rf (Mmt-Cl) = 0.70; Rf (4) = 0.56. The reaction mixture was evaporated, redissolved in CHCl3 and purified by flash chromatography (eluting initially with hexane-EtOAc 4:1,later 1:1). Product containing fractions were identified by TLC, pooled and evaporated to dryness. Yield 458 mg (64%) of a white wax. 1H NMR (CDCl3, selected signals in ppm): 7.40 (d, 4H, Mmt), 7.31(d, 2H, Mmt), 7.25 (t, 4H, Mmt), 7.18 (t, 2H, Mmt), 6.80 (d, 2H, MmtCH next to -OMe), 3.77 (s, 3H, -OMe), 2.34 (t, 2H, -CH2COOH), 2.14(t, 2H, -CH2S-), 1.66-1.58 (m, 2H, -CH2CH2COOH). 13C NMR (CDCl3, selected signals in ppm): 180.4 (-COOH), 113.1 (Mmt CH next to -OMe), 65.9 (Mmt quaternary C), 55.2 (-OMe), 34.1 (-CH2COOH), 32.1 (-SCH2-), 24.7 (-CH2CH2COOH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With pyridine at 100℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
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With pyridine; at 20℃;Inert atmosphere; | Commercial 2?-deoxy-2?-difluorouridine (140mg) was dissolved in dry pyridine (2.5mL) undernitrogen and 4-methoxytrityl chloride (246mg, 1.5 eq.) added to the solution. The resulting mixturewas stirred overnight at rt. LC-MS showed complete conversion into the 5?-MMTr protected intermediate. To the mixture was then added acetic anhydride (60L, 1.2 eq.) and the reaction stirredat rt for 2h. LC-MS showed complete conversion into the 5?-MMTr-3?-Ac protected intermediate andthe mixture was quenched by addition of methanol. Solvents were removed by evaporation and theresidue partionated between DCM (10mL) and saturated sodium bicarbonate solution (10mL). Thephases were separated and the water layer extracted with DCM (2x10mL). The combined organiclayers were dried over sodium sulphate, filtered and concentrated to dryness. The crude residue wastaken into 80% acetic acid (30mL) and heated at 45C for 5h. The solution was then concentrated todryness and the residue purified by chromatography on silica gel using DCM/EtOH: 100/0, 98/2, 96/4to yield the desired (2R,3R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4,4-difluoro-2-(hydroxymethyl)tetrahydrofuran-3-yl acetate (68mg, 42%). |
Yield | Reaction Conditions | Operation in experiment |
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343 mg; 84 mg | To a stirred solution of <strong>[69-33-0]tubercidin</strong> (5.0 g, 18.7 mmol) in a mixture of pyridine (7.5 mL) and DMF (18.5 mL) was added silver nitrate (6.36 g, 38.8 mmol). This mixture was stirred at room temperature for 2 h. It was cooled in an ice bath and THF (37.4 mL) and tert-butyldimethylsilyl chloride (5.6 g, 37 mmol) was added and the mixture was stirred at room temperature for 2 h. The mixture was then filtered through a pad of celite and washed with THF. The filtrate and washings were diluted with ether containing a small amount of chloroform. The organic layer was washed successively with sodium bicarbonate and water (3×50 mL), dried over anhydrous sodium sulfate and concentrated. The pyridine was removed by coevaporation with toluene and the residue was purified by flash chromatography on silica gel using 5-7% MeOH in CH2Cl2 as the eluent; yield 3.0 g. ; To a solution of mixture of the compounds from Step A of Examples 140 and 141 (0.32 g, 0.65 mmol) in anhydrous pyridine (6 mL) was added monomethoxytrityl chloride (0.30 g, 0.98 mmol) and the reaction mixture was stirred at room temperature overnight. The mixture was then concentrated and the residue was partitioned between CH2Cl2 (70 mL) and water (20 mL). The organic layer was washed with water and brine, dried (Na2SO4) and concentrated. The residue was purified on silica gel column using 5-13% EtOAc in hexanes as the eluent. The appropriate fractions were collected and concentrated to furnish 2?,5?-bis-O-(tert-butyldimethylsilyl)- and 3?,5?-bis-O-(tert-butyldimethylsilyl) protected nucleosides as colorless foams (343 mg and 84 mg, respectively). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71.5% | With triethylamine; In dimethyl sulfoxide; at 20℃; for 12h; | Ganciclovir (2) (255 mg, 1.0 mmol) was dissolved in DMSO (3 mL)and triethylamine (1.67 mL, 12 mmol) and p-anisyldiphenylmethylchloride (1.85 g, 6.0 mmol) were added to it. The dark grey reactionmixture was stirred at room temperature for 12 h and then added withdeionized water (20 mL). The solid that separated was collected onCelite 521 by filtration and washed with water (30 mL). The solidmaterial was stirred with CH2Cl2 (100 mL) for 30 min and then filtered.The CH2Cl2 filtrate was dried over anhydrous Na2SO4 and evaporatedto give the crude product as a yellow foam. The crude product waspurified by flash chromatography on silica gel (40 g) and eluted withCH2Cl2/MeOH gradient (0-5% MeOH). The monomethoxytrityl protectedproduct 20 obtained from the column was recrystallized fromCH2Cl2 to provide a white solid (766 mg, 71.5% yield). 1H NMR(500 MHz, DMSO-d6): delta 2.67 (m, 4H, 2 X CH2OMMTr), 3.48 (s, 3H,OCH3), 3.64 (m, 1H, CH), 3.75 (s, 6H, 2 X OCH3), 4.94 (s, 2H, NCH2O),6.60 -7.30 (m, 43H, Ar-H and N2H), 7.69 (s, 1H, H-8), 7.87 (s, 1H, N1-H); 13C NMR (125 MHz, DMSO-d6): delta 55.2 (OCH3 of N-MMTr), 55.4(OCH3 of O-MMTr), 63.3 (CH2OMMTr), 69.9 (tC of N-MMTr), 70.6(NCH2), 77.6 (CH), 85.5 (tC of O-MMTr), 113.1 (C3?/C5? of CH3OPh-CN),113.5 (2 X C3?/C5? of CH3OPh-C-O), 117.0 (C5), 126.6, 127.1,127.8, 128.1, 128.2, 128.2, 128.6 (Ph-C), 130.1 (C2?/C6? of CH3OPh-CN),130.2 (C2?/C6? of CH3OPh-C-O), 135.3 (C1? of CH3OPh-C-O), 137.1(C1? of CH3OPh-C-N), 138.2 (C8), 144.4 and 144.6 (C1? of Ph-C-O),145.0 (C1? of Ph-C-N), 150.1 (C4), 151.4 (C2), 157.0 (C6), 158.0 (C4? ofCH3OPh-C-N), 158.5 (C4? of CH3OPh-C-O); HRMS Calcd forC69H62N5O7 (M + H): 1072.4636; Found: 1072.4649. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | Stage #1: 7-iodopyrrolo-[2,1-f][1,2,4]-triazin-4-amine With sodium hydride In N,N-dimethyl-formamide for 0.5h; Inert atmosphere; Stage #2: mono-4-methoxytrityl chloride In N,N-dimethyl-formamide at 20℃; for 2h; Inert atmosphere; | 3 To a solution of 3-1 (2.08 g, 8.0 mmol, WO 2015/133395, published Sept. 11, 2015) in anhydrous DMF (20 mL) was added NaH (0.29 g, 12 mmol) at 0 °C. The reaction was stirred under N2 for 0.5 h. MMTrCl (2.71 g, 8.8 mmol) was added under N2. The mixture was stirred at RT for 2 h. Water was added to quench the reaction. The mixture was extracted with EA (3 X 100 mL). The organic phase was combined and then dried over Na2SO4. After filtration, the solution was concentrated in vacuo to give a residue which was further purified by column chromatograph (PE:EA=20: 1) to give 3-2 (3.5 g, 82%). ESI- LCMS: m/z 533.1 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | To a solution of 2-1 (3.85 g, 18.1 mmol, WO 2007/64931, published June 7, 2007) in anhydrous DMF (30 mL) was added NaH (1.08 g, 27.1 mmol) at 0 C. The reaction was stirred under N2 for 0.5 h. MMTrCl (6.14 g, 19.9 mmol) was added. The mixture was stirred at RT for 2 h. Water was added to quench the reaction. The mixture was extracted with EA (3 X 100 mL). The organic phase was combined and then dried over Na2SO4. After filtration, the solution was concentrated in vacuo to give a residue which was further purified by column chromatograph (PE:EA = 20: 1) to give 2-2 (3.8 g, 45%) as a white solid. ESI-LCMS: m/z 485.2 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
130 g | With hydrogenchloride; In dichloromethane; at 20 - 40℃; for 12h; | 3.2: Add 173g of <strong>[6027-13-0]L-homocysteine</strong> solid to a 2L three-necked flask.Add 1.5 L of chloroform and 192 g of 4-methoxytriphenylchloromethane.Slowly add concentrated hydrochloric acid at room temperature.The temperature was controlled and reacted at 40 C for 12 hours.After the reaction, suction filtration to obtain a milky white liquid, and stirring with 4 L of water.Adjust the pH to neutral with sodium hydroxide and wash the solid with plenty of water.Filtration gave 130 g of S-(4-methoxytrityl)-<strong>[6027-13-0]L-homocysteine</strong>. |
Tags: 14470-28-1 synthesis path| 14470-28-1 SDS| 14470-28-1 COA| 14470-28-1 purity| 14470-28-1 application| 14470-28-1 NMR| 14470-28-1 COA| 14470-28-1 structure
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H200 | Unstable explosive |
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H242 | Heating may cause a fire |
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H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
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H272 | May intensify fire; oxidizer |
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Health hazards | |
Code | Phrase |
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H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
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H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
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H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
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H351 | Suspected of causing cancer |
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H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
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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