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HazMat fee for 500 gram (Estimated)
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USD 0.00
Limited Quantity
USD 15-60
Inaccessible (Haz class 6.1), Domestic
USD 80+
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Structure of 40615-36-9 * Storage: {[proInfo.prStorage]}
* 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.
Reference:
[1] Tetrahedron Letters, 1992, vol. 33, # 48, p. 7319 - 7323
[2] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 1999, vol. 38, # 3, p. 370 - 371
[3] Liebigs Annalen der Chemie, 1982, # 7, p. 1398 - 1402
[4] Helvetica Chimica Acta, 1982, vol. 65, # 8, p. 2372 - 2393
[5] Nucleosides and Nucleotides, 1997, vol. 16, # 5-6, p. 815 - 820
[6] Nucleosides, Nucleotides and Nucleic Acids, 2004, vol. 23, # 11, p. 1683 - 1705
2
[ 40615-36-9 ]
[ 64325-78-6 ]
Reference:
[1] Journal of the American Chemical Society, 1982, vol. 104, # 5, p. 1316 - 1319
3
[ 40615-36-9 ]
[ 4546-72-9 ]
[ 64325-78-6 ]
Reference:
[1] Patent: EP1253154, 2002, A1, . Location in patent: Example 2
4
[ 951-78-0 ]
[ 40615-36-9 ]
[ 23669-79-6 ]
Yield
Reaction Conditions
Operation in experiment
43 g
at 25℃; for 12 h;
To a solution of 308-1 (22.80 g, 99.91 mmol) in anhydrous pyridine (200 mE) was added DMTC1 (37.24 g, 109.90 mmol), and the mixture stirred at 25° C. for 12 h. The reaction was quenched with a sat. NH4C1 solution (200 mE), and extracted with EA (3x200 mE). The combined organic layers were washed with brine (2x 100 mE), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA2: 1 to 0:1) to give the desired product (43.00 g, 72.94 mmol) as a yellow foam.
Reference:
[1] Bioorganic and Medicinal Chemistry, 1996, vol. 4, # 10, p. 1649 - 1658
[2] Organic letters, 2003, vol. 5, # 6, p. 917 - 919
[3] Journal of the American Chemical Society, 2001, vol. 123, # 15, p. 3405 - 3411
[4] Chemical Research in Toxicology, 2006, vol. 19, # 7, p. 968 - 976
[5] Nucleic Acids Research, 2015, vol. 43, # 11, p. 5275 - 5283
[6] Nucleosides, Nucleotides and Nucleic Acids, 2007, vol. 26, # 6-7, p. 709 - 712
[7] ChemMedChem, 2011, vol. 6, # 2, p. 309 - 320
[8] Tetrahedron Letters, 1992, vol. 33, # 1, p. 37 - 40
[9] Chemical & Pharmaceutical Bulletin, 1986, vol. 34, # 5, p. 2044 - 2048
[10] Tetrahedron Letters, 1994, vol. 35, # 29, p. 5221 - 5224
[11] Nucleosides and Nucleotides, 1995, vol. 14, # 3-5, p. 889 - 893
[12] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 14, p. 6824 - 6831
[13] Patent: US2009/264637, 2009, A1, . Location in patent: Page/Page column 29
[14] Bioconjugate Chemistry, 2012, vol. 23, # 3, p. 461 - 471
[15] Photochemical and Photobiological Sciences, 2013, vol. 12, # 8, p. 1366 - 1374
[16] Patent: US2015/366888, 2015, A1, . Location in patent: Paragraph 1309; 1310
[17] Patent: US2015/366887, 2015, A1, . Location in patent: Paragraph 1252-1253
5
[ 40615-36-9 ]
[ 23669-79-6 ]
Reference:
[1] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 4, p. 1181 - 1184
6
[ 100-66-3 ]
[ 98-07-7 ]
[ 40615-36-9 ]
Yield
Reaction Conditions
Operation in experiment
85.13%
Stage #1: at 30℃; for 10 h; Large scale Stage #2: With hydrogenchloride In water at 30℃; for 3 h; Large scale Stage #3: for 6 h; Reflux; Large scale
a.In a 500 L reactor, 75 kg of trichlorotoluene (M = 195.48, n = 383.67 mol)And 103.72 kg of anisole (M = 108.14, n = 959.17 mol)53.35 kg of catalyst aluminum chloride (M = 133.34, n = 400.1 mol) were added,The reaction temperature was controlled at 30 ,Stirring reaction 10h,The mixed reaction liquid I was obtained.b.At 30 ° C,475kg 5percent diluted hydrochloric acid was added to the reaction mixture I was loaded with 1000L reactor,Hydrolysis reaction 3h,Add dichloromethane 200kg,Stir stand still stratification,The organic phase was separated dichloromethane,Then extracted with dichloromethane 200kg * 2 times the aqueous phase,The combined organic phases were extracted with dichloromethane,Dry with anhydrous sodium sulfate for 2h.c.The methylene chloride was concentrated,The solvent methylene chloride was recovered.Oxalyl chloride 70.74 kg (M = 126.93, n = 557.32 mol)In the reflux state reaction 6h,Dropping petroleum ether 130kg,Crystallization after cooling down to 30 ,After solid-liquid separation to get crude DMT-Cl.The crude HPLC purity was 98.91percent.d.Crude DMT-Cl added 4.5 times the mass of dichloromethane, 20 times the mass of petroleum ether for recrystallization,After the solid-liquid separation obtained DMT-Cl wet product,DMT-Cl wet product dried to obtain the finished DMT-Cl 110.66kg,Finished DMT-Cl purity of 99.95percentFinished DMT-Cl yield 85.13percent.The mixed solvent was recovered,Quantitative use of gas chromatography GC and then apply.
Reference:
[1] Patent: CN107056590, 2017, A, . Location in patent: Paragraph 0022; 0023; 0024; 0025; 0026; 0027; 0028-0045
7
[ 40615-35-8 ]
[ 40615-36-9 ]
Reference:
[1] Journal of Heterocyclic Chemistry, 1993, vol. 30, # 5, p. 1197 - 1207
[2] Organic Process Research and Development, 1998, vol. 2, # 6, p. 415 - 417
[3] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1989, p. 769 - 778
[4] Chemische Berichte, 1903, vol. 36, p. 2790
[5] Journal of the American Chemical Society, 1986, vol. 108, p. 3762
[6] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1995, vol. 34, # 7, p. 634 - 635
8
[ 611-94-9 ]
[ 40615-36-9 ]
Reference:
[1] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1989, p. 769 - 778
9
[ 14039-15-7 ]
[ 40615-36-9 ]
Reference:
[1] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1994, # 7, p. 1463 - 1466
10
[ 98-07-7 ]
[ 40615-36-9 ]
Reference:
[1] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1995, vol. 34, # 7, p. 634 - 635
11
[ 40615-36-9 ]
[ 54925-71-2 ]
[ 81246-80-2 ]
Reference:
[1] Nucleosides, nucleotides and nucleic acids, 2003, vol. 22, # 5-8, p. 1007 - 1009
[2] Tetrahedron Letters, 2002, vol. 43, # 11, p. 1983 - 1985
[3] Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 18, p. 6657 - 6665
An operation of dissolving 2’-Deoxy-2’-fluorouridine (3.00 g, 12.2 mmol) in dry pyridine, followed by concentrationunder reduced pressure was repeated 3 times to perform dehydrative azeotropic distillation. Thereafter, under an argonatmosphere, the reaction mixture was dissolved in dry pyridine (120 ml), 4,4’-dimethoxytrityl chloride (4.55 g, 13.4 mmol)was added, and the mixture was stirred at room temperature for 3 hr. The completion of the reaction was confirmed,and ethyl acetate (150 ml) and water (60 ml) were added to the reaction mixture to allow layer separation. The organiclayer was washed 3 times with 5percent aqueous sodium hydrogen carbonate solution (20 ml), washed with water (20 ml)and saturated brine (20 ml), and the obtained organic layer was dried over sodium sulfate. The solvent in the filtrate wasevaporated and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate = 50:50- 0/100(v/v), containing 1percent triethylamine). The object fractions were collected and concentrated to give the title compound(8.48 g, quant).
100%
at 20℃; for 3 h; Inert atmosphere
(1) Synthesis of 5'-O-(4,4'-dimethoxytrityl)-2'-deoxy-2'-fluorouridine An operation of dissolving 2'-Deoxy-2'-fluorouridine (3.00 g, 12.2 mmol) in dry pyridine, followed by concentration under reduced pressure was repeated 3 times to perform dehydrative azeotropic distillation. Thereafter, under an argon atmosphere, the reaction mixture was dissolved in dry pyridine (120 ml), 4,4'-dimethoxytrityl chloride (4.55 g, 13.4 mmol) was added, and the mixture was stirred at room temperature for 3 hr. The completion of the reaction was confirmed, and ethyl acetate (150 ml) and water (60 ml) were added to the reaction mixture to allow layer separation. The organic layer was washed 3 times with 5percent aqueous sodium hydrogen carbonate solution (20 ml), washed with water (20 ml) and saturated brine (20 ml), and the obtained organic layer was dried over sodium sulfate. The solvent in the filtrate was evaporated and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:50-0/100 (v/v), containing 1percent triethylamine). The object fractions were collected and concentrated to give the title compound (8.48 g, quant).
100%
at 20℃; for 16 h;
A solution of 2’-deoxy-2’-fluorouridine (6g, 24.37 mmol) and 4,4'-(chloro(phenyl) methylene)-bis(methoxybenzene) (9.91 g, 29.2 mmol) in pyridine (48.7 ml) was stirred at rt for 16 hours. The mixture was treated with MeOH (20 mL), concentrated to dryness and was partitioned between water (50 mL) and EtOAc (250 mL). The aqueous phase was back extracted with EtOAc (50 mL) and the combined organic layers were washed with water (50 mL) and dried over Na2SO4. The solution was concentrated to give 2’-deoxy-2’-fluoro-5’- (4’,4’-dimethoxytrityl)uridine (14g, quant.) which was used without further purification.
100%
at 20℃; for 16 h;
A solution of 2'-deoxy-2'-fluorouridine (6g, 24.37 mmol) and 4,4'-(chloro(phenyl) methylene)-bis(methoxybenzene) (9.91 g, 29.2 mmol) in pyridine (48.7 ml) was stirred at rt for 16 hours. The mixture was treated with MeOH (20 mL), concentrated to dryness and was partitioned between water (50 mL) and EtOAc (250 mL). The aqueous phase was back extracted with EtOAc (50 mL) and the combined organic layers were washed with water (50 mL) and dried over Na2S04 The solution was concentrated to give 2'-deoxy-2'- fluoro-5'-(4',4'-dimethoxytrityl)uridine (14g, quant.) which was used without further purification.
A solution of 2'-deoxy-2'-fluorouridine (6g, 24.37 mmol) and 4,4'-(chloro(phenyl) methylene)-bis(methoxybenzene) (9.91 g, 29.2 mmol) in pyridine (48.7 ml) was stirred at rt for 16 hours. The mixture was treated with MeOH (20 mL), concentrated to dryness and was partitioned between water (50 mL) and EtOAc (250 mL). The aqueous phase was back extracted with EtOAc (50 mL) and the combined organic layers were washed with water (50 mL) and dried over Na2S04. The solution was concentrated to give 2'-deoxy-2'-fluoro-5'-(4',4'- dimethoxytrityl)uridine (14g, quant.) which was used without further purification.
Compound 129 (570 g, 1.53 mol, 1 wt, 1 vol, 1 eq) was dissolved in pyridine (2.85 L, 35.2 mol, 4.89 wt, 5.0 vols, 23 eq). The mixture was cooled to 2.6 °C and treated with 4,4’- dimethoxytrityl chloride (DMTC1; 543 g, 1.60 mol, 0.953 wt, 1.05 eq). The mixture was stirred at 0 to 5 °C for 2 h and then allowed to warm to ambient temperature. The reaction was monitored by LC/MS and complete conversion was confirmed after overnight stirring. The reaction mixture was cooled to below 5 °C and quenched by treatment with MeOH (124 ml, 3.05 mol, 0.172 wt, 0.217 vol, 2.0 eq) for 15 minutes. The mixture was co-evaporated with toluene (2.00 L, 3.04 wt, 3.51 vol) under vacuum and then diluted with a mixture of EtOAc (2.850 L, 4.5 wt, 5.0 vol) and n-heptane (2.85 L, 3.42 wt, 5.0 vol). The organic layer was washed with saturated NaHCO3 (9 wtpercent solution in water; 2.0 L, 3.5 vol). An additional EtOAc (2.85 L, 4.5 wt, 5.0 vol) was added to completely dissolve the crude product. After stirred for 5 minutes, the two layers were separated. The organic layer was washed with water (2.0 L,3.5 wt, 3.5 vol). Solid began slowly precipitating out of the organic layer. The water layer was separated. The organic layer was then concentrated to approx. 1 vol. The crude product was slurried with a mixture of n-heptane (2.00 L, 2.40 wt, 3.51 vol) and toluene (0.50 L, 0.76 wt, 0.88 vol). After stirring for 15 minutes, the pale yellow solid was collected by vacuum filtration. The filter cake was sequentially rinsed with: (1) a mixture of n-heptane (0.60 L, 0.72 wt, 1.05 vol) and toluene (0.30 L, 0.46 wt, 0.53 vol), and then (2) n-heptane (3.00 L,3.6 wt, 5.26 vol). The solid was dried with no heat for 30 minutes and then transferred to trays for drying at 50 °C in a vacuum oven overnight to give Compound 130 as pale yelllow solid (996.7 g, 1.47 mol, 1.75 wt, 97percent yield).‘H NMR (400 IVIFIz, CHLOROFORM-d) = 8.99 (s, 1H), 8.76 (s, 1H), 8.21 (s, 1H), 8.04 - 8.00 (m, 2H), 7.64 - 7.59 (m, 1H), 7.57 - 7.50 (m, 2H), 7.41 - 7.36 (m, 2H), 7.32 - 7.15 (m, 7H), 6.83 - 6.76 (m, 4H), 6.31 (dd, J= 2.5, 17.0 Hz, 1H), 5.68 (ddd, J 2.3, 4.7, 52.7 Hz, 1H), 4.88 -4.77 (m, 1H), 4.26 -4.21 (m, 1H), 3.77 (s, 6H), 3.57 (dd, J 3.1, 10.9 Hz, 1H),3.43 (dd, J= 4.1, 10.7 Hz, 1H), 2.60 (br s, 1H)
84%
at 20℃; for 16 h;
To a solution of N- (9-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl) tetrahydrofuran-2-yl)-9H-purin-6-yl)- benzamide (35 g, 93.7 mmol) in pyridine (180 mL) was added DMTrCI (38.12 g, 1 12.5 mmol, 1.2 eq) and the resulting mixture was stirred at RT for 16 h. The mixture was then diluted with CH2CI2 (800 mL), washed with sat NaHC03 (2x 400 mL) and brine (400 mL). The organic layer was dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was purified by S1O2 gel chromatography (petroleum ether / EtOAc=10/l to 1/4) to give the title compound as a white solid (53.0 g, 78.4 mmol, 84percent). [0291] 1H-NMR (400 MHz, DMSO-de) δ ppm 11.26 (br s, 1H), 8.74 (s, 1H), 8.62 (s, 1H), 8.05 (d, J=7.4 Hz, 2H), 7.60 - 7.72 (m, 1H), 7.48 - 7.58 (m, 2H), 7.32 (d, J=7.2 Hz, 2H), 7.14 - 7.24 (m, 7H), 6.80 (dd, J=6.2, 8.7 Hz, 4H), 6.43 (d, J=20.0 Hz, 1H), 5.73 - 5.85 (m, 1H), 5.61 (d, J=4.4 Hz, 1H), 4.76 - 4.99 (m, 1H), 4.14 (br d, J=5.4 Hz, 1H), 3.64 - 3.79 (m, 7H), 3.19 - 3.33 (m, 2H).
31.2 g
at 20℃; for 3 h;
To a solution of compound 8b (30 g, 80.35 mmol) in pyridine (250 mL) was added4,4’-dimethoxytrityl chloride (54.45 g,160.71 mmol). After stirring at rt for 3 h, EtOAc (1L) was added and the mixture was filtered. The organic layer was successively washed with brine (300 mL x 3), dried over anhydrous Na2SO4, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (MeOH in DCM = 0percent to 5percent) to give compound 8c (31.2 g) as a white solid. ESI-MS: m/z 676.3 [M + H] .
2-Deoxyuridine (1.0 g; 4.4 mmol; 1.0 equiv.) was dissolved in pyridine (10 mL) followed by portion-wise addition of DMT-Cl (1.9 g; 5.6 mmol; 1.3 equiv.). The reaction mixture was stirred at ambient temperature and the reaction was monitored by TLC. After complete consumption of the starting material (12 hours), MeOH (2 mL) was added and the resulting mixture was concentrated under vacuum. The residue was dissolved in CH2Cl2 and the organic phase was washed consecutively with saturated aqueous NaHCO3 solution and dried over Na2SO4. After filtration, the solvent was evaporated and the residue was purified via column chromatography (50-70% EtOAc in hexanes containing 1% trimethylamine v/v). The product was obtained as a yellow foam (2.1 g; 3.8 mmol; 86 %). TLC: Rf 0.11 (CH2Cl2/EtOAc; UV). 1H NMR (600 MHz, Acetonitrile-d3) delta 9.13 (bs, 1H), 7.61 (d, J = 8.1 Hz, 1H), 7.50-7.38 (m, 2H), 7.36-7.26 (m, 6H), 7.27-7.19 (m, 1H), 6.88 (d, J = 9.0 Hz, 4H), 6.16 (t, J = 6.4 Hz, 1H), 5.35 (d, J = 8.1 Hz, 1H), 4.43 (dt, J = 6.4, 4.4 Hz, 1H), 3.97-3.89 (m, 1H), 3.77 (s, 6H), 3.40 (bs, 1H), 3.31 (dd, J = 10.7, 4.4 Hz, 1H), 3.27 (dd, J = 10.7, 3.2 Hz, 1H), 2.27 (ddd, J = 13.7, 6.5, 4.6 Hz, 1H), 2.21 (dt, J = 13.7, 6.4 Hz, 1H). 13C NMR (151 MHz, Acetonitrile-d3) delta 164.04, 159.71, 151.34, 145.90, 141.38, 136.75, 136.58, 131.05, 129.02, 128.89, 127.91, 114.10, 114.09, 102.43, 87.39, 86.78, 85.71, 71.49, 64.16, 55.92, 41.01..
With pyridine; at 0 - 20℃; for 25h;Inert atmosphere;
2,3'-Anhydro-2'-deoxy-5'-O-(4,4'-dimethoxytrityl)uridine 51; 4,4'-Dimethoxytrityl chloride (5.39 g, 15.9 mmol) is added to a solution, maintained under argon at 0 C., of 2'-deoxyuridine (3.3 g, 14.5 mmol) in anhydrous pyridine (50 ml). The mixture is left stirring for 1 hour at 0 C. and then for 24 h at ambient temperature. Mesyl chloride (1.35 ml, 17.4 mmol) is added and the mixture is left reacting for 4 hours. Water (5 ml) is subsequently added and, after 30 minutes, the solvents are evaporated and coevaporated with toluene. The residue obtained is taken up in dichloromethane (100 ml) and the solution is washed with water (50 ml) and dried over sodium sulfate before being evaporated to dryness. The yellow foam obtained is dissolved in the minimum amount of dichloromethane in order to be chromatographed on silica gel in a dichloromethane-methanol (95:5) mixture comprising 1% of triethylamine.
43 g
With pyridine; at 25℃; for 12h;
To a solution of 308-1 (22.80 g, 99.91 mmol) in anhydrous pyridine (200 mE) was added DMTC1 (37.24 g, 109.90 mmol), and the mixture stirred at 25 C. for 12 h. The reaction was quenched with a sat. NH4C1 solution (200 mE), and extracted with EA (3x200 mE). The combined organic layers were washed with brine (2x 100 mE), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA2: 1 to 0:1) to give the desired product (43.00 g, 72.94 mmol) as a yellow foam.
With pyridine; at 25℃; for 12h;
To a solution of 354-1 (22.80 g, 99.91 mmol) in anhydrous pyridine (200 mL) was added DMTCl (37.24 g, 109.90 mmol), and the mixture stirred at 25 C. for 12 h. The reaction was quenched with a sat. NH4Cl solution (200 mL), and extracted with EA (3×200 mL). The combined organic layers were washed with brine (2×100 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA=2:1 to 0:1) to give the desired product (43.00 g, 72.94 mmol) as a yellow foam.
Compound 129 (570 g, 1.53 mol, 1 wt, 1 vol, 1 eq) was dissolved in pyridine (2.85 L, 35.2 mol, 4.89 wt, 5.0 vols, 23 eq). The mixture was cooled to 2.6 C and treated with 4,4?- dimethoxytrityl chloride (DMTC1; 543 g, 1.60 mol, 0.953 wt, 1.05 eq). The mixture was stirred at 0 to 5 C for 2 h and then allowed to warm to ambient temperature. The reaction was monitored by LC/MS and complete conversion was confirmed after overnight stirring. The reaction mixture was cooled to below 5 C and quenched by treatment with MeOH (124 ml, 3.05 mol, 0.172 wt, 0.217 vol, 2.0 eq) for 15 minutes. The mixture was co-evaporated with toluene (2.00 L, 3.04 wt, 3.51 vol) under vacuum and then diluted with a mixture of EtOAc (2.850 L, 4.5 wt, 5.0 vol) and n-heptane (2.85 L, 3.42 wt, 5.0 vol). The organic layer was washed with saturated NaHCO3 (9 wt% solution in water; 2.0 L, 3.5 vol). An additional EtOAc (2.85 L, 4.5 wt, 5.0 vol) was added to completely dissolve the crude product. After stirred for 5 minutes, the two layers were separated. The organic layer was washed with water (2.0 L,3.5 wt, 3.5 vol). Solid began slowly precipitating out of the organic layer. The water layer was separated. The organic layer was then concentrated to approx. 1 vol. The crude product was slurried with a mixture of n-heptane (2.00 L, 2.40 wt, 3.51 vol) and toluene (0.50 L, 0.76 wt, 0.88 vol). After stirring for 15 minutes, the pale yellow solid was collected by vacuum filtration. The filter cake was sequentially rinsed with: (1) a mixture of n-heptane (0.60 L, 0.72 wt, 1.05 vol) and toluene (0.30 L, 0.46 wt, 0.53 vol), and then (2) n-heptane (3.00 L,3.6 wt, 5.26 vol). The solid was dried with no heat for 30 minutes and then transferred to trays for drying at 50 C in a vacuum oven overnight to give Compound 130 as pale yelllow solid (996.7 g, 1.47 mol, 1.75 wt, 97% yield).?H NMR (400 IVIFIz, CHLOROFORM-d) = 8.99 (s, 1H), 8.76 (s, 1H), 8.21 (s, 1H), 8.04 - 8.00 (m, 2H), 7.64 - 7.59 (m, 1H), 7.57 - 7.50 (m, 2H), 7.41 - 7.36 (m, 2H), 7.32 - 7.15 (m, 7H), 6.83 - 6.76 (m, 4H), 6.31 (dd, J= 2.5, 17.0 Hz, 1H), 5.68 (ddd, J 2.3, 4.7, 52.7 Hz, 1H), 4.88 -4.77 (m, 1H), 4.26 -4.21 (m, 1H), 3.77 (s, 6H), 3.57 (dd, J 3.1, 10.9 Hz, 1H),3.43 (dd, J= 4.1, 10.7 Hz, 1H), 2.60 (br s, 1H)
84%
With pyridine; at 20℃; for 16h;
To a solution of N- (9-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl) tetrahydrofuran-2-yl)-9H-purin-6-yl)- benzamide (35 g, 93.7 mmol) in pyridine (180 mL) was added DMTrCI (38.12 g, 1 12.5 mmol, 1.2 eq) and the resulting mixture was stirred at RT for 16 h. The mixture was then diluted with CH2CI2 (800 mL), washed with sat NaHC03 (2x 400 mL) and brine (400 mL). The organic layer was dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was purified by S1O2 gel chromatography (petroleum ether / EtOAc=10/l to 1/4) to give the title compound as a white solid (53.0 g, 78.4 mmol, 84%). [0291] 1H-NMR (400 MHz, DMSO-de) delta ppm 11.26 (br s, 1H), 8.74 (s, 1H), 8.62 (s, 1H), 8.05 (d, J=7.4 Hz, 2H), 7.60 - 7.72 (m, 1H), 7.48 - 7.58 (m, 2H), 7.32 (d, J=7.2 Hz, 2H), 7.14 - 7.24 (m, 7H), 6.80 (dd, J=6.2, 8.7 Hz, 4H), 6.43 (d, J=20.0 Hz, 1H), 5.73 - 5.85 (m, 1H), 5.61 (d, J=4.4 Hz, 1H), 4.76 - 4.99 (m, 1H), 4.14 (br d, J=5.4 Hz, 1H), 3.64 - 3.79 (m, 7H), 3.19 - 3.33 (m, 2H).
83.9%
With pyridine; at 25℃; for 2h;
N-(9-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2- yl)-9H-purin-6-yl)benzamide (5.0 g, 13.4 mmol, 1.0 eq) was co-evaporated with pyridine (30 mL). DMTrCl (6.81 g, 20.1 mmol, 1.5 eq) was added to a solution of N-(9-((2R,3R,4R,5R)-3- fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-9H-purin-6-yl)benzamide (5.0 g, 13.4 mmol, 1.0 eq) in pyridine (35 mL) at 25 C. The mixture was stirred at 25 C for 2 hours. Two parallel reactions were carried out. The combined mixtures were then diluted with DCM (15 mL), the organic layer was washed with sat.NaHCO3 solution (20 mL) and brine (10 mL), dried over Na2SO4, filtered and concentrated, the crude was purified by column chromatography (petroleum ether:ethyl acetate = 10:1 to 1:2) to give compound N-(9- ((2R,3R,4R,5R)-5-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-3-fluoro-4- hydroxytetrahydrofuran-2-yl)-9H-purin-6-yl)benzamide (16.0 g, 22.5 mmol, 83.9% yield, 95% purity) as a light yellow solid. LCMS (ES, m/z) 676.2 (M+H).1H NMR (400 MHz, DMSO- d6) delta = 11.27 (br s, 1H), 8.75 (s, 1H), 8.63 (s, 1H), 8.06 (br d, J = 7.5 Hz, 2H), 7.69 - 7.62 (m, 1H), 7.60 - 7.51 (m, 2H), 7.33 (br d, J = 7.3 Hz, 2H), 7.28 - 7.15 (m, 7H), 6.82 (dd, J = 6.1, 8.6 Hz, 4H), 6.45 (d, J = 20.0 Hz, 1H), 5.82 - 5.72 (m, 2H), 4.97 - 4.75 (m, 1H), 4.15 (br d, J = 5.0 Hz, 1H), 3.72 (s, 6H), 3.35 - 3.22 (m, 2H).19F NMR (376 MHz, DMSO-d6) delta = -201.14 (s, 1F).
31.2 g
With pyridine; at 20℃; for 3h;
To a solution of compound 8b (30 g, 80.35 mmol) in pyridine (250 mL) was added4,4?-dimethoxytrityl chloride (54.45 g,160.71 mmol). After stirring at rt for 3 h, EtOAc (1L) was added and the mixture was filtered. The organic layer was successively washed with brine (300 mL x 3), dried over anhydrous Na2SO4, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (MeOH in DCM = 0% to 5%) to give compound 8c (31.2 g) as a white solid. ESI-MS: m/z 676.3 [M + H] .
1.9 g
With pyridine; at 20℃;Inert atmosphere;
Step 2:Under the protection of nitrogen,Add DMTrCl (1.6g, 4.8mmol)To intermediate 4-1 (1.2g, 3.2mmol)Pyridine (15mL) solution,Stir at room temperature overnight.Add water (50mL) to the reaction solution,The mixture was extracted with ethyl acetate (40mL × 3),Combine the organic phases and dry with anhydrous sodium sulfate,Concentrate under reduced pressure,Flash column chromatography(2% methanol / dichloromethane) purified to obtain intermediate4-2 (1.9g) is a light yellow solid.
Into a 2000-mL round-bottom flask was placed a solution of 7b (130 g, 459 mmol) in pyridine (500 mL), 1-[chloro(4-methoxyphenyl)benzyl]-4-methoxybenzene (DMT-CI) (233 g, 688 mmol), and 4-dimethylaminopyridine (2.8 g, 22.9 mmol). The resulting solution was stirred overnight at rt. The reaction was then quenched by the addition of water, and the resulting solution was extracted with ethyl acetate (3x 500 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuum. The residue was purified by silica gel chromatography (ethyl acetate/petroleum ether), giving 7c (210 g, 78%) as a brown solid.
78%
With pyridine; dmap; at 20℃;
10608] Into a 2000-mE round-bottom flask was placed asolution of 7b (130 g, 459 mmol) in pyridine (500 mE), 1 -[chloro(4-methoxyphenyl)benzyl] -4-methoxybenzene (DMT-CI) (233 g, 688 mmol), and 4-dimethylaminopyridine (2.8 g, 22.9 mmol). The resulting solution was stirred overnight at it. The reaction was then quenched by the addition of water, and the resulting solution was extracted with ethyl acetate (3x500 mE). The combined organic layers were dried over sodium sulfate and concentrated in vacuum. The residue was purified by silica gel chromatography (ethyl acetate petroleum ether), giving 7c (210 g, 78%) as a brown solid.
5-Trifluoromethyl-5'-dimethoxytrityl-2'-deoxyuridine To a stirred solution of 250 mg of 5-trifluoromethyl-2' deoxyuridine (5-Tf-dU) in 20 mL of dry pyridine at 0 C. was added 227 mg of dimethoxytrityl chloride (DMT-Cl) and 10 mg of 4-dimethylaminopyridine (DMAP). The reaction was stirred for 5 hours at room temperature when a second portion of 144 mg of DMT-Cl was added. After stirring for 12 hours at room temperature, a third portion of 100 mg of DMT-Cl was added to the reaction. The reaction was stirred for an additional 4 hours at room temperature and then diluted with CH2Cl2, washed with water and dried over sodium sulfate (Na2SO4). The crude product was purified by silica gel column chromatography (0-10% methanol (MeOH) in CH2Cl2). 485 mg of the desired product (5'-DMT-5-Tf-dU) was obtained as a yellow foam (96% yield).
72%
With pyridine; at 20℃; for 41.5h;Inert atmosphere;
To a solution of compound 2 (70 mg, 0.24 mmol) in pyridine, DMTrCl (96 mg, 0.28 mmol) was added at room temperature under Ar atmosphere. After being stirred for 41.5 h, the reaction was quenched with MeOH and then concentrated in vacuo. The crude residue was purified by column chromatography (CHCl3-MeOH=100 : 1) to give compound 3 as a white solid (101 mg, 72%). The NMR spectral data were identical to those reported in the literature. 24)
5'-O-(4,4'-Dimethoxytrityl)-<strong>[320-67-2]5-azacytidine</strong> (5) To a solution of <strong>[320-67-2]5-azacytidine</strong> (2.20 g, 9 mmol) in dry pyridine (45 mL) was added 4,4'-dimethoxytrityl chloride (3.15 g, 9.3 mmol) and the mixture was stirred overnight. The reaction mixture was poured into ice-water and extracted with chloroform. The combined organic extracts were dried (MgSO4) and chromatographed through a silica gel column (ethyl acetate--10% methanol/ethyl acetate) to give 2.89 g (59%) of a white product. NMR (CDCl3 +D2 O); delta 3.35 (m, 2H), 3.70 (s, 6H), 4.26 (m, 3H), 5.80 (d, 1H), 6.80 (m, 4H), 7.31 (m, 9H), 8.45 (s, 1H).
To a solution of N-(9- ((2R,3R,4^,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-9H-purin-6-yl)- benzamide (100 g, 269.3 mmol) in pyridine (500 mL) at 0C were added DMAP (1.64 g, 13.46 mmol, 0.05 eq) and DMTrCl (100.4 g, 296.2 mmol, 1.1 eq). The reaction mixture was stirred at RT for 16 h, then quenched by addition of MeOH (500 mL). The volatiles were removed under reduced pressure and the residue was purified by S1O2 gel chromatography (1/1 petroleum ether / EtOAc to 100% EtOAc) to give the title compound as a white foam (150 g, 223 mmol, 83%).
24%
With pyridine; dmap; triethylamine; at 0 - 25℃; for 16h;
To a solution of 70 (150 g, 404 rnmol) in Py (500 rnL) is added DMTrC1 (274 g, 808 mmol), TEA (81.8 g, 808 mmoi. 112 mL) and DMAP (4.93 g. 40.4 mmol) at 0 C. After stirring at 25 C for 16 hours, samrated sodium bicarbonate aqueous solution (1 L) is added and the mixture is extracted with EtOAc (600 mL x 3)? The combined organic layers are dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (EA/PE 1/4 to 1/2 then MeOH/DCM 1/100 to 1/20) to give 71 as a white solid (65.0 g, 24% yield)
Acetic acid (2R,3R,4R,5R)-4-acetoxy-5-acetoxymethyl-2-(6-[bis-(4-methoxy-phenyl)-phenyl-methyl]-amino}-purin-9-yl)-tetrahydro-furan-3-yl ester[ No CAS ]
5-Fluoro-2-deoxyuridine (5-FdU, 2.19 g, 9.0 mmol) was coevaporated two times with anhydrous pyridine and next dissolved in pyridine (20 mL). The resulting solution was chilled, followed by addition of the 4,4-dimethoxytrityl chloride (1.05 eq, 3.16 g, 9.34 mmol). The mixture was being stirred at room temperature for 3 h under N2 atmosphere and left at low temperature overnight. After that methanol was added and the mixture was evaporated to dryness. The residue oil was purified with silica gel column chromatography, using chloroform- methanol (2?5%) as an eluent to obtain pure 7 (white solid, yield: 4.48 g, 92%). 1H NMR (DMSO-d6) delta: 2.14-2.18 (ddd, 1H, H-2 alpha, 3JH2 H1 = 5.30 Hz, 3JH2 H3 = 4.20 Hz, 2JH2H2 = 13.9 Hz), 2.22-2.27 (m, 1H, H-2 beta, 3JH2H1 = 6.50 Hz, 3JH2H3 = 6.70 Hz, 2JH2H2 = 13.6 Hz), 3.12-3.15 (dd, 1H, H 5, 3JH5H4 = 5.40 Hz, 2JH5H5 = 10.6 Hz), 3.24-3.27 (dd, 1H, H5, 3JH5 H4 = 2.90 Hz, 2JH5H5 = 10.6 Hz), 3.73 (s, 6H, 2× CH3O), 3.87-3.89 (m, 1H, H-4, 3JH4H5 = 5.40 Hz, 3JH4H5 = 2.90, 3JH4H3 = 2.00 Hz), 4.25-4.29 (m, 1H, H-3, 3JH3H2 = 6.70, 3JH3H2 = 4.20, 3JH3H4 = 2.00 Hz), 5.33 (d, 1H, 3- OH, 3JHH = 4.65 Hz), 6.12-6.15 (m, 1H, H-1, 3JH1H2 = 6.50 Hz, 3JH1H2 = 5.30 Hz), 6.87-6.89 (dd, 4H, meta in 4-MeOC6H4-), 7.22-7.32 (m, 7H, DMTr), 7.38, 7.39 (2× brs, 2H, DMTr), 7.88 (d, 1H, H-6, 3JHF = 6.8), 11.85 (brs, 1H, NH). 13C NMR delta: 39.30 (C-2), 55.04, 55.02 (2× CH3OC5H4), 63.65 (C-5), 70.05 (C-3), 84.53 (C-1), 85.58 (C-4), 85.82 (CPh3), 113.2 (C meta in 4-MeOC6H4-), 124.5 (d, C-6, 2JCF = 33.8), 127.6, 127.9 (C ortho in 4-MeOC6H4-), 135.3, 135.5 (C- 1 in 4-MeOC6H4-), 140.0 (d, C-5, 1JCF = 231.5), 144.8 (C in C6H5), 148.9 (C-2), 157.1 (d, C-4, 2JCF = 26.0), 158.11, 158.13 (C para in 4-MeOC6H4-). 15N NMR delta: 136.0 (N-1), 157.9 (N-3). 19F NMR delta: -91.41 (3JFH = 6.8).
80%
With pyridine; at 20℃; for 4h;
First, 4,4-bismethoxytrityl chloride (DMT-Cl) (1.860 g, 5.5 mmol) and deoxyfluorouridine (1.231 g, 5 mmol) were weighed, and 50 mL of anhydrous pyridine was added thereto, and the mixture was stirred uniformly. The reaction was stirred at room temperature for 4 h. Then 5 mL of methanol was added and the reaction was continued for 30 min. The solvent was removed by rotary distillation under reduced pressure, and the product was separated by column chromatography.A white powder (Compound 2) was obtained in a yield of 80%.
65%
With pyridine;
<strong>[50-91-9]5-Fluoro-2'-deoxyuridine</strong> (FdU) (3.2 mmol) was reacted with dimethoxytrityl chloride (4.4 mmol) in dry pyridine. The solution was stirred overnight and the solvent was evaporated. The residue was purified by column chromatography using a gradient from pure CH2C12 to 10% methanol in CH2C12 to afford the desired dimethoxytrityl-5- fluoro-2'-deoxyuridine (DMT-FdU) in 65%.
18 g
With pyridine; at 20℃; for 16h;
To an anhydrous 5-fluoro-2?-deoxyuridine (10 g, 40.6 mmol, 1.0 eq) solution in 9 pyridine (70 mL) was added DMTrCl (15 g, 44.7 mmol, 1.1 eq) and the reaction mixture was stirred at 20 C. for 16 h monitored by TLC (DCM/MeOH=10/1, Rf=0.50). The reaction was quenched by MeOH (30 mL and then concentrated under reduced pressure. The residue was extracted with EtOAc and the combined organic layers were washed with saturated NaHCO3 (300 mL) and brine (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a crude mixture. Silica gel column chromatography (petroleum ether/ethyl acetate=5/1, DCM/MeOH=40/1, 30/1) provided dimethoxytrityl alkylated product as a white solid (18 g, 33 mmol). 1H-NMR (400 MHz, DMSO-d6) 7.86 (d, J=6.8, 1H), 7.40-7.35 (m, 2H), 7.32-7.18 (m, 7H), 6.87 (d, J=8.2, 4H), 6.15-6.10 (m, 1H), 5.73 (s, 1H), 4.29-4.22 (m, 1H), 3.91-3.83 (m, 1H), 3.72 (s, 6H), 3.25 (dd, J=5.6, 10.4, 1H), 3.13 (dd, J=2.8, 10.4, 1H), 2.29-2.10 (m, 2H).
2,2-Bis(ethoxycarbonyl)-3-(4,4'-dimethoxytrityloxy)propyl pivalate. Diethyl 2,2-bis(hydroxymethyl)malonate was reacted with 1 equiv. of 4,4'-dimethoxytrityl chloride in 1,4-dioxane containing 1 equivalent of pyridine. Diethyl 2-(4,4'-dimethoxytrityloxymethyl)-2-(hydroxymethyl)malonate (2.35 g, 4.50 mmol) was acylated with pivaloyl chloride (0.83 mL, 6.75 mmol) in dry MeCN (10 mL) containing 3 equivalent pyridine (1.09 mL, 13.5 mmol). After 3 days at room temperature, the reaction was quenched with MeOH (20 mL) and a conventional CH2Cl2/aq HCO3- workup was carried out. Silica gel chromatography (EtOAc/hexane 1:1, v/v) gave 2.47 g (90%) of the desired product as yellowish syrup. 1H NMR (CDCl3, 200 MHz): 7.13-7.39 [m, 9H, (MeO)2 Tr], 6.81 (d, 4H, [MeO]2 Tr), 4.71 (s, 2H, CH2OPiv); 4.15 (q, J=7.1, 4H, OCH2CH3); 3.78 [s, 6H, (CH3O)2Tr]; 3.67 (s, 2H, CH2ODMTr); 1.27 (t, J=7.1, 6H, OCH2CH3); 1.02 [s, 9H, COC(CH3)3].
With pyridine; In 1,4-dioxane;
Diethyl 2,2-bis(hydroxymethyl)malonate was reacted with 1 equiv. of 4,4'-dimethoxytrityl chloride in 1,4-dioxane containing 1 equiv. of pyridine. Diethyl 2-(4,4'-dimethoxytrityloxymethyl)-2-(hydroxymethyl)malonate obtained (2.35 g, 4.50 mmol) was acylated with pivaloyl chloride (0.83 mL, 6.75 mmol) in dry MeCN (10 mL) containing 3 equiv. pyridine (1.09 mL, 13.5 mmol).
With pyridine; In 1,4-dioxane;
2,2-Bis(ethoxycarbonyl)-3-(4,4'-dimethoxytrityloxy)propyl pivalate. Diethyl 2,2-bis(hydroxymethyl)malonate was reacted with 1 equiv. of 4,4'-dimethoxytrityl chloride in 1,4-dioxane containing 1 equivalent of pyridine.
With pyridine; In 1,4-dioxane;
Diethyl 2,2-bis(hydroxymethyl)malonate was reacted with 1 equiv. of 4,4'-dimethoxytrityl chloride in 1,4-dioxane containing 1 equivalent of pyridine. Diethyl 2-(4,4'- dimethoxytrityloxymethyl)-2-(hydroxymethyl)malonate (2.35 g, 4.50 mmol) was acylated with pivaloyl chloride (0.83 niL, 6.75 mmol) in dry MeCN (10 mL) containing 3 equivalent pyridine (1.09 mL, 13.5 mmol). After 3 days at room temperature, the reaction was quenched with MeOH (20 mL) and a conventional CH2Cl2/aq HC(V workup was carried out. Silica gel chromatography (EtOAc/hexane 1:1, v/v) gave 2.47 g (90 %) of the desired product as yellowish syrup. 1H NMR (CDCl3, 200 MHz): 7.13-7.39 [m, 9H, (MeO)2 Tr]; 6.81 (d, 4H, [MeO]2 Tr); 4.71 (s, 2H, CH20Piv); 4.15 (q, /= 7.1, 4Eta, OCH2CH3); 3.78 [s, 6H, (CHjO)2Tr]; 3.67 (s, 2Eta, CH2ODMTr); 1.27 (t, J = 7.1, 6Eta, OCH2CH5); 1.02 [s, 9Eta, COC(CHj)3].
With pyridine; In 1,4-dioxane;
Diethyl 2,2-bis(hydroxymethyl)malonate was reacted with 1 equiv. of 4,4'-dimethoxytrityl chloride in 1,4-dioxane containing 1 equiv. of pyridine. Diethyl 2-(4,4'-dimethoxytrityloxymethyl)-2-(hydroxymethyl)malonate obtained (2.35 g, 4.50 mmol) was acylated with pivaloyl chloride (0.83 mL, 6.75 mmol) in dry MeCN (10 mL) containing 3 equiv. pyridine (1.09 mL, 13.5 mmol).
1-{(2R,4S,5R)-4-[Bis-(4-methoxy-phenyl)-phenyl-methoxy]-5-[bis-(4-methoxy-phenyl)-phenyl-methoxymethyl]-tetrahydro-furan-2-yl}-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carbaldehyde[ No CAS ]
Starting with 5-iodouridine 6 the compound 9 was made in a 5 step synthesis. First, Sonogashira coupling (JACS 2005, 127, 15071) with propargylamine trifluoroacetamide, copper iodide and tetrakistriphenylphosphine palladium (0) in DMF with triethylamine gave 5-propargyl(trifluoroacetamide) nucleotide 7 in 37% yield after silica chromatography. The nucleoside was dried well and the 5'DMT group was added by using DMT chloride in dry pyridine to give 8 in 87% yield after chromatography. The TFA amine protecting group was removed with methylamine in ethanol, to give 5-propargylamine nucleoside. Next, BHQ1 C3 carboxylic acid was added to the amine nucleoside with BOP and N-methylmorpholine to produce 5'-DMTdU-5-alkynyl(BHQ1) nucleoside 11. After drying by evaporation from pyridine, the nucleoside 11 was converted into 5'-DMTdU-5-alkynyl(BHQ1)3'-diisopropyl cyanoethyl phosphoramidite 12 with tetraisopropyl cyanoethyl phosphoramidite and tetrazole in a mixture of dry acetonitrile and dichloromethane. After purification on a silica column with a gradient of methanol in dichloromethane with 2% pyridine, 700 mg of 12 were obtained. The phosphramidite was coupled to 5'-TTTTTTTTTT-3' immobilized on CPG with standard phosphoramidite chemistry. Analysis of the product by ESMS showed a mass of 3809.5 AMU (Calc'd 3808.5).
With pyridine; In N,N-dimethyl-formamide; at 20℃; for 24.0h;Inert atmosphere;
A mixture of <strong>[491-19-0]1-deoxy-D-ribofuranose</strong> (1.41 g, 10.5 mmol) and 4,4'-dimethoxytrityl chloride (4.63 g, 13.7 mmol) in pyridine (29 mL) and DMF (29 mL) was stirred at room temperature for 24 h. The reaction mixture was quenched with cooled H2O and partitioned between EtOAc and H2O. The organic layer was wash with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane/EtOAc, 10:1~0:1) to give 1-deoxy-5-O-(4,4'- dimethoxytrityl)-D-ribofuranose as a pail yellow solid (3.92 g, 89%).
To a 50 L glass reactor equipped with air stirrer and Ar gas line was added thymidine (1.00 kg, 4.13 mol) in anhydrous pyridine (6 L) at ambient temperature. Dimethoxytrityl (DMT) chloride (1.47 kg, 4.34 mol, 1.05 eq) was added as a solid in four portions over 1 h. After 30 min, TLC indicated approx. 95% product, 2% thymidine, 5% DMT reagent and by-products and 2% 3',5'-bis DMT product (Rf in EtOAc 0.45, 0.05, 0.98, 0.95 respectively). Saturated sodium bicarbonate (4 L) and CH2Cl2 were added with stirring (pH of the aqueous layer 7.5). An additional 18 L of water was added, the mixture was stirred, the phases were separated, and the organic layer was transferred to a second 50 L vessel. The aqueous layer was extracted with additional CH2Cl2 (2×2 L). The combined organic layer was washed with water (10 L) and then concentrated in a rotary evaporator to approx. 3.6 kg total weight. This was redissolved in CH2Cl2 (3.5 L), added to the reactor followed by water (6 L) and hexanes (13 L). The mixture was vigorously stirred and seeded to give a fine white suspended solid starting at the interface. After stirring for 1 h, the suspension was removed by suction through a ½ diameter teflon tube into a 20 L suction flask, poured onto a 25 cm Coors Buchner funnel, washed with water (2×3 L) and a mixture of hexanes-CH2Cl2 (4:1, 2×3 L) and allowed to air dry overnight in pans (1 deep). This was further dried in a vacuum oven (75 C., 0.1 mm Hg, 48 h) to a constant weight of 2072 g (93%) of a white solid, (mp 122-124 C.). TLC indicated a trace contamination of the bis DMT product. NMR spectroscopy also indicated that 1-2 mole percent pyridine and about 5 mole percent of hexanes was still present.
93%
With pyridine; at 20℃; for 1.5h;
To a 50 L glass reactor equipped with air stirrer and Ar gas line was added thymidine (1.00 kg, 4.13 mol) in anhydrous pyridine (6 L) at ambient temperature. Dimethoxytrityl (DMT) chloride (1.47 kg, 4.34 mol, 1.05 eq) was added as a solid in four portions over 1 h. After 30 min, TLC indicated approx. 95% product, 2% thymidine, 5% DMT reagent and by-products and 2% 3',5'-bis DMT product (Rf in EtOAc 0.45, 0.05, 0.98, 0.95 respectively). Saturated sodium bicarbonate (4 L) and CH2Cl2 were added with stirring (pH of the aqueous layer 7.5). An additional 18 L of water was added, the mixture was stirred, the phases were separated, and the organic layer was transferred to a second 50 L vessel. The aqueous layer was extracted with additional CH2Cl2 (2x2 L) The combined organic layer was washed with water (10 L) and then concentrated in a rotary evaporator to approx. 3.6 kg total weight. This was redissolved in CH2Cl2 (3.5 L), added to the reactor followed by water (6 L) and hexanes (13 L). The mixture was vigorously stirred and seeded to give a fine white suspended solid starting at the interface. After stirring for 1 h, the suspension was removed by suction through a 1/2" diameter teflon tube into a 20 L suction flask, poured onto a 25 cm Coors Buchner funnel, washed with water (2x3 L) and a mixture of hexanes-CH2Cl2 (4:1, 2x3 L) and allowed to air dry overnight in pans (1" deep). This was further dried in a vacuum oven (75 C., 0.1 mm Hg, 48 h) to a constant weight of 2072 g (93%) of a white solid, (mp 122-124 C.). TLC indicated a trace contamination of the bis DMT product. NMR spectroscopy also indicated that 1-2 mole percent pyridine and about 5 mole percent of hexanes was still present.
5'-O-Dimethoxytriphenylmethyl-2'-O-methyl-5-methyluridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In pyridine; methanol; dichloromethane; acetonitrile;
ii. 5'-O-Dimethoxytriphenylmethyl-<strong>[55486-09-4]2'-O-methyl-5-methyluridine</strong> Crude 2'-O-methyl-5-methyl uridine (12 g) was coevaporated in pyridine (2*50 mL) and dissolved in dry pyridine (50 mL). Dimethoxytriphenylmethyl chloride (18.1 g, 0.054 mol) was added. the flask was stoppered and allowed to stand for 45 min at room temperature. Methanol (10 mL) was added to quench the reaction and the solution was concentrated under reduced pressure to an oil. The residue was partitioned between ethyl acetate (2*400 mL) and saturated sodium bicarbonate solution (500 mL). The organic layers were combined, dried (sodium sulfate), filtered and concentrated to a yellow foam. The foam was dissolved in methylene chloride (60 mL) and put onto a silica gel column (300 g) and eluted with ethyl acetate-hexanes-triethylamine, 60:40:1. The product containing fractions were combined, concentrated and coevaporated with dry acetonitrile (2*50 mL). The resulting residue was dried at 1 mm Hg for 24 h to a crisp white foam, 17.0 g (60.4% in three steps from 5-methyluridine).
In pyridine; methanol; dichloromethane; acetonitrile;
EXAMPLE 21 5'-O-Dimethoxytriphenylmethyl-<strong>[55486-09-4]2'-O-methyl-5-methyluridine</strong> Crude 2'-O-methyl-5-methyl uridine (12 g) was coevaporated in pyridine (2*50 mL) and dissolved in dry pyridine (50 mL). Dimethoxytriphenylmethyl chloride (18.1 g, 0.054 mol) was added the flask was stoppered and allowed to stand for 45 min at room temperature. Methanol (10 mL) was added to quench the reaction and the solution was concentrated under reduced pressure to an oil. The residue was partitioned between ethyl acetate (2*400 mL) and saturated sodium bicarbonate solution (500 mL). The organic layers were combined, dried (sodium sulfate), filtered and concentrated to a yellow foam. The foam was dissolved in methylene chloride (60 mL) and put onto a silica gel column (300 g) and eluted with ethyl acetate-hexanes-triethylamine, 60:40:1. The product containing fractions were combined, concentrated and coevaporated with dry acetonitrile (2*50 mL). The resulting residue was dried at 1 mm Hg for 24 h to a crisp white foam, 17.0 g (60.4% in three steps from 5-methyluridine).
In pyridine; methanol; dichloromethane; acetonitrile;
EXAMPLE 21 5'-O-Dimethoxytriphenylmethyl-<strong>[55486-09-4]2'-O-methyl-5-methyluridine</strong> Crude 2'-O-methyl-5-methyl uridine (12 g) was coevaporated in pyridine (2*50 mL) and dissolved in dry pyridine (50 mL). Dimethoxytriphenylmethyl chloride (18.1 g, 0.054 mol) was added. the flask was stoppered and allowed to stand for 45 min at room temperature. Methanol (10 mL) was added to quench the reaction and the solution was concentrated under reduced pressure to an oil. The residue was partitioned between ethyl acetate (2*400 mL) and saturated sodium bicarbonate solution (500 mL). The organic layers were combined, dried (sodium sulfate), filtered and concentrated to a yellow foam. The foam was dissolved in methylene chloride (60 mL) and put onto a silica gel column (300 g) and eluted with ethyl acetate-hexanes-triethylamine, 60:40:1. The product containing fractions were combined, concentrated and coevaporated with dry acetonitrile (2*50 mL). The resulting residue was dried at 1 mm Hg for 24 h to a crisp white foam, 17.0 g (60.4% in three steps from 5-methyluridine).
3-Dimethylamino-l,2-propanediol (6.0 g, 50 mmol) was weighed into a 1 L round bottomed flask with a stir bar. The flask was sealed, flushed with argon, charged with pyridine and cooled to 0 0C. 4,4'-Dimethoxytrityl chloride (17.9 g, 1.05 equiv.) was weighed into a 100 mL round bottomed flask, sealed and then dissolved in pyridine (80 mL). The 4,4'- dimethoxytrityl chloride solution was transferred to the stirring reaction mixture slowly, using additional fresh pyridine (20 mL) to effect the transfer of residual 4,4'-dimethoxytrityl chloride. The reaction was allowed to come to room temperature while stirring overnight. The reaction was concentrated in vacuo and re-dissolved in dichloromethane (300 mL). The organic phase was washed with saturated bicarbonate (2 x 200 mL) and brine (I x 200 mL), dried over MgSO4, filtered, concentrated and dried under high vacuum to afford 22.19g of a yellow gum that was used without further purification.
To a stirring slurry of <strong>[1788-08-5]4-ethynylbenzenesulfonamide</strong> (1.8Ig, 10.0 mmol) and DMTr-Cl (4.07 g, 12.0 mmol) in DCM (100 mL) was added TEA (2.8 mL). The resulting solution was allowed to stir at room temperature for overnight. Silica gel (3 g) was added to the solution followed by rotary evaporation of solvent in vacuo. The sample was absorbed onto silica gel was then loaded onto a pre-equilibrated column (with 10% TEA in hexane). Flash chromatography using 0-30% EtOAc in hexane as the gradient eluents gave the product 5 as a yellow solid (4.8g, 99%).
2-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)propane- 1 ,3 -diol To a solution of 2-(hydroxymethyl)propane- 1,3 -diol (1 g, 9.42 mmol) in pyridine (10 ml) was added 4,4'-(chloro(phenyl)methylene)bis(methoxybenzene) (1.596 g, 4.71 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate (3x). The combined organics were washed with water and brine, dried over Na2SO4, <n="89"/>filtered, and concentrated. The crude material was purified by flash silica gel chromatography (hexanes/ethyl acetate). MS (ESI) m/z 431 (M+Na)+.
To a solution of 298-1 (12 g, 45.42 mmol) in pyridine (100 mL) was added DMTrCl (16.16 g, 47.69 mmol) in portions at 0 C. over a period of 30 mins under N2. The mixture was warmed to 25 C. and stirred for 16 h. LCMS and TLC (DCM:MeOH=20:1) showed that the starting material was consumed. The reaction was quenched with MeOH (10 mL) and then concentrated in vacuum. The residue was purified by silica gel chromatography (100-200 mesh silica gel, PE:EA2981:1) to give pure DMTr-298-1 (20 g, 77.7%) as a white solid
With pyridine; at 0 - 20℃; for 15h;
102991 To a solution of P24-4 (21.0 g, 79.5 mmol) in pyridine (250 mL) was added DMTrC1 (28.2 g, 83.5 mmol) at 0C. The solution was stirred at R.T. for 15 hours. The reaction was quenched with MeOH and concentrated to dryness under reduced pressure. The residue was dissolved in EtOAc and washed with water. The organic layer was dried over Na2SO4 and concentrated. The residue was dissolved in DCM (300 mL). Imidazole (13.6 g, 200 mmol) and TBSC1 (30.0 g, 200 mmol) were added. The reaction mixture was stirred at R.T. for 12 hours. The reaction mixture was washed with NaHCO3 and brine. The organic layer was dried over Na2SO4 and concentrated. The residue (48.5 g, 79.5 mniol) was dissolved in 80% HOAc aq. solution (400 mL). The mixture was stirred at R.T. for 20 hours. The mixture was diluted with EtOAc and washed with NaHCO3 solution and brine. The organic layer was dried over Na2SO4 and purified by silica gel column chromatography (1- 2% MeOH in DCM) to give P24-5 as a white solid (21.0 g, 70%). ESI-MS: m/z 379.1 [M+H1.
With pyridine; at 20℃; for 15h;
To a solution of 1-1 (100.0 g, 378.7 mmol) in pyriHOdine (750 mL) was added DMTrC1 (164.9 g, 487.8 mmol). added, and the mixture was concentrated to dryness under The solution was stirred at RT for 15 h. MeOH (300 mL) wasreduced pressure. The residue was dissolved in EA andwashed with water. The organic layer was dried over Na2504and concentrated. The residue was dissolved in DCM (500mL). To this solution were added imidazole (44.3 g, 650.4 mmol) and TI3SC1 (91.9 g, 609.8 mmol). The mixture was stirred at RT for 14 h. The solution was washed with NaHCO3 and brine. The organic layer was dried over Na2SO4, and concentrated to give the crude product as a light yellow solid. The crude (236.4 g, 347.6 mmol) was dissolved in 80% HOAc aqueous solution (500 mE). The mixture was stirred at RT for 15 h. The mixture was diluted with EA, and washed with NaHCO3 solution and brine. The organic layer was dried over Na2SO4 and purified on a silica gel colunm chromatography (1-2% MeOH in DCM) to give 1-2 (131.2 g, 91.9%) as a light yellow solid. ESI-MS: mlz 802 [M+H].
With pyridine; at 20℃; for 15h;
To a solution of 1-1 (100.0 g, 378.7 mmol) in pyridine (750 mL) was added DMTrCl (164.9 g, 487.8 mmol). The solution was stirred at RT for 15 h. MeOH (300 mL) was added, and the mixture was concentrated to dryness under reduced pressure. The residue was dissolved in EA and washed with water. The organic layer was dried over Na2SO4 and concentrated. The residue was dissolved in DCM (500 mL). To this solution were added imidazole (44.3 g, 650.4 mmol) and TBSCl (91.9 g, 609.8 mmol). The mixture was stirred at RT for 14 h. The solution was washed with NaHCO3 and brine. The organic layer was dried over Na2SO4, and concentrated to give the crude product as a light yellow solid. The crude (236.4 g, 347.6 mmol) was dissolved in 80% HOAc aqueous solution (500 mL). The mixture was stirred at RT for 15 h. The mixture was diluted with EA, and washed with NaHCO3 solution and brine. The organic layer was dried over Na2SO4 and purified on a silica gel column chromatography (1-2% MeOH in DCM) to give 1-2 (131.2 g, 91.9%) as a light yellow solid. ESI-MS: m/z 802 [M+H]+.
To a solution of Lambda^-acetylcytidine (65.0 g, 0.228 mol) in anhydrous pyridine (60OmL) cooled in an ice bath, DMTrCl (84.7 g, 0.251 mol) was added. The reaction mixture was stirred at room temperature overnight. To the reaction mixture cooled with an ice bath, THF (600 ml) and AgNO3 (58.1 g, 0.342 mmol) were added. Then TBSCl (51.5 g, 0.342 mmol) was added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered, solvent was removed under vacuum to give a residue which was diluted with EtOAc (500 mL) and washed with water (200 ml) and brine (200 ml). The organic layer was separated and dried over anhydrous Na2SO4 and the filtrate was concentrated to a syrup which was purified by chromatography on silica gel (eluted with PE : EA = 5:1 to 3 : 1) to give N4-acetyl-2'-O-(t-butyldimethylsilyl)-5'-O- (4,4'-dimethoxytrityl)cytidine as yellow solid (80 g, 50percent). 1H NMR (CDCl3) delta 8.39 (d, J = 7.6 Hz, IH), 7.34 (dd, Jl = 1.6 Hz, J2 = 8.4 Hz, 2H), 7.21 - 7.27 (m, 6H), 7.02 (d, J = 7.2 Hz, IH), 6.80 (dd, Jl = 2.0 Hz, J2 = 6.8 Hz, 4H), 5.82 (d, J = 1.2 Hz, IH), 4.26 - 4.32 (m, IH), 4.20 (dd, Jl = 1.2 Hz, J2 = 4.4 Hz, IH), 4.00 - 4.02 (m, IH), 3.74 (d, J = 1.6 Hz, 6 H), 3.43 - 3.53 (m, 2H), 2.32 (d, J = 9.6 Hz, IH), 2.18 (s, 3H), 0.86 (s, 9H), 0.22 (s, 3H), 0.11 (s, 3H).
A mixture of 0.27 g (1.0 mmol) of 2'-deoxy-2' -fluoroadenosine, DMAP (244 mg, 2.0 mmol) and TBDMS-Cl (1.1 mmol, 181 mg) in anhydrous pyridine (15 mL) was stirred at room temperature overnight and then at 30 0C for 8 hours. DMTr-Cl (1.0 g, 3 mmol) was added and the mixture stirred at 560C for 3 days, cooled to 00C and quenched with water (1.5 mL). The resulting mixture was stirred at room temperature for 2 hours, diluted with ethyl acetate, washed with brine 3 times, and dried over sodium sulfate. Chromatography on silica gel with 20-35percent ethyl acetate in hexane gave 746 mg of 3',N6- b1s(4,4'-dimethoxytpityl)-5'-O-(f-butyldimethyls1lyl)-2'-deoxy-2'-fluoroadenos1ne as white foam.
Reference Example 23 8-<strong>[764-89-6]hydroxyoctanoic acid</strong> (100 mg, 0.59 mmol) was dissolved in 1.5 mL of pyridine. To the solution, 4,4'-dimethoxytrityl chloride (237 mg, 0.7 mmol) was added, and the mixture was stirred overnight. The completion of the reaction was confirmed by TLC. Then, the reaction solution was separated into organic and aqueous phases using methylene chloride and water. The organic phase was dried over sodium sulfate, and the solvent was then concentrated under reduced pressure. The residue was purified with a silica gel column (4 g, methylene chloride) to obtain amorphous 8-(4,4'-dimethoxytrityloxy)octanoic acid (348 mg).
With pyridine; In N,N-dimethyl-formamide; at 20℃; for 12h;Inert atmosphere;
Preparation of 3-(4,4'-dimethoxytrityloxymethyl)benzonitrile (4) In DMF (23 mL) and pyridine (23 mL), suspended were <strong>[874-97-5]3-hydroxymethylbenzonitrile</strong> (1.12 g, 8.38 mmol) and 4,4'-dimethoxytritylchloride (3.41 g, 10.06 mmol). The suspension was stirred for 12 hours at a room temperature under Ar atmosphere. TLC was used to confirm there was no starting material in the reaction mixture. Then, to the suspension was added iced water (20 mL). The mixture was subjected to extraction with EtOAc and water. The organic layer was washed with sat. NaCl aq., dried over anhydrous Na2SO4, and evaporated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (Hex:EtOAc=10:1) to give 3-(4,4'-dimethoxytrityloxymethyl)benzonitrile (4) (3.31 mg, 91%) as a colorless oil. 1H-NMR(CDCl3, 400MHz) 8= 7.23-7. 68 (17H, m, Ar-H), 6. 84 (4H, d, J= 8. 8Hz, Ar-H), 4.21 (2H, s, CH2O), 3.79 (6H, s, CH3O) 13C-NMR(CDCl3, 100 MHz) delta= 158.3, 144.4, 135.4, 130.5, 130.4, 129.5, 128.9, 128.5, 126.9, 118.6, 113.7, 112.1, 111.9, 111.8, 86.4, 56.9, 55.5, 54.0
91%
With pyridine; In N,N-dimethyl-formamide; at 20℃; for 12h;Inert atmosphere;
A mixture of <strong>[874-97-5]3-hydroxymethylbenzonitrile</strong> (9) (1.12 g, 8.38 mmol) and 4,4?-dimethoxytritylchloride (3.41 g, 10.1 mmol) in pyridine (23 mL) and DMF (23 mL) was stirred at room temperature for 12 h. The reaction was quenched by the addition of cold H2O (20 mL) and the mixture was partitioned between EtOAc and H2O.The organic layer was wash with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane/EtOAc, 10:1) to give 10 as a colourless oil (3.31 g, 91%).This was used in the next step without further purification
Synthesis of compound 5; Step(ii)[1]: The reaction was performed in a 5 necked 15 L glass reactor fitted with an overheadstirrer over an ice bath. To a stirred solution of 4 (450 g, 2.94 mole) in acetonitrile (8 L) wereadded Et3N (1 L, 7.2 mole) and ethyl trifluoroacetate (1000 g, 7.04 mole), and stirred at room temperature overnight. The white solid (Et3N.HC1) was filtered over sintered funnel and washedwith ethyl acetate ( 4 L). The organic solution was concentrated followed by co-evaporationwith toluene (2 L x 2) and dried under reduced pressure overnight in a 22 L rotary evaporator toobtain crude product as a gummy mass ( -600 g). Step (ii)[2]: Above obtained crude compound (2.94 mole) was dissolved in 2 L of anhyd.pyridine and transferred to the four necked 15 L flask. Another 6 L of anhyd. pyridine wasadded. This solution was cooled to -5 oc using ice bath followed by addition of DMTr-Cl (1000g, 2.95) portion wise under nitrogen atmosphere over 20 min. and the reaction mixture wasstirred at room temperature overnight. 12 L of water was added while stirring and let it stand for6 h. The compound was settled at the bottom of the flask as a brownish gummy mass. Waterpyridinelayer was decanted using transfer pump and the aqueous layer was extracted with ethylacetate (2 x 5 L). Combined the ethyl acetate extract with the viscous material remained in thereactor, after decanting water layer. Concentration of the solvent gave the correspondingproduct as viscous oil which was used for the next step without purification. Step (ii)[3]: To a stirred solution of trifluoroacetyl compound (2.94 mole) in MeOH (5 L) wasadded KOH (330 g, 5.88 mole) dissolved in water (2 L) drop wise over 30 min. and stirred atroom temperature for 1 h. Concentrated to 3 L volume followed by addition of 15 L of waterand allowed to stand overnight. The product was settled at the bottom as reddish brown viscousoil. Decanted the water using transfer pump followed by addition of 6 L of DCM to dissolve,washed with 5 L of water and separated the organic solvent. Concentration of the solventfollowed by silica gel column chromatography ( 4 Kg silica, eluent: hexane/ethyl acetate andethyl acetate/MeOH) purification gave compound 5 (1000 g, 81 %) as foamy yellowish whitesolid. 1H NMR (CDCb): 1.35-1.42 (m, lH), 1.65-1.70 (m, lH), 2.33 (br s, lH), 2.59-2.62 (m,lH), 2.72-2.75 (m, lH), 2.82-2.91 (m, 2H), 3.36-3.41 (m,lH), 3.71 (s, 6H), 4.1 (br s, lH), 4.525(d, J = 4.0 Hz, lH).
Taking <strong>[95058-81-4]gemcitabine</strong> as an example, the synthesis of phosphoramidite monomers was carried out according to the following synthetic route.First, 4,4-bismethoxytrityl chloride (DMT-Cl) (3.38 g, 10 mmol) and <strong>[95058-81-4]gemcitabine</strong> (2.63 g, 10 mmol) were weighed, 50 mL of anhydrous pyridine was added, stirred well, and stirred at room temperature for 4 h. . Then 5 mL of methanol was added and the reaction was stirred for a further 30 min. Vacuum distillation to removeSeparation product by column chromatographyA white powder (Compound 2) was obtained in a yield of 80%.
64%
With pyridine; at 0 - 20℃; for 4h;
4,4-Dimethoxytrityl chloride (745mg; 2.2 mmol) was added to a solution of <strong>[95058-81-4]gemcitabine</strong> (680mg, 2 mmol) in dry pyridine (20 mL). The reaction mixture was stirred at 0C for 3 hours andthen allowed to stand 1h at room temperature. Pyridine was then removed under reducedpressure and the residue was dissolved in CHCl3 (10 mL) and washed with H2O (3x 10 mL),dried over anhydrous MgSO4 and concentrated in vacuo. The product was isolated by silicagel column chromatography using methanol in chloroform (08%) as an eluent. 5?-ODimethoxytrityl-2?,2?-difluoro-2?-deoxycytidine was obtained in 64% yield. FAB- MS m/z:(M-1) 564; 1H NMR (CDCl3): 7.74-7.70 (d, 2H), 7.43-7.28 (m, 9H), 6.85-6.80 (d, 4H), 6.47-6.39 (t, 1H), 5.52-5.48 (d, 1H), 4.46-4.12 (m, 1H), 4.07-4.03 (d, 1H), 3.77 (s, 6H), 3.58-3.39(m, 2H).
(3-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-5-bromophenyl)methanol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
36%
With pyridine; at 20℃; for 16.0h;
A solution of 5-bromo-1 ,3-dihydroxymethyl benzene 1 (3.00 g, 13.8 mmol), 4,4'-dimethoxytrityl chloride (4.68 g, 13.8 mmol) in pyridine (60 mL) was stirred at room temperature for 16 h. The reaction mixture was partitioned between EtOAc and water. The EtOAc layer was dried over anhydrous Na2S04 and evaporated. The crude product was purified by flash chromatography eluting with 1 % Et3N in 5-30% EtOAc/Heptane to provide 2.57 g (36 %) of 2. MS (ESI+) m/z: calcd for C29H27Br04 518.1 ; found 303.5 [DMT]+. 1H NMR (400 MHz, CDCI3) delta 7.54 - 7.48 (m, 2H), 7.47 - 7.37 (m, 6H), 7.36 - 7.29 (m, 2H), 7.27 - 7.21 (m, 2H), 6.87 (d, J = 8.8 Hz, 4H), 4.67 (d, J = 6.0 Hz, 2H), 4.22 (s, 2H), 3.82 (s, 6H), 1 .67 (t, J = 6.0 Hz, 1 H).
36%
With pyridine; at 20℃; for 16.0h;
(3-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-5-bromophenyl)methanol (2) A solution of <strong>[51760-22-6]5-bromo-1,3-dihydroxymethyl benzene</strong> 1 (3.00 g, 13.8 mmol), 4,4'-dimethoxytrityl chloride (4.68 g, 13.8 mmol) in pyridine (60 mL) was stirred at room temperature for 16 h. The reaction mixture was partitioned between EtOAc and water. The EtOAc layer was dried over anhydrous Na2SO4 and evaporated. The crude product was purified by flash chromatography eluting with 1% Et3N in 5-30% EtOAc/Heptane to provide 2.57 g (36%) of 2. MS (ESI+) m/z: calcd for C29H27BrO4 518.1. Found 303.5 [DMT]+. 1H NMR (400 MHz, CDCl3) b 7.54-7.48 (m, 2H), 7.47-7.37 (m, 6H), 7.36-7.29 (m, 2H), 7.27-7.21 (m, 2H), 6.87 (d, J=8.8 Hz, 4H), 4.67 (d, J=6.0 Hz, 2H), 4.22 (s, 2H), 3.82 (s, 6H), 1.67 (t, J=6.0 Hz, 1H).
1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(((3-methoxyphenyl)(4-methoxyphenyl)(phenyl)methoxy)methyl)tetrahydrofuran-2-yl)pyrimidin-2(1H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
63%
With pyridine; at 0 - 25℃;
To a cooled (0 °C) solution of the compound 16 (3.0 g, 13.2 mmol) in pyridine (33 mL) was added 4,4'-dimethoxytriphenylmethyl chloride (DMTCl) (5.6 g, 16.5 mmol) and the reaction mixture was stirred at 25 °C for 50 min. After evaporated under reduced pressure, the residue was purified by silica gel column chromatography (DCM : MeOH = 20 : 1) to give the compound 17 (4.4 g, 63percent) as a white solid. 1HNMR (400 MHz, CDC13) delta 8.63 (dd, J= 4.4, 3.2 Hz, 1H), 8.40 (dd, 7 = 5.6, 2.4 Hz, 1H), 7.63-7.16 (m, 9H), 6.84-6.81 (m, 4H), 6.14 (dd, J = 6.8, 4.0 Hz, 1H), 5.87 (d, J= 3.2 Hz, 1H), 4.43-4.39 (m, 3H), 3.80 (s, 6H), 3.51-3.41 (m, 2H).
1-((2R,3R,4R,5R)-5-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-3,4-bis((tert-butyldimethylsilyl)oxy)tetrahydrofuran-2-yl)pyrimidin-2(1H)-one[ No CAS ]
In pyridine; dichloromethane; at 20℃;Inert atmosphere;
Pyridoxine hydrochloride 3 (25.0 g, 0.121 mol) was azeotroped with pyridine (200 mL), suspended in pyridine (250 mL) and placed under an Ar blanket. DMTrCI (90.6 g, 0.267 mol) dissolved in a mixture of CH2CI2 (300 mL) and pyridine (50 mL) was added to the suspension dropwise, complete dissolution was observed after approximately half the DMTrCI solution was added and the solution stirred at rt overnight. The reaction mixture was concentrated in vacuo to afford a yellow gum which was subsequently dissolved in CH2CI2 (750 ml_) and washed sequentially with deionised water (500 ml_) and brine (500 ml_). The aqueous phase was back-extracted with CH2CI2 (50 ml_), the combined organic phases were then dried over Na2S04, filtered and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel (packed hexane/EtOAc/NEts, 2: 1 :0.01 and eluted with hexane/EtOAc, 2: 1 to 1 : 1 ), pure fractions were identified by TLC (hexane/EtOAc, 1 : 1 ), pooled and concentrated to afford a bright yellow foam. Acetonitrile (200 ml_) was added to the product and the solids from the resulting suspension isolated by filtration. The solids were washed with further acetonitrile (2 x 100 ml_) to afford a free-flowing pale yellow powder, which on drying for 2 h under vacuum afforded the desired bis-ether 25 (79.4 g, 85%); Rf 0.26 (0335) (hexane/EtOAc, 1 : 1 , PMA stain); 1H NMR (500 MHz, DMSO-d6) delta 8.76 (s, 1 H, OH), 8.29 (s, 1 H, CH-C1 ), 7.35-7.30 (m, 2H, CH-Ph), 7.28-7.13 (m, 14H, CH-Ph), 7.06 (d, J = 8.9 Hz, 4H, CH-Ph), 6.79 (d, J = 8.9 Hz, 4H, CH-Ph), 6.73 (d, J = 8.9 Hz, 4H, CH-Ph), 4.09 (s, 2H, CH2-C7), 3.97 (s, 2H, CH2-C8), 3.72 (s, 6H, CH3-MeOPh), 3.71 (s, 6H, CH3-MeOPh), 2.43 (s, 3H, CH3-C6); 13C NMR (125 MHz, DMSO) delta 158.1 (C-Ph), 158.0 (C- Ph), 148.5 (C-C5), 145.9 (C-C4), 145.0 (C-Ph), 144.6 (C-C2), 138.0 (CH- C1 ), 135.6 (C-Ph), 135.3 (C-Ph), 131 .9 (C-C3), 129.5 (CH-Ph), 129.4 (CH- Ph), 127.8 (CH-Ph), 127.7 (C-Ph), 127.5 (CH-Ph), 127.4 (CH-Ph), 126.6 (C-Ph), 126.6 (C-Ph) 1 13.1 (CH-Ph), 1 13.0 (CH-Ph), 86.1 (C-CPh3), 86.1 (C-CPh3), 61 .2 (CH2-C7), 57.3 (CH2-C8), 55.0 (CH3-OMe), 19.9 (CH3-C1 );
7-[2,5-bis-O-(tert-butyldimethylsilyl)-β-D-ribofuranosyl]-4-[di-(4-methoxyphenyl)phenylmethyl]amino-7H-pyrrolo[2,3-d]pyrimidine[ No CAS ]
7-[3,5-bis-O-(tert-butyldimethylsilyl)-β-D-ribofuranosyl]-4-[di-(4-methoxyphenyl)phenylmethyl]amino-7H-pyrrolo[2,3-d]pyrimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
2.2 g; 1 g
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 (3.0 g, 6.0 mmol) in anhydrous pyridine (30 mL) was added 4,4?-dimethoxytrityl chloride (2.8 g, 8.2 mmol) and the reaction mixture was stirred at room temperature overnight. The mixture was then triturated with aqueous pyridine and extracted with ether. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated to a yellow foam (5.6 g). The residue was purified by flash chromatography over silica gel using 20-25% EtOAc in hexanes as the eluent. The appropriate fractions were collected and concentrated to furnish 2?,5?-O-bis-O-(tert-butyldimethylsilyl)- and 3?,5?-bis-O-(tert-butyldimethylsilyl) protected nucleosides as colorless foams (2.2 g and 1.0 g, respectively).
0.5 g (0.57 mmol) of fine diosgenin, 0.77 g (1.70 mmol) of DMT-Cl was dissolved in 10 mL of pyridine, reacted at room temperature overnight, and TCL showed the end of the reaction. The reaction solution was concentrated under reduced pressure, and water was added to precipitate a white solid which was filtered through a silica gel column, trichloromethane / methanol 30: 1 and the eluent was concentrated to give 0.12 g of a white solid.
10 g of decitabine (43.82 mmol, 1 eq) was added to 60 mL of pyridine, and distilled under reduced pressure three times to remove the water content in the raw material, and dissolved in 50 mL of dry pyridine. 22.27 g of 4,4'-dimethoxytriphenylchloromethane (65.7 mmol, 1.5 eq) was dissolved in 30 mL of pyridine, and the system was added dropwise at room temperature under nitrogen. After the reaction was completed, dichloromethane and water were added, and the organic layer was washed with saturated sodium hydrogen sulfate. Filtration and evaporation of the solvent under reduced pressure gave a crude material. After the crude product was separated and purified by chromatography (V (CH2CI2):V (MeOH) =45:1), 2,2 g of white solid of I-2-B was obtained, yield: 92.0%.
(2R,3R,4R,5R)-5-(6-benzamido-9H-purin-9-yl)-2-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-4-fluorotetrahydrofuran-3-yl (2-cyanoethyl) diisopropylphosphoramidite[ No CAS ]