* 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] Chemische Berichte, 1952, vol. 85, p. 1000,1005
4
[ 58-61-7 ]
[ 28128-28-1 ]
Yield
Reaction Conditions
Operation in experiment
85.2%
With m-chloroperoxybenzoic acid; 3-chloro-benzenecarboperoxoic acid In hydrogenchloride; water; 2,4-dichlorophenoxyacetic acid dimethylamine; toluene
EXAMPLE 1 8-Chloroadenine (1) To a solution of adenosine (2.67 g, 10 mmol) in DMA/HCl (0.5M, 45 mL) was added m-chloroperoxybenzoic acid (MCPBA, 3.22 g, 16 mmol 87percent) and stirred at room temperature for 2.5 h. An additional portion of MCPBA (0.9 g, 5 mmol) was added and stirring continued for another 1 h. Toluene (50 mL) was added to the reaction mixture and the solvents evaporated at 60° C. under vacuo to dryness. The residue was dissolved in water (50 mL) and extracted with ether (3*50 mL). The pH of the aqueous phase was adjusted to 5 with 2N NaOH and then diluted with EtOH (100 mL). The solution was stored in the refrigerator overnight. The light yellow solid that separated was collected, washed with cold EtOH (2*25 mL) and dried to give 1.44 g (85.2percent) of 1: mp 305°-310° C. (dec.) [Lit. mp>300° C. (dec.)]: IR (KBr): 630 (C-C1), 3100-3300 (NH2) cm-1: UV: λmax (pH 1) 262 nm (ε 8,700): λmax (pH 7) 268 nm (ε 7,900): λmax (pH 11) 269 nm (ε 8,300): 1 H NMR (Me2 SO-d6): δ 7.48 (br s, 2, NH2), 8.10 (s, 1, C2 H) and 13.60 (br s, 1, N9 H).
Reference：
[1] Patent: US4861873, 1989, A,
5
[ 3083-77-0 ]
[ 58-61-7 ]
[ 5536-17-4 ]
Reference：
[1] Russian Journal of Bioorganic Chemistry, 2016, vol. 42, # 4, p. 372 - 380[2] Bioorg. Khim., 2016, vol. 42, # 4, p. 411 - 420,10
6
[ 58-61-7 ]
[ 5536-17-4 ]
Reference：
[1] Patent: CN107556356, 2018, A,
[2] Patent: CN107556356, 2018, A,
[3] Patent: CN107556356, 2018, A,
[4] Patent: CN107556356, 2018, A,
[5] Patent: CN107556356, 2018, A,
7
[ 634-01-5 ]
[ 5536-17-4 ]
[ 58-61-7 ]
[ 524-69-6 ]
Reference：
[1] Doklady Chemistry, 1987, vol. 296, # 10, p. 431 - 434[2] Dokl. Akad. Nauk SSSR Ser. Khim., 1987, vol. 296, # 4, p. 872 - 876
8
[ 958-09-8 ]
[ 5536-17-4 ]
[ 58-61-7 ]
[ 524-69-6 ]
Reference：
[1] Doklady Chemistry, 1987, vol. 296, # 10, p. 431 - 434[2] Dokl. Akad. Nauk SSSR Ser. Khim., 1987, vol. 296, # 4, p. 872 - 876
9
[ 362-75-4 ]
[ 5536-17-4 ]
[ 958-09-8 ]
[ 58-61-7 ]
[ 524-69-6 ]
Reference：
[1] Doklady Chemistry, 1987, vol. 296, # 10, p. 431 - 434[2] Dokl. Akad. Nauk SSSR Ser. Khim., 1987, vol. 296, # 4, p. 872 - 876
10
[ 58-61-7 ]
[ 892-48-8 ]
Yield
Reaction Conditions
Operation in experiment
89%
With thionyl chloride In N,N,N,N,N,N-hexamethylphosphoric triamide; water
EXAMPLE 2 Preparation of 5'-deoxy-5'-ethylthioadenosine 1 kg of adenosine is dissolved under a nitrogen atmosphere in 10 l of hexamethylphosphoramide, and 7.5 l of thionyl chloride are added under cooling. The mixture is left to react at ambient temperature for 20 hours. 10 l of water are added, and the mixture neutralised with 2 N NaOH. The 5'-deoxy-5'-chloroadenosine which thus forms is allowed to crystallise overnight at 3° C. It is filtered off. 0.950 kg of 5'-deoxy-5'-chloroadenosine are obtained (yield 89percent).
86%
Stage #1: With pyridine; thionyl chloride In acetonitrile at 0 - 5℃; Stage #2: With ammonium hydroxide In methanol; water; acetonitrile at 20℃; for 0.5 h;
Compound 308l-(3-((((2S,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methyl)thio)propyl)-3-(4-(tert-butyI)phenyl)ureaStep 1. (2R,3R,4S,5S)-2-(6-amino-9H-purin-9-yl)-5- (chloromethyl)tetrahydrofuran-3,4-diol To a solution of (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5- (hydroxymethyl)tetrahydrofuran-3,4-diol (1 g, 3.47 mmol) in pyridine (593 mg, 0.6 ml, 7.49 mmol) in acetonitrile (10ml) cooled in an ice bath was added SOCl2 (2.22g, 1.36ml,18.65mmol). Stirring was continued at 0-5° C for 3-4 h, and warning to ambient temperature for overnight. The resulting suspension was concentrated in vacuo. To the reaction mixture was added methanol (20 ml), water (2ml), and NH4OH (4 ml), followed by stirring for 0.5 h at room temperature. The reaction mixture was concentrated to dryness. The compound was dissolved in MeOH, silica gel (3g) was added and then solvent was removed. The residue was purified by SGC to elute with EA : MeOH (0percent-10percent) to obtain the title compound (0.915 g, yield 86percent) as yellowish solid. NMR (500 MHz, MeOD): δ 8.24 (s, 1H), 8.02 (s, 1H), 7.27-7.20 (m, 5H), 6.19 (d, J = 2.0 Hz, 1H), 5.48-5.46 (m, 1H), 5.08-5.06 (m, 1H), 4.43 (t, J = 4.0, Hz, 1H), 3.83- 3.81 (m, 2H).
86%
Stage #1: With pyridine; thionyl chloride In acetonitrile at 0 - 5℃; Stage #2: With ammonium hydroxide In methanol; water; acetonitrile at 20℃; for 0.5 h;
((3aS,4S,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2 dimethyltetrahydro furo[3,4- d][l,3]dioxol-4-yl)methanethiolStep 1. Preparation of (2R,3R,4S,5S)-2-(6-amino-9H-purin-9-yl)-5- (chloromethyl) tetrahydrofuran-3,4-diolTo a solution of (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5- (hydroxymethyl)tetrahydrofuran-3,4-diol (1 g, 3.47 mmol) in pyridine (593 mg, 0.6 ml, 7.49 mmol) in acetonitrile (10ml) cooled in an ice bath was added SOCl2 (2.22g, 1.36ml,18.65mmol). Stirring was continued at 0-5° C for 3-4 h, and warning to ambient temperature for overnight. The resulting suspension was concentrated in vacuo. To this reaction mixture was added methanol (20 ml), water (2ml), and NH4OH (4 ml), followed by stirring for 0.5 h at room temperature. The reaction mixture was concentrated to dryness. The compound was dissolved in MeOH, silica gel (3g) was added and then solvent was removed. The residue was purified by SGC to elute with EA : MeOH (0percent-10 ) to obtain the target compound (0.915 g, yield 86percent) as yellowish solid. NMR (500 MHz, MeOD): δ 8.24 (s, IH), 8.02 (s, IH), 7.27-7.20 (m, 5H), 6.19 (d, / = 2.0 Hz, IH), 5.48-5.46 (m, IH), 5.08-5.06 (m, IH), 4.43 (t, J = 4.0, Hz, IH), 3.83- 3.81 (m, 2H), 3.01-2.99 (br s, 2H), 1.60 (s, 3H), 1.38 (s, 3H) ppm, LCMS (m/z): 395.8 [M+H]+.
60%
Stage #1: With pyridine; thionyl chloride In acetonitrile at 0 - 20℃; Stage #2: With ammonium hydroxide In methanol; water at 20℃; for 0.5 h;
To a cold suspension (0°С) of adenosine (3.0 g, 11.2 mmol) in acetonitrile (35 ml) and pyridine (22.4 mmol, 1.8 ml), thionyl chloride (4.1 ml, 56.1 mmol) was slowly added and the mixture was stirred 4 h under 0°С. The resulting solution was kept at ambient temperature overnight. The precipitate was filtered and dissolved in H2O/MeOH (5:50 ml) and 25percent aqueous ammonia (4.7 ml) was added to the mixture. The reaction mixture was kept at ambient temperature for 30 min and evaporated in vacuum. The residue was transferred to a glass filter, washed with cold water (2 * 20 ml) and dried in vacuum desiccator over P2O5. Yield 1.92 g (60percent) as white crystals. Rf 0.15 (CH2Cl2-EtOH, 9:1 v/v). 1H NMR (DMSO-d6): δ = 3.84 (dd, 1H, J5'b-4' = 6.3 Hz, J5'ba = -11.6 Hz, H5'b), 3.94 (dd, 1H, J5'a-4' = 5.1 Hz, J5'ab = -11.6 Hz, H5'a), 4.10 (ddd, 1H, J4'-5'b = 6.3 Hz, J4'-5'a = 5.1 Hz, J4'-3' = 4 Hz, H4'), 4.23 (ddd, 1H, J3'-4' = 4 Hz, J3'-OH = 5.1 Hz, J3'-2' = 5 Hz, H3'), 4.75 (dd, 1H, J2'-3' = 5 Hz, J2'-1' = 5.6 Hz, H2'), 5.41 (d, 1H, JOH-3' = 5.1 Hz, 3'OH), 5.56 (d, 1H, JOH-2' = 6.03 Hz, 2'OH), 5.93 (d, 1H, J1'-2' = 5.6 Hz, H1'), 7.26 (s, 2H, NH2), 8.15 (s, 1H, H8), 8.33 (s, 1H, H2).
Reference：
[1] Journal of Medicinal Chemistry, 2012, vol. 55, # 18, p. 8066 - 8074,9
[2] Angewandte Chemie - International Edition, 2016, vol. 55, # 46, p. 14277 - 14280[3] Angew. Chem., 2016, vol. 128, # 46, p. 14489 - 14492,4
[4] Tetrahedron Letters, 2018, vol. 59, # 4, p. 415 - 417
[5] Patent: US4373097, 1983, A,
[6] Collection of Czechoslovak Chemical Communications, 1985, vol. 50, # 7, p. 1514 - 1518
[7] Journal of Sulfur Chemistry, 2015, vol. 36, # 2, p. 135 - 144
[8] Patent: US2016/90397, 2016, A1, . Location in patent: Paragraph 0056
[9] Patent: WO2012/82436, 2012, A2, . Location in patent: Page/Page column 179-180
[10] Patent: WO2012/82436, 2012, A2, . Location in patent: Page/Page column 190-191
[11] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1992, p. 1349 - 1358
[12] Tetrahedron Letters, 1990, vol. 31, # 51, p. 7485 - 7488
[13] Journal of Medicinal Chemistry, 2011, vol. 54, # 21, p. 7734 - 7738
[14] European Journal of Medicinal Chemistry, 2016, vol. 111, p. 84 - 94
[15] Chemistry - A European Journal, 2014, vol. 20, # 18, p. 5397 - 5402
[16] Tetrahedron Letters, 1988, vol. 29, # 45, p. 5729 - 5732
[17] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 22, p. 6239 - 6244
[18] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 5, p. 1484 - 1487
[19] ChemBioChem, 2012, vol. 13, # 8, p. 1167 - 1173
[20] Patent: WO2014/144776, 2014, A1,
[21] ACS Medicinal Chemistry Letters, 2015, vol. 6, # 4, p. 408 - 412
[22] Patent: EP3144001, 2017, A1,
[23] Patent: WO2017/218802, 2017, A1, . Location in patent: Paragraph 00168
11
[ 58-61-7 ]
[ 58-63-9 ]
Reference：
[1] Nucleosides, Nucleotides and Nucleic Acids, 2004, vol. 23, # 3, p. 613 - 624
[2] Journal of the American Chemical Society, 2013, vol. 135, # 9, p. 3465 - 3473
[3] ChemPlusChem, 2013, vol. 78, # 2, p. 157 - 165
12
[ 58-61-7 ]
[ 2946-39-6 ]
Yield
Reaction Conditions
Operation in experiment
82.5%
With bromine; sodium acetate In water
Example 1: Modified siRNA Molecules8-methoxyadenosine phosphoramidite was synthesized and incorporated into the anti- sense strand of caspase 2 siRNA. Figure 7A shows a schematic of the double-stranded positive control siRNA (SEQ ID NO: 20 (top) and SEQ ID NO: 21 (bottom)) and the double-stranded negative control siRNA (SEQ ID NO: 22 (top) and SEQ ID NO: 23 (bottom). Figure 7B shows a schematic for a singly modified siRNA, wherein the modification can be, but is not limited to, 8-proparglyoxyadenosine, 8-phenethyloxyadenosine, and 8-cyclohyexylethyloxyadenosine. In Figure 7B, 4AS corresponds to SEQ ID NO: 24, 6AS corresponds to SEQ ID NO: 25, 10AS corresponds to SEQ ID NO: 26, and 15AS corresponds to SEQ ID NO: 27.The bromination of adenosine is known in the art; generally, a three to four- fold excess of bromine generates a yield of about 75percent to about 82.5percent of 8-bromoadenosine. To protect the 2'-OH group during the synthesis of ribo-phosphoramidites, the 5' -OH ofN^-benzoyladenosine was first protected; and then t-butyldimethylsilyl chloride (TBDMS-C1) was used to protect the 2' -OH. Although the addition of Ag+ ion is recommended to minimize unavoidable reaction at the 3 '-OH, the unwanted reaction generally occurs and the overall yield is significantly reduced. Therefore, to accomplish a good overall yield, a novel protecting group di-ibutylsilyl ditriflate (DTBSDT), which protects the 5' -OH and the 3' -OH simultaneously and leaves the 2'-OH ready to be protected by TBDMS-C1 was used. The two reactions were basically a one- pot reaction, which eliminated the need for tedious separation. The reaction was almost quantitative with about 96percent to about 98percent product yield observed. (See Figures 3 and 4).Synthesis of the methoxy derivative using sodium methoxide reagent in methanol yielded the 8-methoxyadenosine derivative as well as the 8-oxoadenosine derivative. The separation of these two derivates was not trivial and the yield of the desired compound was below 50percent. Thus, the methoxy anion was generated in situ by reacting n-BuLi with excess anhydrous methanol. This reaction was much more efficient and yielded about 85percent to about 93percent of the desired product. The deprotection of 5' -OH and the 3'-OH was accomplished using a special fluoride reagent, HF -pyridine, at sub-zero temperature. These DMT reactions generated low yields (about 40percent to about 50percent) of the desired product. The phosphoramidite synthesis step yielded about 95percent to about 98percent of desired product. The 8- methoxy adenosine phosphoramidite was then incorporated into the antisense strand at position 9 or 14 (opposite to positions 11 and 6 of the sense strand, respectively), or both positions 9 and 14. The propargyl moiety at position 8 of adenosine can simplify the syntheses of other position 8 substituted adenosine analogs. The alkyne moiety of 8- propargyladenosine in siRNA can be "clicked" with suitable water-soluble azides leading to the formation of desirable minor groove modification.
81%
With bromine In water at 20℃; for 47 h; aq. acetate buffer
Saturated bromine-water (18.5 mL) was added slowly to a suspension of adenosine (0.5 g, 1.9 mmol) in NaOAc buffer (11.4 mL, 0.5 M, pH 4). The mixture was stirred at r.t. for 47 h. The solution was decolorized by the addition of 5 N NaHSO3, and the pH of the solution was then adjusted to 7 with 2 N NaOH. The resulting solids were collected by filtration, successively washed with water and acetone, and dried in vacuo to yield 19 (81percent). 1H NMR (270 MHz, DMSO-d6) δ: 3.46-3.74 (2H, m, H-5'), 3.98 (1 H, dd, J = 6.3, 4.0 Hz, H-4'), 4.16-4.22 (1 H, m, H-3'), 5.08 (1 H, dd, H-2'), 5.24 (1 H, d, J = 4.6 Hz, 3'-OH), 5.47 (1H, d, J = 6.3 Hz, H-1'), 5.52 (1 H, dd, J = 8.6, 4.0 Hz, 5'-OH), 5.83 (1 H, d, J = 6.5 Hz, 2'-OH), 7.56 (2H, br s, NH2), 8.11 (1H, s, H-2). ESI MS: m/z 345.1 Da [M+H]+,C10H12BrN5O4 Mol. Wt. 346.14.
73%
With sodium azide; bromoisocyanuric acid monosodium salt In water; N,N-dimethyl-formamide at 20℃; for 0.5 h;
General procedure: 5'-O-Monomethoxytrityl-N2-phenoxyacetylguanosine (33, 0.138 g, 0.2 mmol) was dissolved inaqueous DMF solution (H2O:DMF 1:4, 5 mL) under stirring. SMBI (1.1 equiv., 0.051 g, 0.22 mmol)was added at r.t. and the mixture stirred. Progress of the reaction was followed by TLC. An additionalamount of the reagent (0.15 equiv., 0.007 g) was added into the reaction mixture after 1.5 h. Oncompletion of the reaction by 2 h, the reaction mixture was filtered, evaporated to dryness underreduced pressure and coevaporated with water (2 × 2 mL). The crude reaction mixture was purified bycolumn chromatography (4percent–5percent MeOH in DCM, v/v) to afford nucleoside 34 (0.148 g, 96percent) in pureform as a white solid.8-Bromo-5'-O-monomethoxytrityl-N2-phenoxyacetylguanosine (34).
48%
With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione In N,N-dimethyl-formamide at 25℃; for 5 h;
Typical procedure for the bromination of unprotected nucleosides: DBH (323 mg, 1.13 mmol) was added to a stirred solution of 1d (500 mg, 2.05 mmol) in DMF (5 mL). The resulting pale-yellow solution was stirred at room temperature for 20 minutes or until TLC showed absence of starting material and formation of less polar product. Volatiles were evaporated and the residue was coevaporated with MeCN. The resulting pale solid was crystallized from hot acetone to give 2d (500 mg, 75percent) as colorless crystals with data as reported.14
53.1 kg
Stage #1: With sodium acetate; acetic acid In water at 75℃; for 0.5 h; Industrial scale Stage #2: With bromine In water at 30℃; for 10 h; Industrial scale
First, in a 2t reactor, 50 kg (185 mol) of adenosine and 600 kg of water, acetic acid-sodium acetate buffer solution (0.4 M, pH 4.5) were sequentially added, and then the temperature was raised to 75 ° C, and the temperature was kept for 30 minutes until the reaction system was dissolved;Then, the temperature was lowered to 30 ° C, 59 kg of Br 2 was further added, and then reacted at 30 ° C for 10 h, and the reaction was carried out by a high-performance liquid phase method, and the reaction was terminated when the content of the raw material in the reaction system was less than 1percent.Finally, after the reaction is completed, the reaction system is cooled to room temperature.Unreacted Br2 was removed by adding 19.5 kg of NaHSO3, then the pH was adjusted to 7 with a 5percent NaOH solution, filtered, and the filter cake was washed with water.Drying in vacuo gave a yellow product, 8-bromoadenosine, 53.1 kg.
Reference：
[1] Journal of Organic Chemistry, 2014, vol. 79, # 21, p. 9992 - 9997
[2] European Journal of Organic Chemistry, 2009, # 10, p. 1515 - 1521
[3] Patent: WO2011/119674, 2011, A1, . Location in patent: Page/Page column 50-51
[4] Journal of the American Chemical Society, 2012, vol. 134, # 42, p. 17643 - 17652
[5] Synthesis, 2004, # 17, p. 2799 - 2804
[6] European Journal of Medicinal Chemistry, 2012, vol. 54, p. 202 - 209
[7] Journal of Medicinal Chemistry, 2011, vol. 54, # 10, p. 3492 - 3499
[8] Tetrahedron, 2007, vol. 63, # 18, p. 3782 - 3789
[9] Tetrahedron, 1993, vol. 49, # 19, p. 4035 - 4050
[10] Journal of Organic Chemistry USSR (English Translation), 1985, vol. 21, p. 1639 - 1644[11] Zhurnal Organicheskoi Khimii, 1985, vol. 21, # 8, p. 1795 - 1800
[12] Biological Chemistry, 2011, vol. 392, # 4, p. 357 - 369
[13] Molecules, 2013, vol. 18, # 10, p. 12740 - 12750
[14] Journal of the American Chemical Society, 2013, vol. 135, # 9, p. 3423 - 3438
[15] Journal of Natural Products, 2005, vol. 68, # 11, p. 1689 - 1691
[16] Tetrahedron Letters, 2012, vol. 53, # 26, p. 3333 - 3336
[17] Angewandte Chemie - International Edition, 2017, vol. 56, # 13, p. 3536 - 3540[18] Angew. Chem., 2017, p. 3590 - 3594,5
[19] Indian Journal of Chemistry - Section A Inorganic, Physical, Theoretical and Analytical Chemistry, 2013, vol. 52, # 8-9, p. 1004 - 1013
[20] Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 8, p. 2653 - 2659
[21] Chemistry - A European Journal, 2007, vol. 13, # 12, p. 3441 - 3449
[22] Structural Chemistry, 2010, vol. 21, # 1, p. 245 - 254
[23] Journal of Medicinal Chemistry, 2011, vol. 54, # 7, p. 2114 - 2126
[24] Beilstein Journal of Organic Chemistry, 2017, vol. 13, p. 495 - 501
[25] Patent: CN108129535, 2018, A, . Location in patent: Paragraph 0017-0028
[26] Organometallics, 2018, vol. 37, # 22, p. 4181 - 4185
13
[ 58-61-7 ]
[ 43157-50-2 ]
Reference：
[1] ACS Medicinal Chemistry Letters, 2011, vol. 2, # 12, p. 890 - 895
[2] Journal of Fluorescence, 2014, vol. 24, # 1, p. 213 - 230
[3] European Journal of Medicinal Chemistry, 2016, vol. 107, p. 204 - 218
14
[ 58-61-7 ]
[ 34408-14-5 ]
Yield
Reaction Conditions
Operation in experiment
52%
With N-chloro-succinimide; acetic acid In N,N-dimethyl-formamide at 20℃; for 48 h;
Procedure 2: Adenosine (1.09g, 4.08 mmol) was suspended in DMF (50 mL) and glacial acetic acid (10 mL) was added. A solution of N-chlorosuccinimide (2 g, 15 mmol) in DMF (15 mL) was added dropwise. The reaction mixture was stirred at rt for 48 hours and the volatiles were evaporated in vacuo to give yellow gum. The crude was absorbed on silica and purified by silica gel CC (packed in 5percent MeOHICHC13, eluted with 7percent MeOHICHC13) to yield a white powder (0.65 g, 52 percent).‘H NIVIR (500 MHz, DMSO-d6) 8.16 (s, 1H, H-2), 7.55 (br s, 2H, NH2), 5.86 (d, J = 6.8 Hz, 1H, Hi’), 5.48 (d, J 6.2 Hz, iH, 2’OH), 5.45 (d, J 4.0 Hz, iH, 5’-OH), 5.23 (d, J4.6 Hz, iH, 3’OH), 5.08-5.06 (m, iH, H-2’), 4.23-4.i8 (m, iH, H3’), 4.01-3.96 (m, iH, H4’),3.72-3.65 (m, iH, H5’), 3.57-3.50 (m, iH, H5’).
Reference：
[1] Patent: WO2017/207989, 2017, A1, . Location in patent: Page/Page column 55; 56
[2] Journal of Organic Chemistry, 1981, vol. 46, # 13, p. 2819 - 2823
[3] Nucleosides, nucleotides and nucleic acids, 2002, vol. 21, # 8-9, p. 599 - 617
15
[ 7732-18-5 ]
[ 58-61-7 ]
[ 34408-14-5 ]
Yield
Reaction Conditions
Operation in experiment
65%
With acetic acid In methanol; N,N-dimethyl-formamide
Method B to a solution of adenosine (1.09 g, 4.1 mmol) in DMF (50 mL) and AcOH (10 mL) was added N-Chlorosuccinamide (NCS, 2.0 g, 15 mmol). The reaction mixture was stirred at room temperature for 6 days. The solvents were evaporated to dryness and the residue was purified by HPLC on a C-18 reverse phase column using MeOH:AcOH:H2 O (18:1:18, v/v) to give 0.8 g (65percent) of 2, which was identical to the title compound prepared by Method A.
Reference：
[1] Patent: US4861873, 1989, A,
16
[ 58-61-7 ]
[ 69304-45-6 ]
Yield
Reaction Conditions
Operation in experiment
94%
With pyridine In dichloromethane; water; toluene
(1) 3',5'-O-(1,1,3,3-Tetraisopropyldisiloxane-1,3-diyl)-adenosine Adenosine (4.61 g, 17.3 mmol.) was subjected to azeotropic distillation with anhydrous pyridine. To the residue were added anhydrous pyridine (43 mL) and 1,1,3,3-tetraisopropyl-1,3-dichlorodisiloxane (5.70 mL, 1.72 mmol.). The resulting mixture was stirred at room temperature for 5 hours. Then, to the mixture were added dichloromethane (30 mL) and a mixture of pyridine and water (1:1, vol/vol, 20 mL). The organic layer was extracted three times with dichloromethane (30 mL x 3). The extracts were combined and placed under reduced pressure to remove the solvent. To the residue was added toluene, and the resulting solution was subjected to azeotropic distillation, to remove pyridine. The residual solution was placed on a silica gel column and eluted with 0.5percent pyridine-methanol/ dichloromethane (1/50) to give the subject compound (8.30 g, 94percent).
94%
With pyridine In dichloromethane; water; toluene
(1) 3',5'-O-(1,1,3,3-Tetraisopropyldisiloxane-1,3-diyl) adenosine Adenosine (4.61 g, 17.3 mmol.) was subjected to azeotropic distillation with anhydrous pyridine. To the residue were added anhydrous pyridine (43 mL) and 1,1,3,3-tetraisopropyl-1,3-dichlorodisiloxane (5.70 mL, 1.72 mmol.). The mixture was stirred at room temperature for 5 hours. Then, to the mixture were added dichloromethane (30 mL) and a mixture of pyridine and water (1:1, vol/vol, 20 mL). The organic layer was extracted three times with dichloromethane (30 mL x 3). The extracts were combined and placed under reduced pressure to remove the solvent. To the residue was added toluene, and the resulting solution was subjected to azeotropic distillation, to remove pyridine. The residual solution was placed on a silica gel column and eluted with 0.5percent pyridine-methanol/ dichloromethane (1/50) to give the subject compound (8.30 g, 94percent).
94%
at 20℃; for 24 h;
To a suspension of adenosine (3 g, 11 mmol) in anhydrous pyridine (40 mL)were added dimethylaminopyridine (0.7 g, 5.6 mmol) and dichloro-1,1,3,3-tetraisopropyldisiloxane (4 mL, 13 mmol). After stirring for 24h, the reaction mixture was concentrated in vacuo. The residue was purified by silica gel chromatography (CH2Cl2/ MeOH: 95/05) to afford 1 as a white solid (5.3 g, 94percent). 1H NMR (300 MHz, DMSO-d6) δ 8.21 (s, 1H, H8), 8.07 (s, 1H, H2),7.32 (br, 2H, NH2), 5.87 (s, 1H, H1’), 5.62 (d, J = 4.6 Hz, 1H, OH), 4.79 (m, 1H, H3’), 4.51 (t, J = 4.7 Hz, 1H, H2’), 4.08-3.90 (m, 3H,2H5’ and H4’), 1.09-0.98 (m, 28H); UV (EtOH) λmax= 260 nm (εmax=16700); MS (ESI+): m/z = 510.2 (M+H)+; HRMS calculated for C22H40N5O5Si2(M+H+): 510. 2575, found 510.2568.
Reference：
[1] Chemistry Letters, 1982, p. 15 - 18
[2] Patent: EP617046, 1994, A1,
[3] Patent: EP624372, 1994, A2,
[4] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 17, p. 4227 - 4230
[5] Organic Letters, 2006, vol. 8, # 1, p. 55 - 58
[6] Journal of Organic Chemistry, 2008, vol. 73, # 2, p. 603 - 611
[7] Acta Chemica Scandinavica, 1995, vol. 49, # 3, p. 217 - 224
[8] Journal of the American Chemical Society, 1981, vol. 103, # 4, p. 932 - 933
[9] Journal of Medicinal Chemistry, 2015, vol. 58, # 18, p. 7349 - 7369
[10] Carbohydrate Research, 1991, vol. 216, # 1, p. 257 - 269
[11] Journal of the American Chemical Society, 1990, vol. 112, # 25, p. 9059 - 9068
[12] Journal of the American Chemical Society, 1983, vol. 105, # 12, p. 4059 - 4065
[13] Canadian Journal of Chemistry, 1983, vol. 61, p. 1911 - 1920
[14] Journal of Organic Chemistry, 2008, vol. 73, # 13, p. 4994 - 5002
[15] Chemical and Pharmaceutical Bulletin, 2008, vol. 56, # 4, p. 423 - 432
[16] Collection of Czechoslovak Chemical Communications, 1982, vol. 47, # 1, p. 156 - 166
[17] Bulletin of the Polish Academy of Sciences, Chemistry, 1984, vol. 32, # 11-12, p. 433 - 451
[18] Journal of Organic Chemistry, 1991, vol. 56, # 25, p. 7108 - 7113
[19] Tetrahedron, 1998, vol. 54, # 3-4, p. 573 - 592
[20] Nucleosides, Nucleotides and Nucleic Acids, 2005, vol. 24, # 5-7, p. 513 - 518
[21] Patent: WO2012/75140, 2012, A1, . Location in patent: Page/Page column 149-151
17
[ 18043-71-5 ]
[ 58-61-7 ]
[ 69304-45-6 ]
Reference：
[1] European Journal of Organic Chemistry, 2011, # 6, p. 1140 - 1147
18
[ 13154-24-0 ]
[ 58-61-7 ]
[ 69304-45-6 ]
Reference：
[1] Nucleosides, Nucleotides and Nucleic Acids, 2009, vol. 28, # 11-12, p. 1042 - 1050
19
[ 58-61-7 ]
[ 3056-18-6 ]
Reference：
[1] Canadian Journal of Chemistry, 1981, vol. 59, # 17, p. 2601 - 2607
With dmap; triethylamine; In acetonitrile; at 20℃; for 24h;
A suspension of adenosine (5 g, 0.02 mol) in acetonitrile (100 mL) was treated with 4-(dimethylamino)pyridine (DMAP) (4 equiv., 0.008 mol, 0.23 g), triethylamine (4 equiv., 0.08 mol, 7.69 g, 10.59 mL) and acetic anhydride (4 equiv., 0.08 mol, 7.76 g, 7.18 mL ). The resulting mixture was stirred at room temperature for 24 hours and then reaction mixture was cooled in the ice bath and quenched by addition of water (20 mL). Product was extracted with chloroform (3 x 20 mL). The organic phase was washed with water (3 x 20 mL), dried over MgSO4 filtered, and concentrated in vacuo. The solid residue was purified by crystallization from hot ethanol (100 mL) to afford the acetylated nucleosides 1 (7.1 g ) as a white solid in 96 % yield.
With pyridine; In dichloromethane; water; toluene;
(1) 3',5'-O-(1,1,3,3-Tetraisopropyldisiloxane-1,3-diyl)-adenosine Adenosine (4.61 g, 17.3 mmol.) was subjected to azeotropic distillation with anhydrous pyridine. To the residue were added anhydrous pyridine (43 mL) and 1,1,3,3-tetraisopropyl-1,3-dichlorodisiloxane (5.70 mL, 1.72 mmol.). The resulting mixture was stirred at room temperature for 5 hours. Then, to the mixture were added dichloromethane (30 mL) and a mixture of pyridine and water (1:1, vol/vol, 20 mL). The organic layer was extracted three times with dichloromethane (30 mL x 3). The extracts were combined and placed under reduced pressure to remove the solvent. To the residue was added toluene, and the resulting solution was subjected to azeotropic distillation, to remove pyridine. The residual solution was placed on a silica gel column and eluted with 0.5% pyridine-methanol/ dichloromethane (1/50) to give the subject compound (8.30 g, 94%).
94%
With pyridine; In dichloromethane; water; toluene;
(1) 3',5'-O-(1,1,3,3-Tetraisopropyldisiloxane-1,3-diyl) adenosine Adenosine (4.61 g, 17.3 mmol.) was subjected to azeotropic distillation with anhydrous pyridine. To the residue were added anhydrous pyridine (43 mL) and 1,1,3,3-tetraisopropyl-1,3-dichlorodisiloxane (5.70 mL, 1.72 mmol.). The mixture was stirred at room temperature for 5 hours. Then, to the mixture were added dichloromethane (30 mL) and a mixture of pyridine and water (1:1, vol/vol, 20 mL). The organic layer was extracted three times with dichloromethane (30 mL x 3). The extracts were combined and placed under reduced pressure to remove the solvent. To the residue was added toluene, and the resulting solution was subjected to azeotropic distillation, to remove pyridine. The residual solution was placed on a silica gel column and eluted with 0.5% pyridine-methanol/ dichloromethane (1/50) to give the subject compound (8.30 g, 94%).
94%
With pyridine; dmap; at 20℃; for 24h;
To a suspension of adenosine (3 g, 11 mmol) in anhydrous pyridine (40 mL)were added dimethylaminopyridine (0.7 g, 5.6 mmol) and dichloro-1,1,3,3-tetraisopropyldisiloxane (4 mL, 13 mmol). After stirring for 24h, the reaction mixture was concentrated in vacuo. The residue was purified by silica gel chromatography (CH2Cl2/ MeOH: 95/05) to afford 1 as a white solid (5.3 g, 94%). 1H NMR (300 MHz, DMSO-d6) delta 8.21 (s, 1H, H8), 8.07 (s, 1H, H2),7.32 (br, 2H, NH2), 5.87 (s, 1H, H1?), 5.62 (d, J = 4.6 Hz, 1H, OH), 4.79 (m, 1H, H3?), 4.51 (t, J = 4.7 Hz, 1H, H2?), 4.08-3.90 (m, 3H,2H5? and H4?), 1.09-0.98 (m, 28H); UV (EtOH) lambdamax= 260 nm (epsilonmax=16700); MS (ESI+): m/z = 510.2 (M+H)+; HRMS calculated for C22H40N5O5Si2(M+H+): 510. 2575, found 510.2568.
With pyridine; at 0℃;
Example 17. Preparation of (5S,6R,8R,9R)-6-(6-amino-9H-purin-9-yl)-8- (hydroxymethyl)-l,7-dioxaspiro[4.4]nonan-9-oI (94)94 78 88 89MgBr THF/-78C93 94In the preparation of 94, it is possible to forego protection of the 6-amino- purine, which means that 94 can be prepared from adenine (78) using a seven-step sequence. Step 1: Preparation of compound 88
With 1H-imidazole; In N,N-dimethyl-formamide; at 20℃; for 2h;Inert atmosphere;
To a solution of adenosine (20 g, 74.838 mmol) and imidazole (7.642 g, 1 12.257 mmol) in dry DMF (100 mL) at r.t. was added 1,3-dichloro-l, 1,3,3- tetraisopropyldisiloxane (26.335 mL, 0.986 g/mL, 82.322 mmol) under nitrogen atmosphere. The mixture was stirred at r.t. for 2h. The mixture was poured into a mixture of ice and water (200mL), and then extracted with EtOAc (2x300mL). The organic layer was successively washed with brine (4x300mL), dried over Na2S04, filtered and concentrated to afford crude intermediate 58 as white foam (41.3g) that was used as such for the next step. 'H NMR (400 MHz, DMSC /6) delta ppm 1.01 - 1.09 (m, 28 H), 3.91 - 3.96 (m, 1 H), 4.00 (dt, J=8.5, 2.9 Hz, 1 H), 4.04 (d, J=3.3 Hz, 1 H), 4.52 (t, J=4.5 Hz, 1 H), 4.80 (dd, J=8.5, 5.2 Hz, 1 H), 5.59 (d, J=4.6 Hz, 1 H), 5.87 (d, J=l .l Hz, 1 H), 7.29 (s, 2 H), 8.07 (s, 1 H), 8.20 (s, 1 H) MS (ES+): 560.3,
8.61 g
With pyridine; dmap; at 0 - 20℃; for 5h;
To a suspension of adenosine (i7, 5.80 g, 21.70 mmol) in pyridine (40 mL) at 0 C. was added DMAP (1.33 g, 10.85 mmol) followed by 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane (7.64 mL, 23.87 mmol). The resulting mixture was warmed to rt and allowed to stir 5 h after which time the mixture was concentrated in vacuo to give a yellow oil. A mixture of MeCN and diethyl ether were added to the oil resulting in the formation of a white precipitate. The resulting precipitate was filtered off and collected to give compound i18 as a white solid (8.61 g): 1H (400 MHz, CD3OD) delta 8.28 (s, 1H), 8.16 (s, 1H), 5.97 (d, J 0.8 Hz, 1H), 4.83 (dd, J 8.4, 4.9 Hz, 1H), 4.57 (d, J=4.8 Hz, 1H), 4.22-4.13 (m, 2H), 4.06 (dd, J 12.8, 2.5 Hz, 1H), 1.15-1.05 (m, 28H); LCMS (Method C) Rt 3.20 mins; m/z 510.1 (M+H+).
Adenosine 5'e [purchased from Shanghai Bied Pharmaceutical Technology Co., Ltd.] (5.0 g, 18.71 mmol) was suspended in acetonitrile (50 mL).Pyridine (6.02 mL, 74.84 mmol) was added to the suspension under nitrogen.Cool to 0 C and stir for 10 minutes.Slowly drip the thionyl chloride (13.6 mL, 187.10 mmol),The reaction was stirred at a temperature of 0 C for 4 hours.After the temperature was raised to room temperature, the reaction was stirred overnight, and the reaction mixture was evaporated to dryness. Methanol (100 mL) was added, and the mixture was stirred and the solution became clear. Ammonia water (20 mL) was added and stirred for 30 minutes.TLC check the reaction is complete,The reaction mixture was stirred to give a yellow or red oil. Water (100 mL) was added to the oil. After stirring at room temperature for 5 minutes, a white solid was precipitated, filtered, and the filter cake was vacuum dried to constant weight.The amorphous white solid product 6e (4.8 g, 16.80 mmol) was obtained, yield: 90%.
89%
With thionyl chloride; In N,N,N,N,N,N-hexamethylphosphoric triamide; water;
EXAMPLE 2 Preparation of 5'-deoxy-5'-ethylthioadenosine 1 kg of adenosine is dissolved under a nitrogen atmosphere in 10 l of hexamethylphosphoramide, and 7.5 l of thionyl chloride are added under cooling. The mixture is left to react at ambient temperature for 20 hours. 10 l of water are added, and the mixture neutralised with 2 N NaOH. The 5'-deoxy-5'-chloroadenosine which thus forms is allowed to crystallise overnight at 3 C. It is filtered off. 0.950 kg of 5'-deoxy-5'-chloroadenosine are obtained (yield 89%).
86%
Compound 308l-(3-((((2S,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methyl)thio)propyl)-3-(4-(tert-butyI)phenyl)ureaStep 1. (2R,3R,4S,5S)-2-(6-amino-9H-purin-9-yl)-5- (chloromethyl)tetrahydrofuran-3,4-diol To a solution of (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5- (hydroxymethyl)tetrahydrofuran-3,4-diol (1 g, 3.47 mmol) in pyridine (593 mg, 0.6 ml, 7.49 mmol) in acetonitrile (10ml) cooled in an ice bath was added SOCl2 (2.22g, 1.36ml,18.65mmol). Stirring was continued at 0-5 C for 3-4 h, and warning to ambient temperature for overnight. The resulting suspension was concentrated in vacuo. To the reaction mixture was added methanol (20 ml), water (2ml), and NH4OH (4 ml), followed by stirring for 0.5 h at room temperature. The reaction mixture was concentrated to dryness. The compound was dissolved in MeOH, silica gel (3g) was added and then solvent was removed. The residue was purified by SGC to elute with EA : MeOH (0%-10%) to obtain the title compound (0.915 g, yield 86%) as yellowish solid. NMR (500 MHz, MeOD): delta 8.24 (s, 1H), 8.02 (s, 1H), 7.27-7.20 (m, 5H), 6.19 (d, J = 2.0 Hz, 1H), 5.48-5.46 (m, 1H), 5.08-5.06 (m, 1H), 4.43 (t, J = 4.0, Hz, 1H), 3.83- 3.81 (m, 2H).
86%
((3aS,4S,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2 dimethyltetrahydro furo[3,4- d][l,3]dioxol-4-yl)methanethiolStep 1. Preparation of (2R,3R,4S,5S)-2-(6-amino-9H-purin-9-yl)-5- (chloromethyl) tetrahydrofuran-3,4-diolTo a solution of (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5- (hydroxymethyl)tetrahydrofuran-3,4-diol (1 g, 3.47 mmol) in pyridine (593 mg, 0.6 ml, 7.49 mmol) in acetonitrile (10ml) cooled in an ice bath was added SOCl2 (2.22g, 1.36ml,18.65mmol). Stirring was continued at 0-5 C for 3-4 h, and warning to ambient temperature for overnight. The resulting suspension was concentrated in vacuo. To this reaction mixture was added methanol (20 ml), water (2ml), and NH4OH (4 ml), followed by stirring for 0.5 h at room temperature. The reaction mixture was concentrated to dryness. The compound was dissolved in MeOH, silica gel (3g) was added and then solvent was removed. The residue was purified by SGC to elute with EA : MeOH (0%-10 ) to obtain the target compound (0.915 g, yield 86%) as yellowish solid. NMR (500 MHz, MeOD): delta 8.24 (s, IH), 8.02 (s, IH), 7.27-7.20 (m, 5H), 6.19 (d, / = 2.0 Hz, IH), 5.48-5.46 (m, IH), 5.08-5.06 (m, IH), 4.43 (t, J = 4.0, Hz, IH), 3.83- 3.81 (m, 2H), 3.01-2.99 (br s, 2H), 1.60 (s, 3H), 1.38 (s, 3H) ppm, LCMS (m/z): 395.8 [M+H]+.
84%
With pyridine; thionyl chloride; In acetonitrile; at 0 - 20℃; for 18h;
In acetonitrile (100 mL) at 0 C,(2R,3R,4S,5R)-2-(6-Amino-9H-indol-9-yl)-5-(hydroxymethyl)oxolane-3,4-diol (I- 1, adenosine, 10.0g, 37.4mmol),Pyridine (5.91 g, 74.8 mmol)And thionyl chloride (22.0 g, 185 mmol),The resulting solution was stirred at room temperature for 18 hours.It was then carefully quenched with ice water (30 mL).After removing the organic solvent under vacuum,Adjust the pH to ~8 with a saturated aqueous solution of sodium carbonate.It was then extracted with ethyl acetate (150 mL×3).Combine the organic phases,Dry with sodium sulfate and filter.The filtrate was concentrated in vacuo.The residue was purified by silica gel column chromatography (eluent:0-10% methanol in ethyl acetate solution) 9.0 g (yield: 84%)(2R,3R,4S,5S)-2-(6-Amino-9H-indol-9-yl)-5-(chloromethyl)oxolane-3,4-diol (XI-1 ),It is a white solid.
60%
To a cold suspension (0?) of adenosine (3.0 g, 11.2 mmol) in acetonitrile (35 ml) and pyridine (22.4 mmol, 1.8 ml), thionyl chloride (4.1 ml, 56.1 mmol) was slowly added and the mixture was stirred 4 h under 0?. The resulting solution was kept at ambient temperature overnight. The precipitate was filtered and dissolved in H2O/MeOH (5:50 ml) and 25% aqueous ammonia (4.7 ml) was added to the mixture. The reaction mixture was kept at ambient temperature for 30 min and evaporated in vacuum. The residue was transferred to a glass filter, washed with cold water (2 * 20 ml) and dried in vacuum desiccator over P2O5. Yield 1.92 g (60%) as white crystals. Rf 0.15 (CH2Cl2-EtOH, 9:1 v/v). 1H NMR (DMSO-d6): delta = 3.84 (dd, 1H, J5'b-4' = 6.3 Hz, J5'ba = -11.6 Hz, H5'b), 3.94 (dd, 1H, J5'a-4' = 5.1 Hz, J5'ab = -11.6 Hz, H5'a), 4.10 (ddd, 1H, J4'-5'b = 6.3 Hz, J4'-5'a = 5.1 Hz, J4'-3' = 4 Hz, H4'), 4.23 (ddd, 1H, J3'-4' = 4 Hz, J3'-OH = 5.1 Hz, J3'-2' = 5 Hz, H3'), 4.75 (dd, 1H, J2'-3' = 5 Hz, J2'-1' = 5.6 Hz, H2'), 5.41 (d, 1H, JOH-3' = 5.1 Hz, 3'OH), 5.56 (d, 1H, JOH-2' = 6.03 Hz, 2'OH), 5.93 (d, 1H, J1'-2' = 5.6 Hz, H1'), 7.26 (s, 2H, NH2), 8.15 (s, 1H, H8), 8.33 (s, 1H, H2).
2'-fluoro oligonucleotides were synthesized as described previously [Kawasaki, et. al., J. Med. Chem., 1993, 36, 831-841] and U.S. Pat. No. 5,670,633, herein incorporated by reference. The preparation of 2'-fluoropyrimidines containing a 5-methyl substitution are described in U.S. Pat. No. 5,861,493. Briefly, the protected nucleoside N6-benzoyl-2'-deoxy-2'-fluoroadenosine was synthesized utilizing commercially available 9-beta-D-arabinofuranosyladenine as starting material and whereby the 2'-alpha-fluoro atom is introduced by a SN2-displacement of a 2'-beta-triflate group. Thus N6-benzoyl-9-beta-D-arabinofuranosyladenine was selectively protected in moderate yield as the 3',5'-ditetrahydropyranyl (THP) intermediate. Deprotection of the THP and N6-benzoyl groups was accomplished using standard methodologies to obtain the 5'-dimethoxytrityl-(DMT) and 5'-DMT-3'-phosphoramidite intermediates.
2'-fluoro oligonucleotides were synthesized as described previously [Kawasaki, et. al., J. Med. Chem., 1993, 36, 831-841] and U.S. Pat. No. 5,670,633, herein incorporated by reference. The preparation of 2'-fluoropyrimidines containing a 5-methyl substitution are described in U.S. Pat. No. 5,861,493. Briefly, the protected nucleoside N6-benzoyl-2'-deoxy-2'-fluoroadenosine was synthesized utilizing commercially available 9-beta-D-arabinofuranosyladenine as starting material and whereby the 2'-alpha-fluoro atom is introduced by a SN2-displacement of a 2'-beta-triflate group. Thus N6-benzoyl-9-beta-D-arabinofuranosyladenine was selectively protected in moderate yield as the 3',5'-ditetrahydropyranyl (THP) intermediate. Deprotection of the THP and N6-benzoyl groups was accomplished using standard methodologies to obtain the 5'-dimethoxytrityl-(DMT) and 5'-DMT-3'-phosphoramidite intermediates.
With ammonia; sodium hydrogencarbonate;tin(IV) chloride; In methanol; water; ethyl acetate; acetonitrile;
Synthesis of Various 1-beta-Xylofuranosyl-5-Alkyluracils and Related Nucleosides. Nucleosides, Nucleotides, 1, 139-146 (1982). Adenine (19.6 g, 144 mmol) was suspended in acetonitrile (400 ml) with 1-O-acetyl-2,3,5-tri-O-benzoyl-beta-L-ribofuranose 143 (60 g, 119 mmol). To this suspension was added stannic chloride fuming (22 ml, 187 mmol). After 12 hrs, the reaction was concentrated to a small volume (about 100 ml), and sodium hydrogencarbonate (110 g) and water (120 ml) were added. The resulting white solid (tin salts) was extracted with hot chloroform (5*200 ml). The combined extracts were filtered on a cellite bed. The organic phase was washed with a NaHCO3 5% solution and water, dried over sodium sulfate, filtered and evaporated to give compound 144 (60 g, colorless foam). The foam was treated with methanol saturated with ammonia (220 ml) in sealed vessel at room temperature under stirring for 4 days. The solvent was evaporated off under reduced pressure and the resulting powder was suspended in ethyl acetate (400 ml) at reflux for 1 hr. After filtration, the powder was recrystallized from water (220 ml) to give L-adenosine 145 (24 g, crystals, 75%)
With m-chloroperoxybenzoic acid; 3-chloro-benzenecarboperoxoic acid; In hydrogenchloride; water; 2,4-dichlorophenoxyacetic acid dimethylamine; toluene;
EXAMPLE 1 8-Chloroadenine (1) To a solution of adenosine (2.67 g, 10 mmol) in DMA/HCl (0.5M, 45 mL) was added m-chloroperoxybenzoic acid (MCPBA, 3.22 g, 16 mmol 87%) and stirred at room temperature for 2.5 h. An additional portion of MCPBA (0.9 g, 5 mmol) was added and stirring continued for another 1 h. Toluene (50 mL) was added to the reaction mixture and the solvents evaporated at 60 C. under vacuo to dryness. The residue was dissolved in water (50 mL) and extracted with ether (3*50 mL). The pH of the aqueous phase was adjusted to 5 with 2N NaOH and then diluted with EtOH (100 mL). The solution was stored in the refrigerator overnight. The light yellow solid that separated was collected, washed with cold EtOH (2*25 mL) and dried to give 1.44 g (85.2%) of 1: mp 305-310 C. (dec.) [Lit. mp>300 C. (dec.)]: IR (KBr): 630 (C-C1), 3100-3300 (NH2) cm-1: UV: lambdamax (pH 1) 262 nm (epsilon 8,700): lambdamax (pH 7) 268 nm (epsilon 7,900): lambdamax (pH 11) 269 nm (epsilon 8,300): 1 H NMR (Me2 SO-d6): delta 7.48 (br s, 2, NH2), 8.10 (s, 1, C2 H) and 13.60 (br s, 1, N9 H).
General procedure: Adenosine (0.26 g, 1.0 mmol) and 5-fluorouracil (0.13 g, 1.0 mmol) were mixed in a chloroform-ethanol-water mixture (v/v %, 50:45:5, 20 mL). The resulting solution was refluxed for 8 h. and filtered through Celite. Colorless crystals of co-crystal 1 suitable for X-ray data collection were obtained by slow evaporation at room temperature. Similar procedure was adopted for the preparation of co-crystals 2-4.
2'-O-(4,5-dimethoxy-2-nitrobenzyl)adenosine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
54%
General procedure: Compound 2a was prepared from N2-isobutyrylguanosine (1a) in two steps (21% yield). Under argon N2-Isobutyrylguanosine (1a) (1.717 g, 4.86 mmol) was treated with NaH (292 mg, 12.2 mmol) in dry DMF (40 mL) at 0C. After hydrogen gas generation ceased (about 40 minutes), o-nitrobenzyl bromide (1.575 g, 7.29 mmol) was added and the mixture was stirred for 5 h at 0C. The reaction was quenched with EtOH and neutralized with 1 N HCl. The mixture was evaporated and the crude product was purified by silica gel chromatography, eluting with 4-6% methanol in dichloromethane, to give N2-isobutyryl-2-O-(o-nitrobenzyl)guanosine[16,19] as a yellow foam: 0.76 g (32% yield). To a solution of N2-isobutyryl-2'-O-(o-nitrobenzyl)guanosine (192 mg, 0.393 mmol) in dry pyridine (4.0 mL) under dry argon, DMTrCl (400 mg, 1.18 mmol) was added. After the mixture was stirred at rt overnight, methanol (2.0 mL) was added to quench the reaction. The solvent was removed by rotary evaporation, and the crude product was purified by silica gel chromatography, eluting with 2% MeOH in CH2Cl2 containing 0.5% Et3N to give compound 2a[19] as a yellow foam (206 mg, 66% yield).
With 2-methoxy-ethanol; sodium hydroxide; In N,N-dimethyl-formamide; at 8 - 65℃;Large scale;
10kg of Adenosine was added to 130L of anhydrous DMF and stirred to dissolve, then 50L anhydrous ethylene glycol monomethyl ether was added controlling the temperature 8-15C , added 6.89Kg of <strong>[16427-44-4]2-methoxyethyl methanesulfonate</strong> and 2.99Kg solid sodium hydroxide, stirred reaction was incubated 60-65C , HPLC monitoring completion of the reaction to the main raw material, then concentrated under reduced pressure at 60 degrees to dryness to give a brown oil as 2'-O-(2-methoxyethyl) adenosine.
With sodium hydroxide; In water; at 20℃; for 4h;pH 8.0;
General procedure: Nucleoside/nucleotide (2; 100 mM) and N-acetyl imidazole (1a;10 equiv) were dissolved in water (pH 8; adjusted with 4 MNaOH). The solution was incubated at r.t. for 4 h, and NMR spectra were periodically acquired. The product was purified byreverse-phase (C18) flash coumn chromatography (eluted at pH4 with 100 mM NH4HCO2/MeCN = 98:2 to 80:20). The fractions containing 5 were lyophilised to yield a white powder.
With purine nucleoside phosphorylase; uridine phosphorylase; In aq. phosphate buffer; at 60℃; for 1.5h;Enzymatic reaction;
Transglycosylation reaction was carried out at analytical scale in the followingconditions: 250 ml of cell lysates (equivalent to 14 units of each UPase and PNPase enzymatic activities) was added to10 ml of a solution having the following composition: 4 mM 1-beta-D-ribofuranosyluracil (uridine nucleoside), 4 mM <strong>[73-24-5]adenine</strong>base, 30 mM potassium phosphate buffer pH 7, thermostatically controlled at 60C. After 1.5 hours at 60C, the reactionwas stopped by diluting the mixture 1:5 and cooling in ice. The percentage of bioconversion of <strong>[73-24-5]adenine</strong> base to 9-beta-Dribofuranosyl<strong>[73-24-5]adenine</strong>(adenosine nucleoside) was determined by analyzing an aliquot of the reaction mixture by highperformance liquid chromatography (HPLC) with the use of Kromasil 100-5C18 (Akzo Nobel) column of a size of 250 x4.6mm and eluted with a 4% methanol-water solution. The transglycosylation catalytic activity was expressed as units· ml -1 (mmoles ofAra-A formed in 1.5 hours · ml -1 of mixture of cell lysates) or in units · g -1 of moist resin (mmoles ofD-ribofuranosyl<strong>[73-24-5]adenine</strong> formed in 1.5 hours · ml -1 of cell lysate) and was calculated relative to a standard D-ribofuranosyl<strong>[73-24-5]adenine</strong>solution eluted by HPLC in the same conditions. Under these conditions, about 55 percent of adenosinenucleoside was formed (approximately 9 units per ml of cell lysate).
With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 20℃; for 9h;Cooling with ice; Inert atmosphere;
Adenosine (7.0 g, 1 eq) was dissolved in 200 mL of anhydrous DMF, NaH (1.6 g, 1.5 eq), purity 60%, was added under ice-cooling with nitrogen and stirred well for 30 min.A solution of 2-bromoethyl methyl ether (2.9 mL, 1.2 eq) was added dropwise,After 30 min, the ice bath was removed and stirred at room temperature for 8 h.After the reaction, ice water (5 mL) was added and stirred for 10 min. The reaction solution was concentrated,O-MOE-adenosine (1.7 g, yield 20.3%) was isolated by silica gel column chromatography.
(0117) A 10-mL vial was loaded with 0.33 g of NAD+, 0.29 g of zirconium dioxide (Zr02) . The powders were dissolved/dispersed with 9.5 mL of distilled water, and the mixture was heated at 80 C for 48 h. Zr02 was removed by centrifugation (10,000 rpm for 30 min) using 29x32x25-cm HSCEN-204 centrifuge. (0118) The 31P-NMR demonstrated a small peak at -11.15 ppm, attributed to NAD+, a peak at -0.03 ppm attributed to beta- nicotinamide mononucleotide, a peak at 0.09 ppm attributed to adenosine, and two peaks at 0.027 and 0.3 ppm, attributed to the two P atoms of adenosine diphosphate (ADP) .
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
