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[ CAS No. 118-00-3 ] {[proInfo.proName]}

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Chemical Structure| 118-00-3
Chemical Structure| 118-00-3
Structure of 118-00-3 * Storage: {[proInfo.prStorage]}
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Product Details of [ 118-00-3 ]

CAS No. :118-00-3 MDL No. :MFCD00010182
Formula : C10H13N5O5 Boiling Point : -
Linear Structure Formula :- InChI Key :NYHBQMYGNKIUIF-UUOKFMHZSA-N
M.W : 283.24 Pubchem ID :135398635
Synonyms :
DL-Guanosine;Vernine;NSC-19994, Guanine Ribonucleoside;NSC 19994;Guanine Ribonucleoside

Calculated chemistry of [ 118-00-3 ]

Physicochemical Properties

Num. heavy atoms : 20
Num. arom. heavy atoms : 9
Fraction Csp3 : 0.5
Num. rotatable bonds : 2
Num. H-bond acceptors : 7.0
Num. H-bond donors : 5.0
Molar Refractivity : 65.5
TPSA : 159.51 Ų

Pharmacokinetics

GI absorption : Low
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -9.94 cm/s

Lipophilicity

Log Po/w (iLOGP) : -0.9
Log Po/w (XLOGP3) : -2.69
Log Po/w (WLOGP) : -3.0
Log Po/w (MLOGP) : -2.36
Log Po/w (SILICOS-IT) : -2.22
Consensus Log Po/w : -2.23

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 1.0
Egan : 1.0
Muegge : 2.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -0.1
Solubility : 224.0 mg/ml ; 0.79 mol/l
Class : Very soluble
Log S (Ali) : -0.11
Solubility : 220.0 mg/ml ; 0.777 mol/l
Class : Very soluble
Log S (SILICOS-IT) : 0.51
Solubility : 910.0 mg/ml ; 3.21 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 0.0
Synthetic accessibility : 3.86

Safety of [ 118-00-3 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P280-P301+P312-P302+P352-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H320-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 118-00-3 ]

* 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.

  • Upstream synthesis route of [ 118-00-3 ]
  • Downstream synthetic route of [ 118-00-3 ]

[ 118-00-3 ] Synthesis Path-Upstream   1~33

  • 1
  • [ 118-00-3 ]
  • [ 1818-71-9 ]
Reference: [1] Journal of Organic Chemistry, 1985, vol. 50, # 3, p. 406 - 408
  • 2
  • [ 118-00-3 ]
  • [ 2140-67-2 ]
Reference: [1] Canadian Journal of Chemistry, 2001, vol. 79, # 12, p. 1881 - 1886
  • 3
  • [ 118-00-3 ]
  • [ 67-64-1 ]
  • [ 362-76-5 ]
YieldReaction ConditionsOperation in experiment
92%
Stage #1: at 20℃; for 1.16667 h;
Stage #2: With ammonia In water at 0℃;
2-amino-9-(6-(hydroxymethyl)-2,2-dimethyl-tetrahydrofuro[3,4-d][l,3]dioxoI-4- yl)-lH-purin-6(9H)-one (11). To a slurry of guanosine (0.25 g, 1.0 eq) (10) and acetone (15 mL) at room temperature was added 70percent HC1O4 (0.103 mL, 1.35 eq). The reaction was stirred for approximately 70 minutes, at which time it was clear and colorless. The reaction was then cooled to 0° C in an ice/water bath and concentrated NH4OH (0.167 mL, 1.41 eq) was added causing the formation of a milky white, gelatinous precipitate. The precipitate was collected on filter paper, resulting in a white papery solid that was dried at reduced pressure and ambient temperature for approximately 1 hour yielding 11 (0.262 g, 92percent).
83.2%
Stage #1: for 1.16667 h;
Step 1=2', 3'-Isopropylideneguanosine (E3a-I)To a suspension of guanosine (10 g, 35.31 mmol) in 600 ml of acetone was added 70percent perchloric acid (4.1 ml, 47.54 mmol). After 70 minutes, concentrated ammonium hydroxide (6.7 ml, 49.79 mmol) was added to the reaction mixture and cooled down with ice-water bath. The solid was filtered out and dried over vacuum, 9.5 g (83.2percent).
70% With perchloric acid In waterInert atmosphere To a solution of Guanosine (0,5 g; 1,76 mmoli) in 30 mL of acetone was added HClO4 60percent(0.203 mL, 2.36 mmol) and the reaction mixture was stirred under Ar overnight. The solvent was then evaporated to dryness and the residue obtained was purified by flash chromatography (eluent: CH2Cl2/MeOH, 98:2-->95:5, v/v) to afford desiderated compound 31 (yield 70percent). 1H-NMR (200MHz, DMSO-d6) d:1.31, 1.50 (6H, m, (CH3)2C), 3.34-3.55 (2H, m, H-5'), 4.09-4.12 (1H, m, H-4'), 4.94 (1H, dd, J=3.2 Hz, H-3'), 5.04 (1H, t, OH-5'), 5.16 (1H, dd, J=3.9 Hz, H-2'), 5.91 (1H, d, J=2.8 Hz, H-1'), 6.50 (2H, br s, NH2), 7.91 (1H, s, H-8), 10.60 (1H, br s, NH-3). ESI MS: m/z 324.2 Da [M+H]+, C13H17N5O5 Mol. Wt. 323.30.
70% for 2 h; Cooling with ice A.
2', 3'-O-isopropylidene Guanosine (8)
To guanosine (5.01 g, 17.7 mmol) suspended in acetone (300 ml) was added catalytic amount of perchloric acid (1.25 ml) drop-wise while under ice-bath.
The reaction mixture suspension became gradually clear and was monitored using TLC (20:80:0.1 MeOH/CHCl3/TEA solvent).
At the end of 2 hours, TLC indicated 90percent of the product formation.
Ammonium hydroxide (2 equivalent to perchloric acid, 2.75 ml) was added drop-wise under ice-bath to neutralize the reaction mixture upon which the product precipitated out from the solution.
The reaction mixture was then evaporated under rotary evaporator to complete dryness.
The crude reaction mixture was then triturated with ice-cold water (200 ml) overnight.
The insoluble material was vacuum-filtered and washed with cold diethyl ether to collect the product (3.99 g, 12.39 mmol) in 70percent yield.
The 1H NMR spectrum was (DMSO-d6): 0.00 (s, TMS internal standard), 1.32 (s, 3H), 1.52 (s, 3H), 3.50-3.56 (m, 2H), 4.10-4.13 (t, 1H), 4.97 (d, 1H), 5.04 (t, 1H), 5.18 (d, 1H), 5.93 (d, 1H), 6.5 (s, 2H), 7.91 (s, 1H) and 10.66 (s, 1H).
13C-DMSO-d6:
157.16, 154.15, 151.20, 136.30, 117.21, 113.51, 88.87, 87.09, 84.04, 81.64, 62.07, 27.53 and 25.71 ppm. HRMS (ESI+) calcd for C13H18N5O5 [(M+H)+] 324.1308 found 324.1304

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[2] Synlett, 2010, # 19, p. 2959 - 2963
[3] Patent: WO2006/130161, 2006, A2, . Location in patent: Page/Page column 29
[4] Chemistry - A European Journal, 2013, vol. 19, # 35, p. 11502 - 11506
[5] Chemistry - A European Journal, 2014, vol. 20, # 11, p. 3023 - 3028
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[10] European Journal of Medicinal Chemistry, 2012, vol. 54, p. 202 - 209
[11] ACS Medicinal Chemistry Letters, 2016, vol. 7, # 8, p. 780 - 784
[12] Patent: US2018/65965, 2018, A1, . Location in patent: Page/Page column 0126
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[14] ChemMedChem, 2011, vol. 6, # 6, p. 1074 - 1080
[15] Organic and Biomolecular Chemistry, 2013, vol. 11, # 9, p. 1525 - 1532
[16] Chemical Communications, 2013, vol. 49, # 30, p. 3128 - 3130
[17] Macromolecules, 2014, vol. 47, # 5, p. 1810 - 1818
[18] Organic and Biomolecular Chemistry, 2015, vol. 13, # 15, p. 4506 - 4513
  • 4
  • [ 118-00-3 ]
  • [ 77-76-9 ]
  • [ 362-76-5 ]
YieldReaction ConditionsOperation in experiment
31% With toluene-4-sulfonic acid In acetone at 20℃; for 24 h; 2,2-dimetoxypropane (7.62 mL, 62.0 mmol) and p-toluenesulfonic acid (1.77 g, 9.30 mmol) were added to guanosine (2.00 g, 7.06 mmol) suspended in acetone (90 mL). The mixture was stirred for 24h at RT. As the reaction proceeded, the mixture became clear. The remaining precipitate was centrifuged, and the supernatants mixed and evaporated to half its original volume. Then, ammonia (25percent) was added dropwise to pH=9. The precipitate was filtered, dried and crystallized from water yielding 2’,3’-O,O-isopropylideneguanosine (0.704 g, 2.18 mmol, 31percent).
Reference: [1] Tetrahedron, 2009, vol. 65, # 43, p. 8851 - 8857
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[6] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 8, p. 2177 - 2180
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[13] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 17, p. 5369 - 5381
[14] Patent: CN105384789, 2016, A, . Location in patent: Paragraph 0042; 0043; 0044; 0045
[15] Patent: WO2018/33719, 2018, A1, . Location in patent: Page/Page column 115
[16] Organic and Biomolecular Chemistry, 2018, vol. 16, # 36, p. 6741 - 6748
  • 5
  • [ 108-24-7 ]
  • [ 118-00-3 ]
  • [ 6979-94-8 ]
YieldReaction ConditionsOperation in experiment
98% With dmap; triethylamine In acetonitrile at 0 - 20℃; for 3 h; 2.2 mL of acetic anhydride (22 mmol) was added dropwise to a suspension of guanosine (2 g, 7.0 mmol) (dried for 2 days over P4O10 in high vacuum), triethylamine (7.7 mL, 55.2 mmol) and N,N-(dimethylamino)pyridine (92 mg, 0.75 mmol) in 27 mL of acetonitrile at 0 °C. The mixture was stirred until it became homogeneous and kept an additional 3 h at room temperature. The reaction was quenched with methanol (2.3 mL). The volume was reduced to 1/3 using a rotary evaporator and diethyl ether was added dropwise to induce precipitation of a fine white powder. The product was collected by filtration, washed with diethyl ether, and then stirred for 2 hr with acetone (30 mL) at 50 °C. The filtrate produced 2.8 g (98percent) of a fine white powder. 1H NMR (200 MHz, DMSO) δ 10.54 (s, 1H, NH) 7.93 (s, 1H, H-8), 6.34 (br, 2H, NH2), 5.98 (d, J = 6.1 Hz, 1H, H-1'), 5.79 (t, J = 5.8 Hz, 1H, H-2'), 5.51-5.48 (m, 1H, H-3'), 4.40-4.37 (m, 1H, H-4'), 4.33-4.31 (m, 1H, H-5'), 4.23-4.28 (m, 1H, H-5), 2.11 (s, 3H, CH3, acetyl), 2.05 (s, 3H, CH3, acetyl), 2.04 (s, 3H, CH3, acetyl); 13C NMR (200 MHz, CDCl3) δ 172.1 (CO), 171.0 (CO), 169.9 (CO), 156.3 (C-6), 152.8 (C-2), 151.2 (C-4), 137.6 (C-8), 119.6 (C-5), 86.1 (C-1'), 82.3 (C-4'), 73.6 (C-2'), 72.3 (C-3'), 61.8 (C-5'), 21.1 (C, acetyl), 20.6 (C, acetyl), 20.2 (C, acetyl); m/z: calcd for C18H21N5O5 (M+H)+: 410.1306, found: 410.1305.
98% With dmap; triethylamine In acetonitrile at 0 - 20℃; for 1 h; 2.2 mL of acetic anhydride (22 mmol) was added dropwise to a suspension of commercially available guanosine (2 g, 7.0 mmol), triethylamine (7.7 mL, 55.2 mmol) and N,N-(dimethylamino)pyridine (92 mg, 0.75 mmol) in 27 mL of acetonitrile at 0oC. The mixture was stirred until it became homogeneous and kept an additional 1 hr at room temperature. The reaction was quenched with methanol (2.3 mL). The volume was reduced to 1/3 using a rotary evaporator and diethyl ether was added dropwise to induce precipitation of a fine white powder. The product was collected by filtration, washed with diethyl ether, and then stirred for 2 hr with acetone (30 mL) at 50 C. The filtrate produced 2.8 g (98percent) of a fine white powder.
96% With pyridine In DMF (N,N-dimethyl-formamide) at 75 - 80℃; for 3.75 h; A suspension of 113 g (0.4 mol) of dry guanosine (6.1), acetic anhydride (240 mL, 2.5 mol), dry pyridine (120 mL) and dry DMF (320 mL) was heated for 3.75 hours at 75°C without allowing the temperature to exceed 80°C. The clear solution was then transferred to a 3L Erlenmyer flask and filled with 2-propanol. Upon cooling the solution to room temperature crystallization was initiated and allowed to proceed at 4°C overnight. The white solid filtrate was filtered, washed with 2-propanol and recrystallized from 2-propanol to give 6.2 (96percent). 1H NMR (300 Mhz, CDCl3) δ 8.20 (s, 1H, H-8), 6.17 (d, J= 5.41 Hz, 1 H, H-1') 5.75 (t, J= 5.39 Hz, 1H, H-2'), 5.56 (t, J = 5.0, H-3'), 4.41 (m, 3H, H-4',5'), 2.14 (s, 3H, Ac), 2.11 (s, 3H, Ac), 2.10 (s, 3H, Ac). 13C NMR (300 MHz, CD3OD) δ 171.0, 170.3, 1702, 157.7, 154.8, 152.4, 136.7, 117.7, 85.5, 80.4, 73.0, 71.3, 64.0, 31.3, 21.2, 21.0.
96% With dmap; triethylamine In acetonitrile at 20℃; for 0.5 h; Guanosine 1 (11.3 g, 40 mmol) and N,N-dimethylaminopyridine (366 mg, 3 mmol, 0.07 equiv) were dissolved in 500 mL acetonitrile. After addition of triethylamine (22.9 mL, 158.4 mmol) and Ac2O (13.6 mL, 144 mmol), the mixture was stirred at room temperature for 30 min. The reaction was quenched by addition of 5 mL MeOH and the solvent evaporated in vacuo. The oily residue was recrystallized from 2-propanol to afford 2 as a white powder (15.7 g, 96percent). mp 229-231 oC (lit.[1] mp 228-229 oC); 1H NMR (300 MHz, DMSO-d6): δ 10.75 (1H, br s, OH), 7.94 (1H, s, H-8), 6.55 (2H, br s, NH2), 5.98 (1H, d, J = 6.2 Hz, H-1'), 5.79 (1H, dd, J = 6.0, 6.2 Hz, H-2'), 5.59 (1H, dd, J = 3.9, 6.0 Hz, H-3'), 4.37 (1H, ddd, J = 3.9, 4.9, 5.5 Hz, H-4'), 4.31(1H, dd, J = 4.9, 12.4 Hz, H-5'a), 4.23 (1H, dd, J = 5.5, 12.4 Hz, H-5'b), 2.11 (3H, s, CH3CO), 2.04 (3H, s, CH3CO), 2.03 (3H, s, CH3CO).
80% With dmap; triethylamine In acetonitrile at 20℃; for 2 h; Cooling with ice To a stirred suspension of guanosine (5.0 g, 17.7 mmol) in MeCN (65 mL) was added Et3N (6.47 mL, 46.5 mmol) and DMAP (0.22 g, 1.8mmol). The resulting suspension was cooled in an ice bath prior to dropwise addition of Ac2O (5.84 mL, 61.84 mmol). Once the addition was completed, the mixture was allowed to reach room temperature and was stirred for a further 2 h. The reaction was quenched by the addition of MeOH (6.5 mL) and concentrated in vacuo to a white semi-solid precipitate which was boiled with iPrOH and filtered, leaving the product as a white solid. (5.79 g, 80percent). 1H NMR (500 MHz, DMSO-d6): δ (ppm) 10.70 (1H, s, NH); 7.91 (1H, s, H8); 6.49 (2H, s, NH2); 5.98 (1H, d, 3JH1'H2' = 6.1Hz, H1'); 5.79 (1H, t, 3JH2'H3' = 6.0 Hz, H2'); 5.50 (1H, dd, 3JH3'H4' = 4.2, H3'); 4.37 (1H, dd, 3JH5''H4' = 3.8 and 2JH5H5 =11.5 Hz, H5); 4.31 (1H, m, H4); 4.26 (1H, dd, 3JH5H4 = 5.7 Hz, H5'); 2.11 [3H, s, (CH3)3']; 2.04 [3H, s, (CH3)5']; 2.03 [3H, s, (CH3)2']. 13C NMR (125 MHz, DMSOd6): δ (ppm) 170.89 [(CO)5']; 170.24 [(CO)3']; 170.07 [(CO)2']; 157.46 (C6); 154.75 (C2); 151.95 (C4); 136.45 (C8); 117.74 (C5); 85.35 (C1'); 80.40 (C4'); 72.93 (C2'); 71.18 (C3'); 63.92 (C5'); 21.34 [(CH3)5']; 21.20 [(CH3)3'] and 21.01 [(CH3)2'].
79% With dmap; N,N-dimethyl-ethanamine In acetonitrile at 20℃; for 1 h; Guanosine (6) 8.40 g (29.7 mmol) and 0.2 g of dimethylaminopyridine were suspended in a mixture of ethyldimethylamine 8.8 g (120 mmol), acetic anhydride 10.2 g (100 mmol) and acetonitrile 100 mL. The reaction mixture was stirred for 60 minutes at room temperature until the solution becomes clear. Methanol was added to the reaction mixture and the solvents were removed under vacuum. The product was recrystallized from isopropanol, washed with acetone and dried to give 6a as pure product. Yield 9.6 g (79percent)
75% With pyridine In N,N-dimethyl-formamide at 60 - 100℃; for 4 h; Step A:
Preparation of 2',3',5'-Tri-O-acetylguanosine
A 12-liter, 3-necked, round bottom flask equipped with a mechanical stirrer, dropping funnel, condenser, and argon inlet is charged with dimethylformamide (9 liters) and guanosine (predried for 20 hours at 80° C. over P4O10, 988 g, 3.50 moles), then heated to 60° C. Pyridine (1.1 liters) followed by acetic anhydride (2.15 liters, 22.8 moles) is added and the mixture heated to 90-100° C. for 4 hours.
After cooling to room temperature overnight, the mixture is evaporated to remove approximately 6 liters, then slurried with 10 liters of isopropanol while heating to 70° C. for 1 hour.
The mixture is slowly cooled to room temperature, affording the product as a crystalline solid.
After collecting by filtration, the solid is washed with isopropanol (2*2 liters), then dried under vacuum at 80° C. for 17 hours to provide the desired intermediate (1,080 g, 75percent).
70% With pyridine In N,N-dimethyl-formamide at 75℃; for 4.15 h; Guanosine (1) (90 g, 387.9 mmol) was dissolved in dry pyridine and DMF (95.4 mL) followed by the addition of acetic anhydride (191.15 mL, 2420.0 mmol) and the reaction mixture was stirred at 75 °C for 4.15 h. The resultant clear solution was mixed with 2-propanol and maintained at 4 °C for overnight to afford white solid which was recrystallized from 2-propanol,10percent methanol in chloroform to afforded compound2in 70percent yield.Spectral data is consistent with the literature.

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  • 6
  • [ 2466-76-4 ]
  • [ 118-00-3 ]
  • [ 6979-94-8 ]
YieldReaction ConditionsOperation in experiment
53% With sodium hydroxide In water at 20℃; for 4 h; 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.
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  • 7
  • [ 118-00-3 ]
  • [ 3608-58-0 ]
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  • 8
  • [ 118-00-3 ]
  • [ 4099-84-7 ]
Reference: [1] Patent: WO2013/192078, 2013, A1,
[2] Patent: WO2014/160200, 2014, A1,
  • 9
  • [ 118-00-3 ]
  • [ 4016-63-1 ]
YieldReaction ConditionsOperation in experiment
85% With bromine In water To a suspension of guanosine 5 (4.0 g, 14.4 mmol) in water (100 mL) was added bromine (0.8 mL, 14.6 mmol) at such a rate that reaction mixture became colourless between each addition. The addition was stopped when the reaction mixture stayed slightly yellow due to unreacted bromine. The colourless solid was quickly filtered off, washed with 60 mL of cold water and 30 mL of cold acetone, recrystallized from 150 mL of hot water and dried in vacuo for 6 h at 60 °C. Yield 4.4 g (11.8 mmol, 85percent) of colourless, needle-shaped crystals 13, mp 198-200 °C; 1H NMR (400 MHz, DMSO-d6): δ 10.82 (1H, s), 6.50 (2H, s), 5.69 (1H, d, J = 6.4 Hz), 5.45 (1H, d, J = 6.0 Hz), 5.09 (1H,d, J = 5.2 Hz), 5.02 (1H, dd, J = 6.0, 11.6 Hz), 4.92 (1H, t, J= 6.0 Hz), 4.14 (1H, m), 3.86 (1H, m), 3.66 (1H, m), 3.52 (1H, m). 13C NMR (100 MHz, DMSO-d6): δ 155.5, 153.4, 152.0, 121.2, 117.5, 89.7, 85.8, 70.5, 70.3, 62.0.
51% With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione In N,N-dimethyl-formamide at 25℃; for 2.5 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
15% 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).
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  • [ 79-30-1 ]
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YieldReaction ConditionsOperation in experiment
82%
Stage #1: at 20℃; for 2 h;
Stage #2: at 0 - 20℃;
To a solution of Guanosine (1 g , 3.53 mmol) and pyridine (25 mL) was added Trimethylchlorosilane (TMSCl) (3.35 mL, 26.47 mmoli).The reaction was stirred at r.t. for 2 h, and then isobutyryl chloride was added at 0° C. The solution was stirred at r.t. for 3 h and then 10 mL of water was added at 0° C. After 5 min NH4OH was added and after 15 min water (50 mL) and CH2Cl2 (20 mL) were added. The aqueous phase was evaporated and crystallized with hot water, then filtered and evaporated to give desiderated compound 35 (yield 82percent). 1H-NMR (200MHz, DMSO-d6) d: 1.10, 1.13 (6H, s, (CH3)2CH), 2.75-2.76 (1H, m, CH), 3.56-3.59 (2H, m, H-5'), 3.88-3.90 (1H, m, H-4'), 4.11-4.13 (1H, m, H-3'),4.41-4-44 (1H, m, H-2'), 5.04 (1H, t, J=4.6 Hz, OH-5'), 5.45 (1H, d, J=3.8 Hz, OH-3'), 5.48 (1H, d, J=4.0 Hz, OH-2'), 5.80 (1H, d, J=5.4 Hz, H-1'), 8.26 (1H, s, H-8), 11.90 (1H, br s, NH-CO),12.16 (1H, br s, NH-3). ESI MS: m/z 354.2 Da [M+H]+, C14H19N5O6 Mol. Wt. 353.33.
79%
Stage #1: at 20℃; for 2 h; Inert atmosphere
Stage #2: at 0 - 20℃; for 3.33333 h;
Stage #3: at 0 - 20℃; for 0.25 h;
Preparation of A9 where YCH2, XOHStep 1-N2-Isobutyrylguanosine (A9-I)Guanosine hydrate (10 g, 35.3 mmol) was dried by co-evaporation of its suspension in dry pyridine (3.x.100 mL) in vacuum. The residue was suspended in dry pyridine (250 mL) under a nitrogen atmosphere, and chlorotrimethylsilane (28.8 g, 265 mmol) was added. The reaction mixture was stirred at ambient temperature for 2 h, cooled to 0° C., and isobutyryl chloride (11.3 g, 106 mmol) was added dropwise over 20 min. The mixture was allowed to warm to room temperature and stirred for 3 h. The reaction mixture was cooled to 0° C., and the reaction was quenched by addition of H2O (30 mL). After stirring for 5 min at 0° C. and then 5 min at room temperature, concentrated aqueous NH4OH (65 mL) was added. After stirring for an additional 15 min at room temperature, the mixture was diluted with H2O (500 mL) and washed with CH2Cl2 (200 mL). The aqueous layer was concentrated by evaporation in vacuum. The residue was recrystallized from hot H2O to obtain N2-isobutyrylguanosine (9.90 g, 79percent) as a white solid.
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