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[ CAS No. 106941-25-7 ] {[proInfo.proName]}

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Chemical Structure| 106941-25-7
Chemical Structure| 106941-25-7
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Product Details of [ 106941-25-7 ]

CAS No. :106941-25-7 MDL No. :MFCD00866943
Formula : C8H12N5O4P Boiling Point : -
Linear Structure Formula :- InChI Key :SUPKOOSCJHTBAH-UHFFFAOYSA-N
M.W : 273.19 Pubchem ID :60172
Synonyms :
GS-0393;PMEA

Calculated chemistry of [ 106941-25-7 ]

Physicochemical Properties

Num. heavy atoms : 18
Num. arom. heavy atoms : 9
Fraction Csp3 : 0.38
Num. rotatable bonds : 5
Num. H-bond acceptors : 7.0
Num. H-bond donors : 3.0
Molar Refractivity : 62.68
TPSA : 146.19 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) : -9.41 cm/s

Lipophilicity

Log Po/w (iLOGP) : -0.09
Log Po/w (XLOGP3) : -2.03
Log Po/w (WLOGP) : -0.43
Log Po/w (MLOGP) : -1.8
Log Po/w (SILICOS-IT) : -2.08
Consensus Log Po/w : -1.29

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 1.0
Egan : 1.0
Muegge : 1.0
Bioavailability Score : 0.56

Water Solubility

Log S (ESOL) : -0.29
Solubility : 139.0 mg/ml ; 0.507 mol/l
Class : Very soluble
Log S (Ali) : -0.51
Solubility : 83.5 mg/ml ; 0.306 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -0.81
Solubility : 42.8 mg/ml ; 0.157 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 0.0
Synthetic accessibility : 2.87

Safety of [ 106941-25-7 ]

Signal Word:Danger Class:6.1
Precautionary Statements:P264-P270-P301+P310+P330-P405-P501 UN#:2811
Hazard Statements:H301 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 106941-25-7 ]

* 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 [ 106941-25-7 ]
  • Downstream synthetic route of [ 106941-25-7 ]

[ 106941-25-7 ] Synthesis Path-Upstream   1~16

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YieldReaction ConditionsOperation in experiment
86.3%
Stage #1: With trimethylsilyl bromide In acetonitrile at 20℃; for 3 h; Large scale
Stage #2: With sodium hydroxide In water for 2 h; Reflux; Large scale
A mechanical stirrer and a thermometer were installed in a 10 L three-necked flask. To this was added 1.4 kg (4.26 mol) of intermediate III, Trimethylsilyl bromide in this orderAnd 8 L of acetonitrile were added thereto. The mixture was stirred at room temperature for 1 hour and heated to reflux for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, 5 L of water was added, and the mixture was stirred and adjusted to pH 3.2 to 3.4 with 25percent sodium hydroxide. The mixture was heated to reflux for 2 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and filtered. The cake was recrystallized once from water and vacuum dried at 70 ° C for 8 hours. 9- (2-phosphomethoxyethyl) adenine as a white crystalline solid powder 1.07kg, Μρ: 298 ~ 300 ° (3, yield 86.3percent.
86% With hydrogen bromide In water at 90℃; for 5 h; The 20g 9 - [2 - (b b oxygen phosphinylidyne methoxy) ethyl] adenine added to the 60g concentration is 48percent HBr in aqueous solution of, stirring and heating to 90 °C, reaction 5h. TLC detection reaction is complete, to stop the reaction. The solution is cooled to the room temperature water is added, keeping the temperature at 45 °C following, for 50percent of sodium hydroxide in and to pH ≈ 2.5. A large number of white solid precipitated, continuing to stir 4h, filtering, drying to obtain the white PMEA. HPLC determining purity: 99.6percent yield: 86percent.
85% With chloro-trimethyl-silane In chlorobenzene at 120℃; for 10 h; In the 1L the reaction bottle, are separately put into 9-[2-(diethyl phosphine acid methoxy) ethyl] adenine 57.6g, trimethylchlorosilane 94g, instillment chlorobenzene 184 ml. Heating to 120 °C reaction 10h, slightly cold, evaporate the solvent under reduced pressure, the residue add 92 ml water, heating up to 70 °C reaction 2h, cold to room temperature. Dropwise NaOH aqueous solution to pH about 3.2, filtering, cake a little water to wash, drying shall 41g white solid, is the target compound, yield 85percent.
41.3%
Stage #1: at 35 - 55℃; for 4 h;
Stage #2: With sodium hydroxide In water at 32 - 44℃;
A 12 L, 3-neck round bottom flask was equipped with a mechanical stirrer. The flask was charged with the crude 9-(2-diethylphosphonylmethyoxyethyl)adenine 6, as a slurry in acetonitrile (4.0 L). The mixture was stirred at ambient temperature for 30 minutes and then filtered. The filter cake was washed with acetonitrile (2.x.0.5 L) and the combined filtrate and washings were used directly as follows. [0163] A 22 L, 3-neck round bottom flask was equipped with a mechanical stirrer, thermometer, condenser and heating mantle. The flask was flushed with nitrogen and charged with the 9-(2-diethylphosphonylmethoxyethyl)adenine 6 solution (2.59 mol), chlorotrimethylsilane (1.315 L) and potassium iodide (1.719 kg). There was a gradual increase in temperature after the addition of KI to 35° C. The stirred mixture was then heated to 55° C. and stirred at 50-55° C. for 1 hour. The mixture was stirred for an additional 3 hours with gradual cooling to 38° C. HPLC was used to determine completeness of the reaction. [0164] HPLC conditions: [0165] Silica column (particle size,10 microns)(Phenomenex Bondclone) 10 C18, 300.x.3.9 mm column; mobile phase: Solvent A=20 mM potassium phosphate, pH 6.2, Solvent B=acetonitrile; Gradient: 0-60percent B/15 min., 60-0percent B/2 min., 0percent B/3 min.; UV detection at 270 nm. [0166] Retention times: Product 7=5.2 min., starting material 6=9.2 min. [0167] The reaction flask was equipped with an addition funnel (2 L) and 3.5 M NaOH solution (4 L) was slowly added with a temperature increase from 32 to 44° C. The two liquid phase system was transferred to a 5 gal. stationary separatory funnel and the layers were separated. The basic aqueous phase was extracted with ethyl acetate (2 L) and then transferred to a 12 L, 3-neck flask, equipped with a mechanical stirrer and an addition funnel (1 L). Concentrated HCl was added slowly with stirring until the pH was 3.0 as determined by standard laboratory pH meter. The resulting yellow solution was stirred at ambient temperature for 12 hours. A precipitate formed. The stirred mixture was cooled to 7° C. in an ice bath and the pH was readjusted to 3.0 with concentrated HCl. The mixture was stirred at ice bath temperature for 5 hours and then filtered. Filtration took approximately 4 hours. The collected solid was washed with acetone and air dried on the filter funnel. [0168] A 5 L, 3-neck round bottom flask was equipped with a mechanical stirrer and a 250 mL addition funnel. The flask was charged with the crude solid and 1 M sodium hydroxide solution (1.25 L). The mixture was stirred until all solids were dissolved (15 minutes). Concentrated HCl solution was added slowly to the stirred solution until the pH was 3.0. The resulting mixture was stirred at ambient temperature for 4 hours and then filtered. The collected solid was washed with water (2.x.250 mL) and acetone (200 mL), and dried to constant weight (-30 in. Hg, 60° C., 14 hours). [0169] Recovery=292 g [0170] Off-white solid (41.3percent). [0171] 1H-NMR (D2O); δ=3.25 (d, J=8 Hz, 2H), 3.70 (t, J=4 Hz, 2H), 4.10 (t, J=4 Hz, 2H), 4.60 (s, 4H), 7.80 (s, 1H), 7.90 (s, 1H)

Reference: [1] Nucleosides and Nucleotides, 1998, vol. 17, # 8, p. 1445 - 1451
[2] Patent: CN104387421, 2016, B, . Location in patent: Paragraph 0032-0034
[3] Patent: CN106317115, 2017, A, . Location in patent: Paragraph 0035; 0036; 0039; 0040; 0046; 0047; 0048
[4] Patent: CN106699814, 2017, A, . Location in patent: Paragraph 0024-0025
[5] Green Chemistry, 2012, vol. 14, # 8, p. 2282 - 2288
[6] Patent: US2003/225277, 2003, A1, . Location in patent: Page 11-12
[7] Collection of Czechoslovak Chemical Communications, 1987, vol. 52, # 11, p. 2801 - 2809
[8] Nucleosides, Nucleotides and Nucleic Acids, 2001, vol. 20, # 4-7, p. 1299 - 1302
[9] Patent: US2012/238753, 2012, A1, . Location in patent: Page/Page column 3
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Reference: [1] Green Chemistry, 2012, vol. 14, # 8, p. 2282 - 2288
[2] Journal of Medicinal Chemistry, 1999, vol. 42, # 12, p. 2064 - 2086
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  • [ 2857-97-8 ]
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Reference: [1] Patent: US5874577, 1999, A,
  • 4
  • [ 707-99-3 ]
  • [ 106941-25-7 ]
Reference: [1] Collection of Czechoslovak Chemical Communications, 1987, vol. 52, # 11, p. 2801 - 2809
[2] Collection of Czechoslovak Chemical Communications, 1987, vol. 52, # 11, p. 2801 - 2809
[3] Patent: CN104387421, 2016, B,
[4] Patent: CN106699814, 2017, A,
  • 5
  • [ 142340-99-6 ]
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Reference: [1] ChemMedChem, 2015, vol. 10, # 8, p. 1351 - 1364
  • 6
  • [ 168537-58-4 ]
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Reference: [1] ChemMedChem, 2015, vol. 10, # 8, p. 1351 - 1364
  • 7
  • [ 66224-66-6 ]
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Reference: [1] Patent: US2012/238753, 2012, A1,
[2] Patent: CN106699814, 2017, A,
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Reference: [1] Nucleosides and Nucleotides, 1998, vol. 17, # 8, p. 1445 - 1451
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Reference: [1] Nucleosides and Nucleotides, 1998, vol. 17, # 8, p. 1445 - 1451
  • 10
  • [ 31618-90-3 ]
  • [ 707-99-3 ]
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Reference: [1] Tetrahedron Letters, 1998, vol. 39, # 14, p. 1853 - 1856
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  • [ 107021-27-2 ]
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Reference: [1] Collection of Czechoslovak Chemical Communications, 1987, vol. 52, # 11, p. 2801 - 2809
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Reference: [1] Collection of Czechoslovak Chemical Communications, 1987, vol. 52, # 11, p. 2801 - 2809
  • 13
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Reference: [1] European Journal of Medicinal Chemistry, 2011, vol. 46, # 9, p. 4281 - 4288
  • 14
  • [ 18997-19-8 ]
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  • [ 142340-99-6 ]
YieldReaction ConditionsOperation in experiment
75% With 1,8-diazabicyclo[5.4.0]undec-7-ene In N,N-dimethyl-formamide at 25℃; for 24 h; Example 1. Preparation of adefovir dipivoxil in an amorphous form[47] An amorphous form of adefovir dipivoxil, a raw material to prepare adefovir dipivoxil in DH-type crystalline form, was prepared as follows.[48] 30 g (0.11 mol) of 9- [2-(phosphonomethoxy)ethyl] adenine (PMEA) was dissolved in240 mL of dimethyl formamide (DMF), 42.4 g of l,8-diazabicyclo[5,4,0]undec-7-ene (DBU) was added thereto, and the mixture was stirred. 82.8 g of chloromethyl pivalate was added thereto, and the mixture was stirred at 250C for 24 hours. After confirming the termination of reaction via thin layer chromatography (TLC), 240 mL of water was added thereto, and the mixture was stirred for about 10 minutes. The mixture was subjected to extraction three times, each time with 500 mL of toluene, dried using sodium sulfate, and concentrated under reduced pressure to obtain 41.3 g of an amorphous form of adefovir dipivoxil (yield: 75percent).[49] Purity: 99.5 percent (HPLC); 1H NMR (CDCl3, ppm) 8.32 (s, IH), 7.91 (s, IH), 6.14 (s,2H, NH2), 5.64 (m, 4H), 4.38 (t, 2H, J = 4.8 Hz), 3.93 (t, 2H, J= 4.8 Hz), 3.84 (d, 2H, J = 7.5 Hz), 1.19 (s, 18H5 CH3)
57.5% With tetrabutylammomium bromide; triethylamine In 1-methyl-pyrrolidin-2-one at 65 - 75℃; for 2 h; To the flask was added adefovir 55 g,200 ml of N-methylpyrrolidone was added,The temperature was raised to 65-75 ° C,160 ml of chloromethyl pivalate was added,Triethylamine 90ml,Tetra-n-butylammonium bromide,Reaction 2h,High-performance liquid chromatography to detect the main peak area of 66percent for the reaction completely,Ethyl acetate (700 ml)Stirring dissolved 30min,filter,And washed three times with 220 ml ethyl acetate each time until the filter cake was white,The filtrate was washed with saturated brine (550 ml) three times,The aqueous phase was discarded,The organic phase was dried over 110 g of anhydrous sodium sulfate for 2 h,filter,Removal of anhydrous sodium sulfate,And the filter cake was washed with 50 ml of ethyl acetate,The filtrate was concentrated to a pale yellow viscous liquid at 40-50 ° C under reduced pressure,10-15 ° C by adding anhydrous ether 600ml,There is a crystal precipitation,filter,50 ml of dry ether,40-50 vacuum drying 4h was adefovir dipivoxil 58g,Yield 57.5percent.HPLC purity:Greater than 99percent.
52% With 1-methyl-pyrrolidin-2-one; triethylamine In ethanol; N,N-dimethyl-formamide at 60 - 70℃; for 1 h; Large scale comprising the steps of: (1) In a clean glass kettle, 5 L of DMF, 5 L of N-methylpyrrolidone and 0.5 L of absolute ethanol, lkg of PMEA And 4.5kg of chloropentyl pivalate, stirring to 60 ~ 70 ° C, dropping 3 kg of triethylamine, 1 h after the drop is completed, and then reaction 2.5 After the hour, the reaction was detected by HPLC, and the amount of PMEA in the reaction solution was less than 0.5percent, and the reaction was terminated. (2) 10 L of ethyl acetate was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour, filtered, and washed with 10 L of ethyl acetate The filter cake was washed with 10 L of a 20percent sodium chloride solution, the aqueous phase of the washing solution was discarded, and the organic phase was washed with anhydrous Calcium chloride lkg dry 2 h, filter, remove the calcium chloride solid, the filtrate. (3) The filtrate was concentrated under reduced pressure at 45 ° C, and then 1L of chloroform was dissolved under stirring at 5 to 10 ° C, and the mixture was transferred to another A reaction kettle, in the 5 ~ 10 ° C dropping 12L methyl tert-butyl ether, 10-15 min after the white crystal precipitation, stirring crystallization 6-7 H, filter, 45 ° C vacuum drying Adefovir dipivoxil finished product 0.96kg: molar yield of 52percent, by HPLC, the content of 99.7percent, containing impurities Adefovir monoester 0.19percent. The product is good crystal, easy to dry, good stability
34.9% With triethylamine In 1-methyl-pyrrolidin-2-one at 60℃; for 2 h; A mechanical stirrer, reflux condenser and thermometer were installed in a 50 L dry reaction flask. (3.66 mol) of PMEA and 3.6 L of N-methylpyrrolidone (NMP) were added thereto in succession, followed by the addition of 2.2 kg (14.67 mol) of chloromethyl pivalate and triethylamine 1. lkg . After heating to 60 ° C for 2 hours, the mixture was cooled to room temperature and extracted three times with 20 L of isopropyl acetate. The filtrate was washed with water and the solvent was distilled off under reduced pressure. The resulting residue was dissolved in 5 L of acetone, With stirring, 25 L of isopropyl ether was slowly added to give a solid product, and stirring was continued for 5 hours, followed by filtration. (1/9, ν / ν). After adding the right amount of acetone to dissolve the filter cake, add appropriate amount of activated carbon, stir for 30 min and filter to the clean area crystallization tank, add isopropyl ether to crystallize completely, filter and use acetone / After sufficient washing, vacuum drying (50 ° C, 20 mmHg)To obtain 767 g of adefovir dipivoxil as an off-white powder with a purity of 99.1percent and a total yield of 34.9percent.

Reference: [1] Patent: WO2010/110506, 2010, A1, . Location in patent: Page/Page column 7
[2] Patent: CN105646586, 2016, A, . Location in patent: Paragraph 0034; 0035; 0036; 0037; 0038; 0039; 0040-0044
[3] Patent: CN106188140, 2016, A, . Location in patent: Paragraph 0019; 0020; 0021; 0022
[4] Patent: CN104387421, 2016, B, . Location in patent: Paragraph 0035-0037
[5] Journal of Medicinal Chemistry, 1994, vol. 37, # 12, p. 1857 - 1864
[6] Patent: WO2010/120074, 2010, A2, . Location in patent: Page/Page column 10
[7] Patent: EP2327708, 2011, A2, . Location in patent: Page/Page column 10
[8] Patent: US2012/238753, 2012, A1, . Location in patent: Page/Page column 3
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YieldReaction ConditionsOperation in experiment
32.6% With triethylamine In 1-methyl-pyrrolidin-2-one at 30 - 60℃; for 16 h; In a 2L reaction flask,Respectively, adefovir 40.2g (0. 147mol),N-methylpyrrolidone 80 g (0.807 mol) and triethylamine (35 mL) were added 110 g of chloropentyl valerate (0 • 73 lmo 1)30 ~ 40 ° C stirring reaction 12h, and then heating 50 ~ 60 ° C stirring 4h;Cooling to room temperature, adding ethyl acetate 608mL, stirring at room temperature 1 ~ 2h; filtration,The filter cake was washed with ethyl acetate and the filtrate was washed with saturated aqueous sodium chloride solution. The resulting organic layer was dried over anhydrous sodium sulfate,The mixture was allowed to stand overnight; the filtrate was concentrated under reduced pressure to give an oil,Add ethanol 70ml, stirring lOmin, stirring evenly, adding isopropyl ether, crystallization, this time the solution becomes turbid, continue stirring 7 ~ 8h; filter, anhydrous ethanol washing, the white solid powder, that is, the target compound Ade Fuwei ester, yield 32.6percent.
Reference: [1] Patent: CN106699814, 2017, A, . Location in patent: Paragraph 0026-0027
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  • [ 323201-04-3 ]
  • [ 142340-99-6 ]
Reference: [1] Patent: EP2330107, 2011, A2, . Location in patent: Page/Page column 6
[2] Patent: US2011/207930, 2011, A1, . Location in patent: Page/Page column 4
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