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[ CAS No. 109113-72-6 ] {[proInfo.proName]}

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Chemical Structure| 109113-72-6
Chemical Structure| 109113-72-6
Structure of 109113-72-6 * Storage: {[proInfo.prStorage]}
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Product Details of [ 109113-72-6 ]

CAS No. :109113-72-6 MDL No. :MFCD09807547
Formula : C10H9ClN2 Boiling Point : -
Linear Structure Formula :- InChI Key :UHCUBOJGMLASBY-UHFFFAOYSA-N
M.W : 192.65 Pubchem ID :241518
Synonyms :

Calculated chemistry of [ 109113-72-6 ]

Physicochemical Properties

Num. heavy atoms : 13
Num. arom. heavy atoms : 10
Fraction Csp3 : 0.2
Num. rotatable bonds : 1
Num. H-bond acceptors : 2.0
Num. H-bond donors : 0.0
Molar Refractivity : 54.27
TPSA : 25.78 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.15 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.31
Log Po/w (XLOGP3) : 1.86
Log Po/w (WLOGP) : 2.53
Log Po/w (MLOGP) : 1.92
Log Po/w (SILICOS-IT) : 3.35
Consensus Log Po/w : 2.39

Druglikeness

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

Water Solubility

Log S (ESOL) : -2.71
Solubility : 0.376 mg/ml ; 0.00195 mol/l
Class : Soluble
Log S (Ali) : -2.02
Solubility : 1.83 mg/ml ; 0.00949 mol/l
Class : Soluble
Log S (SILICOS-IT) : -4.74
Solubility : 0.00351 mg/ml ; 0.0000182 mol/l
Class : Moderately soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.68

Safety of [ 109113-72-6 ]

Signal Word:Danger Class:8
Precautionary Statements:P501-P260-P264-P280-P303+P361+P353-P301+P330+P331-P363-P304+P340+P310-P305+P351+P338+P310-P405 UN#:3261
Hazard Statements:H314 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 109113-72-6 ]

* 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 [ 109113-72-6 ]
  • Downstream synthetic route of [ 109113-72-6 ]

[ 109113-72-6 ] Synthesis Path-Upstream   1~5

  • 1
  • [ 551-93-9 ]
  • [ 107-14-2 ]
  • [ 109113-72-6 ]
Reference: [1] Molecules, 2016, vol. 21, # 8,
[2] MedChemComm, 2013, vol. 5, # 11, p. 1700 - 1707
  • 2
  • [ 107-14-2 ]
  • [ 109113-72-6 ]
Reference: [1] Patent: WO2006/48427, 2006, A1, . Location in patent: Page/Page column 9
  • 3
  • [ 6640-59-1 ]
  • [ 109113-72-6 ]
Reference: [1] Patent: WO2005/51950, 2005, A1, . Location in patent: Page/Page column 20
  • 4
  • [ 70656-87-0 ]
  • [ 109113-72-6 ]
Reference: [1] Journal of Heterocyclic Chemistry, 1986, vol. 23, # 4, p. 1263 - 1264
  • 5
  • [ 666816-98-4 ]
  • [ 109113-72-6 ]
  • [ 853029-57-9 ]
YieldReaction ConditionsOperation in experiment
87.1% With potassium carbonate; methyl tributylammonium chloride In 2-methyltetrahydrofuranReflux 3-methyl-7-(2-butyn-1-yl)-8-bromoxanthine (Compound VII, 1.34 g, 0.0045 mol), potassium carbonate (base 2, 1.42 g, 0.0103 mol), 2-chloromethyl-4-methylquinazoline (Compound III, 0.87 g, 0.0045 mol), tributylmethylammonium chloride (PTC, 0.53 g, 0.002 mol) and 2-methyltetrahydrofuran (50 mL) were added to a reaction flask. The mixture was heated to reflux for 3 to 5 hours, cooled to room temperature, and added with 100 mL of water. After filtration, the filter cake was collected, and dried at 45° C. to give 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-bromo xanthine (Compound VIII). (0072) Yield: 1.78 g (87.1percent of theoretical value) (0073) MS: [M+H]+=453/455 (0074) 1H-NMR (400 MHz, DMSO): δ 1.79 (t, J=2.3 Hz, 3H), 2.89 (s, 3H), 3.44 (s, 3H), 5.11 (q, J=2.2 Hz, 2H), 5.35 (s, 2H), 7.67 (m, 1H), 7.80 (d, J=8.3 Hz, 1H), 7.75 (m, 1H), 8.24 (d, J=8.1 Hz, 1H).
86% With tetrabutylammomium bromide; potassium carbonate In N,N-dimethyl-formamide at 50 - 55℃; for 20 h; N,N-dimethylformamide (750 mL), 2-chloromethyl-4-methylquinazoline (Formula III; 93 g), potassium carbonate (63.9 g), 3-methyl-7-(2-butyn-1-yl)-8-bromoxanthine (Formula IV; 125 g), and tetrabutylammonium bromide (13.56 g) were added into a reaction vessel at ambient temperature. The reaction mixture was heated to 50°C to 55°C, then stirred for 20 hours. The progress of the reaction was monitored by HPLC. Thereaction mixture was cooled to ambient temperature, and then deionized water (1500 mL) was added. The reaction mixture was stirred for about 2 hours, filtered, and then washed with deionized water (625 mL). The wet material was charged in denatured spirits (1250 mL), heated to 75°C, and then stirred at 75°C to 77°C for 1 hour. The reaction mixture was cooled to ambient temperature, stirred for 120 minutes, filtered, and dried underreduced pressure at 55°C to 60°C for 12 hours to obtain the intermediate of Formula II.Yield: 86percentImpurity appearing at 1.03 RRT: 0.02percentImpurity appearing at 1.18 RRT: Not detectedImpurity appearing at 1.47 RRT: Not detected
86.4% With potassium carbonate In N,N-dimethyl acetamide at 75 - 95℃; Autoclave The intermediate (c) is reacted with 2-chloromethyl-4-methylquinazoline (d) to give intermediate (e).Steps:Was charged into a 10 L autoclave550 g (1.851 mol) of intermediate (c),463.3 g (2.405 mol)2-chloromethyl-4-methylquinazoline (d),332.6 g (2.407 mol) of potassium carbonate and 6 L of potassium carbonate(Dimethylacetamide,DMAC).Stirring, heating to 75 ~ 95 ° C reaction,7 ~ 10h after the end of the reaction,Cooling down to 65 ,Add 3L methanol stirring 0.5 ~ 1h,filter,The filter cake was washed with 1 L of methanol.The resulting filter cake was beaten with 2 L of water,filter,The filter cake was washed with 1 L of water,1 L methanol wash,A yellow filter cake,The product after drying was 724.9 g,The yield was 86.4percentPurity 98.5percent.
86.4% With potassium carbonate In N,N-dimethyl acetamide at 75 - 95℃; The intermediate (c) is reacted with 2-chloromethyl-4-methylquinazoline (d) to give intermediate (e).
Steps: Was charged into a 10 L reaction vessel 550g (1.851mol) of intermediate (c), 463.3 g (2.405 mol) of 2-chloromethyl-4-methylquinazoline (d), 332.6 g (2.407 mol) of potassium carbonate and 6 L of potassium carbonate (in dimethylacetamide, DMAC). Stirring, heating to 75 ~ 95 ° C reaction, 7 ~ 10h after the end of the reaction, cooling down to 65 deg. C, add 3L methanol stirring 0.5 ~ 1h, filtered, the filter cake was washed with 1 L of methanol. The obtained filter cake was stirred with 2L of water and filtered. The filter cake was washed with 1L of water and 1L of methanol to obtain a yellow filter cake, and dried to obtain 724.9g of product with yield of 86.4percent and purity of 98.5percent.
85% With sodium carbonate In N,N-dimethyl-formamide at 80℃; for 12 h; To a suspension of 3b (849 mg, 3 mmol) and Na2CO3 (382 mg, 3.6 mmol) in DMF (36 mL) was added 2-chloromethyl-4-methylquinazoline (636 mg, 3.3 mmol). The reaction mixture was stirred at 80 °C for 12 h. After cooling to r.t., the reaction mixture was diluted with DCM, washed with water and brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The resulting residue was purified by flash chromatography (petroleum ether/ethyl acetate, 1:1) to give 4b as a white solid (1.05 g, 80percent).
84% With tetrabutylammomium bromide; potassium carbonate In dimethyl sulfoxide at 75 - 80℃; 700 ml of DMSO, 77.8 g of 2-(Chloromethyl)-4-methyl-quinazoline( 0.4038 moles) , 100 g of 3-methyi-7-(2-butyn-l-yl)-8-bromo-xanthine (0.3365 moles, prepared in Example-2), 0.5 g tetrabutyl ammonium bromide and 55.8 g of anhydrous potassium carbonate (0.4038 moles) were added into a 5 lit a round bottom flask equipped with overhead stirrer & thermo pocket at 20-30°C and the temperature was raised to 75- 80°C. The reaction mixture was maintained at 75-80°C for 2-3 hrs. After completion of the reaction, reaction mixture was cooled to 45-50°C. To the reaction mixture was slowly added 600 ml of methanol and stirred for 60 min at 45-50°C. The solid was filtered and washed with 200 ml of methanol followed by DM water slurry. The wetmaterial was charged into RB flask and charged 700 ml of methanol into RB flask; the temperature was raised to 65°C and maintained for 60 min. The reaction mass was cooled to 40-45°C and maintained for 60 minutes. Filtered the solid and washed with 200 ml methanol. The wet material was dried at 40-45°C for 5-8 hours to get title compound (128 g, yield -84percent, purity > 99 percent).
12.1 g With potassium carbonate In N,N-dimethyl acetamide at 98℃; for 8 h; 3-Methyl-7-(2-butyn-l-yl)-8-bromo-xanthine (10 gm) and N,N-dimethylacetamide (150 mL) were charged into a 1 000 mL round bottomed flask equipped with a mechanical stirrer. Potassium carbonate (10.7 gm) and 2-(chloromethyl)-4- methylquinazoline (7.1 gm) were added to the reaction mixture at room temperature. The reaction mixture was heated to 98 °C and maintained the temperature for 8 hours. The reaction mixture was cooled to 30°C and water (450 mL) was added and the mixture was stirred for 1 hour at 30°C. The solid formed was collected by filtration and washed with water (150 mL). The wet cake was charged into 500 mL round bottomed flask and toluene (220 mL) was added and the mixture was heated to reflux temperature and maintained for 1 hour. The mixture was cooled to 10°C and maintained for 3 hours. The solid was collected by filtration and washed with toluene (5 mL). The solid was dried in oven under vacuum at 77°C to get 12.1 gm of the title compound. Purity by HPLC: 98.22percent.
253 g With potassium carbonate In N,N-dimethyl acetamide at 80 - 85℃; for 10 h; To the stirring mixture of purine (200g) in dimethylacetamide (1400 ml) were added quinazoline (147g), potassium carbonate powder (140 g) at 25-30 °C. The reaction mixture was heated to 80-85°C for 10 hr. To the reaction mixture, water was charged (5600 ml). After addition of water, reaction mixture was cooled to 25-30°C and maintained for 30 min. Filtered reaction mixture to give bromopurine (282 g) which is further purified from dimethyl formamide to give pure bromopurine (253 g). HPLC Purity: 99.47percent
105.5 g at 95 - 105℃; for 3 h; In a 2 L three-necked flask was added 60.0 g (0.245 mol) compound a (8-bromo-3-methylxanthine), 32.6 g (0.245 mol) of compound b (1-bromo-2-butyne), 63.3 g (0.490 mol) of diisopropylethylamine, and 570 g of N,N-dimethylformamide. Heating to 95-105°C, the mixture was stirred for 4 hours. TLC monitoring until no 8-bromo-3-methylxanthine (Rf (8-bromo-3-methylxanthine) = 0.4, Rf (reaction solution) = 0.6, developing solvent: toluene / absolute ethanol = 6/1, volume ratio). 47.2 g (0.245 mol) of compound d (2-(chloromethyl)-4-methylquinazoline) was added. The mixture was further stirred at 95-105°C for 3 hours. TLC monitoring until no compound c (8-bromo-7-but-2-yn-1-yl-3-methyl-3,7-dihydro-1H-purine-2,6-dione) (Rf (compound c) = 0.6, Rf (reaction solution) = 0.7, developing solvent: toluene / absolute ethanol = 6/1, volume ratio). The reaction solution was cooled to 5-25°C. To the system, 600 g of tap water was slowly added dropwise. Stirred at 15-25°C for 0.5 hours. Filtered and rinsed with toluene. The resulting solid was dried in vacuo at 70°C to give compound e (8-bromo-7-(2-butyn-1-yl)-3,7-dihydro-3-methyl-1-[(4-methyl-2-quinazolinyl)methyl]-1H-purine-2,6-dione): 105.5 g, HPLC purity 99.9percent, yield 95percent.

Reference: [1] Patent: WO2005/51950, 2005, A1, . Location in patent: Page/Page column 18
[2] Patent: US2015/274728, 2015, A1, . Location in patent: Paragraph 0070-0074
[3] Patent: WO2015/87240, 2015, A1, . Location in patent: Page/Page column 12
[4] Patent: , 2016, , . Location in patent: Paragraph 0045; 0046; 0047; 0048
[5] Patent: CN105936634, 2016, A, . Location in patent: Paragraph 0064; 0065; 0066; 0067
[6] European Journal of Medicinal Chemistry, 2014, vol. 83, p. 547 - 560
[7] Patent: WO2014/97314, 2014, A1, . Location in patent: Page/Page column 9-10
[8] Molecules, 2016, vol. 21, # 8,
[9] Patent: WO2006/48427, 2006, A1, . Location in patent: Page/Page column 10
[10] Patent: WO2013/98775, 2013, A1, . Location in patent: Page/Page column 20; 21
[11] Patent: US2013/123282, 2013, A1, . Location in patent: Paragraph 0182
[12] MedChemComm, 2013, vol. 5, # 11, p. 1700 - 1707
[13] Patent: WO2015/4599, 2015, A1, . Location in patent: Page/Page column 18
[14] Patent: US2015/239887, 2015, A1, . Location in patent: Paragraph 0148
[15] Patent: CN105541844, 2016, A, . Location in patent: Paragraph 0029
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