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[ CAS No. 2233-18-3 ] {[proInfo.proName]}

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Cat. No.: {[proInfo.prAm]}
Chemical Structure| 2233-18-3
Chemical Structure| 2233-18-3
Structure of 2233-18-3 * Storage: {[proInfo.prStorage]}
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Quality Control of [ 2233-18-3 ]

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Alternatived Products of [ 2233-18-3 ]

Product Details of [ 2233-18-3 ]

CAS No. :2233-18-3 MDL No. :MFCD00006946
Formula : C9H10O2 Boiling Point : -
Linear Structure Formula :- InChI Key :UYGBSRJODQHNLQ-UHFFFAOYSA-N
M.W : 150.17 Pubchem ID :75222
Synonyms :

Calculated chemistry of [ 2233-18-3 ]

Physicochemical Properties

Num. heavy atoms : 11
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.22
Num. rotatable bonds : 1
Num. H-bond acceptors : 2.0
Num. H-bond donors : 1.0
Molar Refractivity : 43.78
TPSA : 37.3 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) : -6.63 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.64
Log Po/w (XLOGP3) : 0.82
Log Po/w (WLOGP) : 1.82
Log Po/w (MLOGP) : 1.44
Log Po/w (SILICOS-IT) : 2.43
Consensus Log Po/w : 1.63

Druglikeness

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

Water Solubility

Log S (ESOL) : -1.63
Solubility : 3.56 mg/ml ; 0.0237 mol/l
Class : Very soluble
Log S (Ali) : -1.19
Solubility : 9.8 mg/ml ; 0.0653 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -2.53
Solubility : 0.446 mg/ml ; 0.00297 mol/l
Class : Soluble

Medicinal Chemistry

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

Safety of [ 2233-18-3 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P280-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H332-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 2233-18-3 ]

* 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 [ 2233-18-3 ]
  • Downstream synthetic route of [ 2233-18-3 ]

[ 2233-18-3 ] Synthesis Path-Upstream   1~7

  • 1
  • [ 2233-18-3 ]
  • [ 74-88-4 ]
  • [ 39250-90-3 ]
YieldReaction ConditionsOperation in experiment
95% With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 18 h; 3,5-Dimethyl-4-hydroxybenzaldehyde(1.54 g, 10.3 mmol), iodomethane (0.77 mL, 12.4 mmol), and K2CO3(1.71 g, 12.4 mmol) were stirred in DMF (10.0 mL) at room temperature.After 18 h, the reaction was extracted into EtOAc (100 mL) and washed with H2O (2x25 mL) and brine (25 mL), dried over Na2SO4, filtered, and concentrated.Flash chromatographic purification over silica (9:1 hexanes:EtOAc) afforded3,5-dimethyl-4-methoxybenzaldehydeas a white solid (1.60 g, 95percent).1H-NMR (500 MHz, CDCl3)d9.88 (s, 1H), 7.56 (s, 2H), 3.78 (s, 3H), 2.35 (s, 6H);13C-NMR (125 MHz, CDCl3)d191.69, 162.41, 132.25, 131.94, 130.73, 59.71, 16.19; GC-MS 163m/z[MH]+, C10H12O2requires 163; RP-HPLC: >99percent pure.
61% With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 18 h; To a solution of 4-hydroxy-3,5-dimethylbenzaldehyde (100mg, 0.67mmol) and potassium carbonate (111mg, 0.80mmol) in DMF (1.5mL) was added methyl iodide (50µL, 0.80mmol). The reaction mixture was stirred at room temperature for 18h. After complete turnover ethyl acetate (10mL) was added and the solution was washed two times with water and brine. The organic layer was dries over MgSO4, filtered and the solvent was removed in vacuum. The residue was purified by silica gel chromatography (cyclohexane : ethyl acetate 6:1) to give 67mg (61percent) as a colorless oil. HPLC: Rt=5.56min. 1H-NMR (CDCl3, 500MHz): [ppm] = 9.88 (s, 1H), 7.55 (s, 2H), 3.78 (s, 3H), 2.35 (s, 6H). 13C-NMR (CDCl3, 125MHz): [ppm]= 191.8, 162.6, 132.4, 132.1, 130.9, 59.9, 16.3.
Reference: [1] Journal of Medicinal Chemistry, 2008, vol. 51, # 20, p. 6348 - 6358
[2] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 15, p. 3441 - 3449
[3] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 19, p. 4630 - 4637
[4] Angewandte Chemie - International Edition, 2014, vol. 53, # 41, p. 11056 - 11059[5] Angew. Chem., 2015, vol. 126, # 41, p. 11236 - 11239,4
  • 2
  • [ 2233-18-3 ]
  • [ 80-48-8 ]
  • [ 39250-90-3 ]
Reference: [1] Organic Process Research and Development, 2015, vol. 19, # 1, p. 270 - 283
  • 3
  • [ 2233-18-3 ]
  • [ 4919-37-3 ]
Reference: [1] Monatshefte fuer Chemie, 1950, vol. 81, p. 1071,1083
  • 4
  • [ 2233-18-3 ]
  • [ 107-07-3 ]
  • [ 1039948-89-4 ]
YieldReaction ConditionsOperation in experiment
95% With potassium carbonate In ethanol for 24 h; Heating / reflux A solution of 2-amino-4,6-dimethoxybenzamide (0.60 g, 3.06 mmol) and 4-[2-(tert-butyidimethylsilanoxy)ethoxy]-3,5-dimethylbenzaldehyde (0.856 g, 2.78 mmol) in N,N-dimethyl formamide (20 mL) was stirred at 70° C. for 1 h. Iodine (0.846 g, 3.33 mmol) and potassium carbonate (0.384 g, 2.78 mmol) were added and the reaction mixture was stirred at 70° C. for 16 h. The reaction mixture was poured into ice, and extracted with ethyl acetate. The organic layer was washed with water, brine, and dried over anhydrous Na2SO4. Removal of the solvent gave the crude product which was purified by column chromatography to give 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (444 mg, 39percent) as a white solid. Selected data: 229-231° C.Alternatively, 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one can be synthesized by the following method. In a 2 L dry round-bottom flask with a reflux condenser and magnetic stirrer was placed 3,5-dimethyl-4-hydroxy benzaidehyde (26.9 g, 0.179 mol) in ethanol (350 mL). 2-chloroethanol (87.6 g, 1.074 mol) and K2CO3 (99 g, 0.716 mol) were added and the reaction mixture was heated to reflux for 24 h. The reaction mixture was cooled to room temperature and filtered. The solvent was removed under reduced pressure. The crude product was diluted with ethyl acetate and the organic layer was washed with water, brine, and dried over Na2SO4. Upon removal of solvent it gave 45 g of crude product. The crude product was purified by column chromatography (silica gel 230-400 mesh; 50percent ethyl acetate in hexane as eluent) to give 33.3 g (95percent) of product. To a solution of 2-amino-4,6-dimethoxy-benzamide (33.45 g, 0.170 mol) and 4-(2-hydroxy ethoxy)-3,5-dimethyl benzaldehyde (33.3 g, 0.170 mol) in N,N-dimethyl acetamide (300 mL), NaHSO3 (33.3 g, 0.187 mol) and p-TSA (3.2 g, 17.1 mmol) were added and the reaction mixture was heated at 150° C. for 14 h. The reaction was cooled to room temperature. The solvent was removed under reduced pressure. The residue was diluted with water and stirred for 30 min at room temperature. The solids separated were filtered and dried to give crude product. The crude product was purified by column chromatography (silica gel 230-400 mesh; 5percent methanol in CH2Cl2 as eluent) to give 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (33 g, 52percent).
95% With potassium carbonate In ethanol for 24 h; Reflux Alternatively, 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one can be synthesized by the following method. In a 2 L dry round-bottom flask with a reflux condenser and magnetic stirrer was placed 3,5-dimethyl-4-hydroxy benzaldehyde (26.9 g, 0.179 mol) in ethanol (350 mL). 2-chloroethanol (87.6 g, 1.074 mol) and K2CO3 (99 g, 0.716 mol) were added and the reaction mixture was heated to reflux for 24 h. The reaction mixture was cooled to room temperature and filtered. The solvent was removed under reduced pressure. The crude product was diluted with ethyl acetate and the organic layer was washed with water, brine, and dried over Na2SO4. Upon removal of solvent it gave 45 g of crude product. The crude product was purified by column chromatography (silica gel 230-400 mesh; 50percent ethyl acetate in hexane as eluent) to give 33.3 g (95percent) of product. To a solution of 2-amino-4,6-dimethoxy-benzamide (33.45 g, 0.170 mol) and 4-(2-hydroxy ethoxy)-3,5-dimethyl benzaldehyde (33.3 g, 0.170 mol) in N,N-dimethyl acetamide (300 mL), NaHSO3 (33.3 g, 0.187 mol) and p-TSA (3.2 g, 17.1 mmol) were added and the reaction mixture was heated at 150° C. for 14 h. The reaction was cooled to room temperature. The solvent was removed under reduced pressure. The residue was diluted with water and stirred for 30 min at room temperature. The solids separated were filtered and dried to give crude product. The crude product was purified by column chromatography (silica gel 230-400 mesh; 5percent methanol in CH2Cl2 as eluent) to give 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (33 g, 52percent).
95% With potassium carbonate In ethanol for 24 h; At 70deg.] C 2-Amino-4,6-dimethoxy-benzamide(0.60g, 3.06mmol) and 4- [2- (tert-butyldimethylsilyloxy)ethoxy]-3,5-dimethyl-benzaldehyde(0.856g,2.78mmol)in N, N- dimethylformamide(20 mL) was stirred for 1hour. Was added iodine (0.846g, 3.33mmol)and potassium carbonate (0.384g, 2.78mmol), thereaction mixture was at 70 stirred for 16 hours. The reactionmixture was poured onto ice, extracted with ethyl acetate. With water, theorganic layer was washed with brine, dried over anhydrous Na 2SO 4dry. The solvent was removed to give acrude product, which was purified by column chromatography to give a white solid of 2- (4- (2-hydroxyethoxy) -3,5-dimethylphenyl) -5,7-methoxy-quinazolin -4 (3H) - one (444mg, 39percent). Selected data: 229-231 . Alternatively, 2- (4-(2-hydroxyethoxy)-3,5-dimethyl-phenyl)-5,7-dimethoxy-quinazolin -4 (3H) - onecan be synthesized by the following method. In ethanol (350 mL of) of 3,5-dimethyl-4-hydroxy-benzaldehyde(26.9g, 0.179mol) disposed dried 2L round bottomed flask with refluxcondenser and magnetic stirrer. 2-chloro-ethanol(87.6g, 1.074mol) and K 2CO 3(99g, 0.716mol),the reaction mixture was heated at reflux for 24 hours. The reaction mixture was cooled toroom temperature and filtered. The solvent was removed under reduced pressure.The crude product was diluted with ethyl acetate, and the organic layer waswashed with water, brine, Na 2SO 4dry. 45g crude product obtained after removalof the solvent. The crude product was purified by column chromatography (silicagel 230-400 mesh; with 50percent hexanes in ethyl acetate as eluent) to afford 33.3g (95percent) of product. 2-amino-4,6-dimethoxy - benzamide (33.45g, 0.170mol)and 4- (2-hydroxyethoxy) -3,5-dimethyl benzaldehyde(33.3g, 0.170 mol) was added NaHSO3(33.3g,0.187mol) in N,N- dimethylacetamide (300mL) solution of and p-TSA(3.2g, 17.1mmol), at 150 reaction mixturewas heated for 14 hours.The reaction was cooled to room temperature. The solvent was removed underreduced pressure. The residue was diluted with water, followed by stirring at room temperature for30 minutes. The solid was isolated by filtration and dried to give the crudeproduct. The crude product was purified by column chromatography (silica gel230-400 mesh; used in CH 2Cl 25percent methanol as eluent) to afford 2- (4- (2-hydroxyethoxy) -3,5-dimethyl-phenyl)-5,7-dimethoxy-quinazoline -4 (3H) - one (33g, 52percent).
95% With potassium carbonate In ethanol for 24 h; Heating / reflux A solution of 2-amino-4,6-dimethoxyben2amide (0.60 g, 3.06 mmol) and 4-t2-(tert-butyldimethylsflanoxy)ethoxy]-3,5-dfmethylbenzaldehyde (0.856 g, 2.78 mmol) in λ/,/V-dimethyl formamide (20 mL) was stirred at 70°C for 1 h. Iodine (0.846 g, 3.33 mmol) and potassium carbonate (0.384 g, 2.78 mmol) were added and the reaction mixture was stirred at 70°C for 16 h, The reaction mixture was poured into ice, and extracted with ethyl acetate. The organic layer was washed with water, brine, and dried over anhydrous Na2SO4. Removal of the solvent gave the crude product which was purified by column chromatography to give 2-(4-{2- hydroxyethoxy)-3,5-dimethylphenyl)-5.7-dimethoxyquinazolin-4(3H)-one (444 mg, 39percent) as a white solid. Selected data: 229-231°C.[0117] Alternatively, 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7- dimethoxyquinazolin-4(3H)-one can be synthesized by the following method. In a 2 L dry round-bottom flask with a reflux condenser and magnetic stirrer was <n="65"/>placed 3, 5-dimethyl-4-hydroxy benzaldehyde (26.9 g, 0.179 mol) in ethanol (350 mL). 2-chloroethanol (87.6 g, 1.074 mol) and K2CO3 (99 g, 0.716 mol) were added and the reaction mixture was heated to reflux for 24 h. The reaction mixture was cooled to room temperature and filtered. The solvent was removed under reduced pressure. The crude product was diluted with ethyl acetate and the organic layer was washed with water, brine, and dried over Na2SO4. Upon removal of solvent it gave 45 g of crude product. The crude product was purified by column chromatography (silica gel 230-400 mesh; 50percent ethyl acetate in hexane as eluent) to give 33.3 g (95percent) of product, To a solution of 2-amino-4, 6- dimethoxy-benzamide (33.45 g, 0.170 mol) and 4-(2-hydroxy ethoxy)-3, 5- dimethyl benzaldehyde (33.3 g, 0.170 mol) in N,N-dimethyl acetamide (300 mL), NaHSOs (33.3 g, 0.187 mol) and p-TSA (3.2 g, 17.1 mmol) were added and the reaction mixture was heated at 150°C for 14 h. The reaction was cooled to room temperature. The solvent was removed under reduced pressure. The residue was diluted with water and stirred for 30 min at room temperature. The solids separated were filtered and dried to give crude product. The crude product was purified by column chromatography (silica gel 230-400 mesh; 5 percent methanol in CHzCI2 as eluent) to give 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7- dimethoxyquinazolin-4(3H)-one (33 g, 52percent).
94% With potassium carbonate In ethanol for 24 h; Reflux In a 50 ml single-neck round bottom flask, 1.05 g (7 mmol) of the starting material B-1 4-hydroxy-3,5-dimethylbenzaldehyde was added.14 ml of ethanol, 3.87 g of anhydrous potassium carbonate (28 mmol) and 2.8 ml of 2-chloroethanol (3.40 g, 42 mmol),The reaction was refluxed for 24 h.The reaction solution was cooled to room temperature, filtered, and the filtrate was evaporated to dryness.Wash with water (20 ml) and saturated brine (20 ml) and dry over anhydrous sodium sulfate. Column chromatography,Petroleum ether/ethyl acetate (v/v, 3:1) elution,1.25 g of compound B-2 was obtained in a yield of 94percent.

Reference: [1] Patent: US2008/188467, 2008, A1, . Location in patent: Page/Page column 33
[2] Patent: US2013/281397, 2013, A1, . Location in patent: Paragraph 0477
[3] Patent: CN103319408, 2016, B, . Location in patent: Paragraph 0406-0410
[4] Patent: WO2008/92231, 2008, A1, . Location in patent: Page/Page column 63-64
[5] Patent: CN108218798, 2018, A, . Location in patent: Paragraph 0057; 0058
[6] Angewandte Chemie - International Edition, 2015, vol. 54, # 23, p. 6770 - 6774[7] Angew. Chem., 2015, vol. 127, # 23, p. 6874 - 6878,5
  • 5
  • [ 96-49-1 ]
  • [ 2233-18-3 ]
  • [ 1039948-89-4 ]
YieldReaction ConditionsOperation in experiment
78.8% With potassium carbonate In N,N-dimethyl-formamide at 110℃; Inert atmosphere The starting material 4-hydroxy-3,5-dimethylbenzaldehyde (1; 70 kg), K2CO3 (9.8 kg) and DMF (133 kg) were mixed and stirred at 110 0C under nitrogen. Ethylene carbonate (45.6 kg) in DMF (46 kg) was added to the mixture over a period of 4 hours, using a diaphragm pump. The reaction mixture was stirred at 110 0C for 12 hours, until less than 5percent of the starting material 1 remained. The reaction mixture <n="17"/>was cooled to 25 0C and water (1300 kg) was added followed by a mixture of dichloromethane and heptane (3V/2V; 1300 kg). The mixture was agitated for 30 minutes. The organic layer was isolated and the aqueous layer was back extracted with a mixture of dichloromethane and heptane (3V/2V; 1300 kg). The combined organic layers were washed with aqueous sodium hydroxide (3 M; 460 kg), followed by three washes with water (3 x 710 kg), and dried over sodium sulfate (60 kg). Dichloromethane was removed from the dried organic layer by distillation, keeping the temperature below 40 0C. Heptane (260 kg) and seed crystals were added to initiate crystallization and the mixture was stirred at 20 0C for 2 hours. The mixture was filtered, washed with heptane (60 kg), and dried under vacuum until constant weight to afford intermediate 2 (71.3 kg, 78.8percent). 1H-NMR (DMSO-d6): δ 9.82 (1 H), 7.54 (2H), 4.96 (1 H), 3.85 (2H), 3.74 (2H), 2.29 (6H).
Reference: [1] Patent: WO2009/158404, 2009, A1, . Location in patent: Page/Page column 15-16
  • 6
  • [ 2233-18-3 ]
  • [ 540-51-2 ]
  • [ 1039948-89-4 ]
YieldReaction ConditionsOperation in experiment
80% With potassium carbonate In methanol at 79℃; for 8 h; The starting materials H30-4 (36 g, 0.24 mol), 2-bromoethanol (60 g, 0.48 mol), potassium carbonate (130 g,0.94 mol), and EtOH (600 mL) were added into a beaker. The mixture was refluxed at 79 °C for 8 h. After the completionof the reaction detected by TLC, the mixture was filtered. The resulting filtrate was distilled under reduced pressure.Water (300 mL) was then added to the residue. The mixture was extracted with EtOAc (3 3 100 mL). The organic layerwas separated, then washed with saturated aqueous NaCl solution (3 3 100 mL), dried by adding sodium sulfate, andfiltered. The resulting filtrate was distilled under reduced pressure. The resulting crude product was purified by silica gelcolumn chromatography (eluent: petroleum ether: ethyl acetate = 4: 1) to give the intermediate H30 -5 (37.5 g, yield 80percent).
Reference: [1] Patent: EP3348548, 2018, A1, . Location in patent: Paragraph 0057; 0059
  • 7
  • [ 2233-18-3 ]
  • [ 1044870-39-4 ]
Reference: [1] Patent: US2013/281397, 2013, A1,
[2] Patent: CN103319408, 2016, B,
[3] Patent: CN108218798, 2018, A,
[4] Patent: EP3348548, 2018, A1,
[5] Patent: WO2008/92231, 2008, A1,
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