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Product Details of [ 63920-73-0 ]

CAS No. :63920-73-0 MDL No. :MFCD20040374
Formula : C9H12N2O3 Boiling Point : -
Linear Structure Formula :- InChI Key :LSDUYZHWQMMNCO-UHFFFAOYSA-N
M.W : 196.20 Pubchem ID :20349016
Synonyms :

Calculated chemistry of [ 63920-73-0 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 14
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.22
Num. rotatable bonds : 3
Num. H-bond acceptors : 3.0
Num. H-bond donors : 2.0
Molar Refractivity : 51.93
TPSA : 87.57 Ų

Pharmacokinetics

GI absorption : High
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) : -7.06 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.48
Log Po/w (XLOGP3) : 0.61
Log Po/w (WLOGP) : 0.39
Log Po/w (MLOGP) : 0.09
Log Po/w (SILICOS-IT) : 0.29
Consensus Log Po/w : 0.57

Druglikeness

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

Water Solubility

Log S (ESOL) : -1.56
Solubility : 5.41 mg/ml ; 0.0275 mol/l
Class : Very soluble
Log S (Ali) : -2.02
Solubility : 1.86 mg/ml ; 0.00948 mol/l
Class : Soluble
Log S (SILICOS-IT) : -1.89
Solubility : 2.54 mg/ml ; 0.0129 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.62

Safety of [ 63920-73-0 ]

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

Application In Synthesis of [ 63920-73-0 ]

* 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 [ 63920-73-0 ]
  • Downstream synthetic route of [ 63920-73-0 ]

[ 63920-73-0 ] Synthesis Path-Upstream   1~14

  • 1
  • [ 21577-57-1 ]
  • [ 63920-73-0 ]
YieldReaction ConditionsOperation in experiment
71%
Stage #1: With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran for 4 h;
Stage #2: at 20℃; for 1 h;
EDC (0.15 g, 0.76 mmol),HOBt (0.10 g, 0.76 mmol), and NMM (84 μL, 0.76 mmol) wereadded to a solution of2-amino-4,6-dimethoxybenzoic acid (0.10 g, 0.51 mmol) in THF (5 mL). Themixture was stirred for 4 h beforeNH3 (g) was bubbled through for 1h at room temperature. Waterwas added (2 mL), and the aqueous layer wasextracted with DCM (3×20 mL). The organic layers were combined, washed withwater (3×25mL), dried (Na2SO4), and concentrated invacuo. Theresidue was purified by flash column chromatography (MeOH:DCM= 3: 100)to give compound12 (70 mg, 71percent).
68%
Stage #1: With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In tetrahydrofuran for 3 h;
Stage #2: With ammonium hydroxide In tetrahydrofuran at 20℃;
The starting materials H30-2 (19.7 g, 0.1 mol), HOBt (20.3 g, 0.15 mol), carbodiimide EDCI (28.8 g, 0.15 mol),DIPEA (32.3 g, 0.25 mol), and THF (1 L) were added into a three-necked round bottom flask, and stirred for 3h. Then40 mL of aqueous ammonia was added, stirring overnight at room temperature. After the completion of reaction detectedby TLC, the mixture was extracted with DCM (2 3 200 mL). The organic layer was separated, then washed twice withwater, and distilled under reduced pressure. Ether (50 mL) was added into the residue. After stirring and mixing homogeneously,the mixture was filtrated. The filtrate was discarded to give the intermediate H30-3 (13.4 g, yield 68percent).
57%
Stage #1: With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran at 20℃; for 3 h;
Stage #2: With ammonia In water at 20℃; for 16 h;
3,5-dimethoxy aniline (199g, 1.30mol) in diethyl ether (5.0 L) was added inthe flask 5L3 Cooled to 0° C. After 45 minutes the HCl gas (227g)introduced into the solution.at 10°C 45 Minutes the mixture was filtered, (4L) and washed withisopropyl acetate, under high vacuum, dried at 45 ° C Night to give the hydrochloride as a white solid (242.3g, 98percent). Under stirring the above hydrochloride (20g, 0The mixture.105mol) and oxalyl chloride (33 mL of) isequipped with a reflux condenser, 3-neck flask was heated 2 Hour (170 ° C externaltemperature), oxalyl chloride was distilled off from the reactionmixture. The flask was cooled to 0° C, was added methanol (40mL). The reactionmixture was heated at reflux for 45 minutes, filtered while hot, with A Alcohol(80mL) and washed to give a yellow-green solid4,6-dimethoxy isatin (17.2g, 79percent). After 2 Hour to isatin (162g,0.78mol) was heated in aqueous NaOH solution(40percent, 1.5L) in (externalTemperature 70 ° C) was slowly added to H 2 O 2(35percent, 405mL). H 2 O 2 was added after each batch, the internal temperature of the reaction Degree(initially 64 ° C) increase (to a maximum temperature of 80 ° C). Afterthe addition was complete, then at 70 ° C will blister The reaction mixture wasstirred for an additional 2hours, the mixture was stirred overnight while cooling to roomtemperature. The mixtureIt was heated to 70 ° C. An additional H 2 O 2 (75mL), at 70 ° C and themixture was stirred for an additional 2 Hours until the reaction was complete.Cooled to 10 ° C (bath temperature), a solution of Na 2 S 2 O 3 solution (150mL, saturation). The mixture was washed with HCl (37percent, 1.6L) was adjusted to pH8, with acetic acid(glacial acetic acid, 75mL) transfer To pH6, while not allowing thereaction mixture was warmed exceed 40 ° C. The reaction mixture was filtered,washed with water (4L) and washed to give the desired brownsolid amino acid (83.7g, 55percent). The amino acid (82.7g, 0.42mol) (4.2L) was added in dry THF EDCl (89.2g, 0.48mol), HOBT(65g, 0.48mol) and NMM (51.3mL), and the mixturewas stirred at roomtemperature for 3 hours. Adding NH3 Aqueoussolution (83mL, 50percent), and the mixture was stirred at room temperature for 16 hours.Was added water (1.25L), the The mixture (2 × 250mL) and extracted with DCM.Then the combined extracts were washed with water (2 × 500mL) washed Fandi.Concentrated, slurried with ethyl ether (550mL), filtered, and dried under highvacuum to afford a brown The solid4,6-dimethoxy-2-amino-benzamide (46.7g, 57percent).2-Amino-4,6-dimethoxy - benzamide (1.06g, 5.4mmol), 3,5- dimethyl-4-hydroxy Benzaldehyde (0.810g,5.4mmol), K 2 CO 3 (0.747g, 5.4mmol) and I 2(1.645g, 6.5mmol) DMF (20mL) in mixing, at 80 ° C and the reaction mixture was heated for 12 hours. It was cooledto Room temperature, poured onto crushed ice. The solid was collected, whichwas purified by column chromatography to give a white solid State of 2- (4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxy-quinazolin -4 (3H) - one (0.9g, 51percent). Selected data:MP291-293 ° C.
57%
Stage #1: With 4-methyl-morpholine; benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide In tetrahydrofuran at 20℃; for 3 h;
Stage #2: With ammonia In tetrahydrofuran; water at 20℃; for 16 h;
A solution of 3,5-dimethoxyaniline (199 g, 1.30 mol) in ether (5.0 L) in a 5 L 3-necked flask was cooled to 0°C. HCI gas (227 g) was bubbled through the solution over 45 min. After 45 min at 10°C, the mixture was filtered, washed with isopropylacetate (4 L), and dried overnight on high vacuum at 45°C to give the hydrochloride (242.3 g, 98percent), as a white solid. A mixture of the hydrochloride above (20 g, 0.105 mol) and oxalyl chloride (33 mL) in a 3-necked flask equipped with a reflux condenser was heated for 2 h with stirring (170°C external <n="58"/>temperature), and the oxalyl chloride was distilled from the reaction mixture. The flask was cooled to 0°C and methanol (40 mL) was added. The reaction mixture was heated to reflux for 45 min, filtered while hot, and washed with methanol (80 mL) to give the 4,6-dimethoxyisatin (17.2 g, 79percent) as a yellow-green solid. To a heated solution (external temp 70°C) of the isatin (162 g, 0.78 mol) in aqueous NaOH (40percent, 1.5 L) was added H2O2 (35percent, 405 mL) slowly over 2 h. After the addition of each portion of H2O2, the internal reaction temperature (initially 64°C) increased (to a maximum temp of 80°C). After the addition was complete, the foaming reaction mixture was then stirred for an additional 2 h at 70°C, and the mixture was allowed to stir overnight while cooling to RT. The mixture was heated to 70°C. Additional H2O2 (75 mL) was added, and the mixture was stirred at 70°C for a further 2 h until the reaction was complete. After cooling to 10°C (bath temperature), aqueous Na2S2O3 (150 mL, saturated) was added. The mixture was brought to pH 8 with HCI (37percent, 1.6 L) and pH 6 with acetic acid (glacial, 75 mL), without allowing the reaction mixture to warm to greater than 40°C. Filtration of the reaction mixture and washing with water (4 L) gave the expected amino acid as a tan solid (83.7 g, 55percent). To a solution of the amino acid (82.7 g, 0.42 mol) in anhydrous THF (4.2 L) was added EDCI (89.2 g, 0.48 mol), HOBT (65 g, 0.48 rnol), and NMM (51.3 mL), and the mixture was allowed to stir at RT for 3 h. Aqueous NH3 (83 mL, 50percent) was added, and the mixture was stirred at RT for 16 h. Water (1.25 L) was added, and the mixture was extracted with DCM (2x250 mL). The combined extracts were then washed with water (2x500 mL). Concentration, formation of a slurry with ether (550 mL), filtration, and drying under high vacuum gave 2-amino-4,6-dimethoxybenzamide (46.7 g,57percent) as a brown solid. <n="59"/>[0111] 2-Amino-4,6-dimethoxy-benzamide (1.06 g, 5.4 mmol), 3,5-dimethyl- 4-hydroxybenzaldehyde (0.810 g, 5.4 mmol), K2CO3 (0.747 g, 5.4 mmol) and I2 (1.645 g, 6.5 mmol) were mixed in DMF (20 ml_) and the reaction mixture was heated at 80°C for 12 h. It was cooled to RT and poured into crushed ice. The solid was collected and purified by column chromatography to give 2-(4-hydroxy- 3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4<3H)-one (0.9 g, 51percent) as a white solid. Selected data: MP 291-293°C.

Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 17, p. 4051 - 4055
[2] Patent: EP3348548, 2018, A1, . Location in patent: Paragraph 0057; 0058
[3] Patent: CN103319408, 2016, B, . Location in patent: Paragraph 0391-0395
[4] Patent: WO2008/92231, 2008, A1, . Location in patent: Page/Page column 56-58
[5] Patent: US2008/188467, 2008, A1, . Location in patent: Page/Page column 27
[6] Patent: US3966965, 1976, A,
[7] Patent: US4137325, 1979, A,
  • 2
  • [ 1545025-44-2 ]
  • [ 63920-73-0 ]
YieldReaction ConditionsOperation in experiment
79% at 100 - 115℃; Inert atmosphere EXAMPLE 5 2-amino-4,6-dimethoxybenzamide [00160] 2-amino-4,6-dimethoxybenzonitrile (10.0 g, 0.056 mol, 1 eq.) was charged to a 1-L glass vessel under N2 atmosphere and agitation was started. Methanesulfonic acid (120 mL, 1.848 mol, 33 eq.) was charged to the vessel and the reaction was heated at 100-115 °C for 1-2 hours. Upon verification of reaction completion by HPLC, the batch was cooled to 20-30 °C. Upon cooling, dichloromethane (67 mL) and cool water (164 mL) (5-10 °C) were added to keep the temperature in the range of 10-30 °C. 50percent caustic (94 mL) was charged to the vessel using an addition funnel while maintaining 0-30 °C. Fine pH adjustment to 6.5 to 7.3 was completed using either 32percent HC1 or 50percent caustic. Upon equilibration, the first organic phase cut was performed. The aqueous layer was extracted two additional times with DCM (74 mL and 57 mL respectively). Dichloromethane (54 mL) was added to the combined organic layers and the organic layer was washed with water (143 mL) to remove methanesulfonate salts. Dichloromethane (16 mL) was added to the combined organic layers and the organic layer was washed once more with water (143 mL) to remove methanesulfonate salts. The batch was distilled using (5-10 inches Hg) vacuum to a pot volume of 4.5 volumes DCM (45 mL). The contents of the vessel were stirred for 1 hour at 38 °C. The vessel was cooled to 23-28 °C over 1 hour with slow agitation. When clouding was observed, the vessel was slowly charged with 14.4 volumes MtBE (144 mL) and the batch was agitated for 30 min at 25 °C (ratio of DCM/MtBE is 1:3.2; total volumes of solvent is 18.9). The batch was slowly cooled to between -5 °C and 5 °C over at least 3 hours. The batch was held for at least 1 hour between -5 °C and 0 °C. Precipitation was verified through collection of at least two samples from the liquor to determine the amount of 2-amino-4,6-dimethoxybenzamide remaining in solution. The batch was isolated by filtration and the wet cake washed with a cold (0 °C) mixture of 1:4 DCM/MtBE (51 mL). The 2-amino-4,6-dimethoxybenzamide wet cake was dried in a vacuum oven (40-45 °C, 25 inches Hg) to give 2-amino-4,6-dimethoxybenzamide (8.33 g, 0.0425 mol, 75.7percent yield; 53percent yield over 5 steps from 3,5-dimethoxyaniline). Use of an alternate solvent to dichloromethane has been studied and performs in a similar fashion to dichloromethane. Examples of alternate solvents include, but are not limited to esters like isopropyl acetate and ethyl acetate, and ethers like 2-methyltetrahydrofuran. In addition, alternate precipitation systems with or without anti- solvent have also been examined. The precipitation system may include, but is not limited to esters like isopropyl acetate, ethers like 2-methyltetrahydrofuran, and alcohols like isopropyl alcohol. The yield range from these modifications in the experimental procedure is 72-79percent. In addition, purity of the desired compound is consistently over 99percent.
75% With methanesulfonic acid In dichloromethane; water at 110℃; for 2 h; Inert atmosphere Compound 7 (1.78 g, 10 mmol) was added to a 100 mL single-mouth bottle.Methanesulfonic acid (31.72 g, 330 mmol) was added to dissolve it.The reaction system is protected by N2,The temperature was raised to 110 ° C for 2 hours.After the reaction is over,A mixture of water and methylene chloride (1:2 by volume) is added to the system.Adjust the pH to neutral with a mass fraction of 30percent sodium hydroxide solution.The mixture was extracted three times with dichloromethane (3*20 mL).Combine the organic phase,Dry with anhydrous sodium sulfate,filter,Distilling under reduced pressure to obtain a mixture,Purified by column chromatography (eluent is petroleum ether / ethyl acetate, volume ratio 1:1).The brown solid was obtained as Compound 8 (1.47 g, yield: 75percent).
Reference: [1] Patent: WO2014/62428, 2014, A1, . Location in patent: Paragraph 00160
[2] Patent: CN108484510, 2018, A, . Location in patent: Paragraph 0041
  • 3
  • [ 21544-81-0 ]
  • [ 63920-73-0 ]
YieldReaction ConditionsOperation in experiment
46.7 g
Stage #1: With dihydrogen peroxide; sodium hydroxide In tetrahydrofuran; water at 70℃;
Stage #2: With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran at 20℃; for 3 h;
Stage #3: With ammonia In tetrahydrofuran; water at 20℃; for 16 h;
A solution of 3,5-dimethoxyaniline (199 g, 1.30 mol) in ether (5.0 L) in a 5 L 3-necked flask was cooled to 0° C. HCl gas (227 g) was bubbled through the solution over 45 min. After 45 min at 10° C., the mixture was filtered, washed with isopropylacetate (4 L), and dried overnight on high vacuum at 45° C. to give the hydrochloride (242.3 g, 98percent), as a white solid. A mixture of the hydrochloride above (20 g, 0.105 mol) and oxalyl chloride (33 mL) in a 3-necked flask equipped with a reflux condenser was heated for 2 h with stirring (170° C. external temperature), and the oxalyl chloride was distilled from the reaction mixture. The flask was cooled to 0° C. and methanol (40 mL) was added. The reaction mixture was heated to reflux for 45 min, filtered while hot, and washed with methanol (80 mL) to give the 4,6-dimethoxyisatin (17.2 g, 79percent) as a yellow-green solid. To a heated solution (external temp 70° C.) of the isatin (162 g, 0.78 mol) in aqueous NaOH (40percent, 1.5 L) was added H2O2 (35percent, 405 mL) slowly over 2 h. After the addition of each portion of H2O2, the internal reaction temperature (initially 64° C.) increased (to a maximum temp of 80° C.). After the addition was complete, the foaming reaction mixture was then stirred for an additional 2 h at 70° C., and the mixture was allowed to stir overnight while cooling to room temperature. The mixture was heated to 70° C. Additional H2O2 (75 mL) was added, and the mixture was stirred at 70° C. for a further 2 h until the reaction was complete. After cooling to 10° C. (bath temperature), aqueous Na2S2O3 (150 mL, saturated) was added. The mixture was brought to pH 8 with HCl (37percent, 1.6 L) and pH 6 with acetic acid (glacial, 75 mL), without allowing the reaction mixture to warm to greater than 40° C. Filtration of the reaction mixture and washing with water (4 L) gave the expected amino acid as a tan solid (83.7 g, 55percent). To a solution of the amino acid (82.7 g, 0.42 mol) in anhydrous THF (4.2 L) was added EDCl (89.2 g, 0.48 mol), HOBT (65 g, 0.48 mol), and NMM (51.3 mL), and the mixture was allowed to stir at room temperature for 3 h. Aqueous NH3 (83 mL, 50percent) was added, and the mixture was stirred at room temperature for 16 h. Water (1.25 L) was added, and the mixture was extracted with DCM (2×250 mL). The combined extracts were then washed with water (2×500 mL). Concentration, formation of a slurry with ether (550 mL), filtration, and drying under high vacuum gave 2-amino-4,6-dimethoxybenzamide (46.7 g, 57percent) as a brown solid. [0454] 2-Amino-4,6-dimethoxy-benzamide (1.06 g, 5.4 mmol), 3,5-dimethyl-4-hydroxybenzaldehyde (0.810 g, 5.4 mmol), K2CO3 (0.747 g, 5.4 mmol) and I2 (1.645 g, 6.5 mmol) were mixed in DMF (20 mL) and the reaction mixture was heated at 80° C. for 12 h. It was cooled to room temperature and poured into crushed ice. The solid was collected and purified by column chromatography to give 2-(4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.9 g, 51percent) as a white solid. Selected data: MP 291-293° C
Reference: [1] Patent: US2013/281397, 2013, A1, . Location in patent: Paragraph 0452; 0453; 0454
[2] Patent: CN103319408, 2016, B,
[3] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 17, p. 4051 - 4055
[4] Patent: WO2008/92231, 2008, A1,
  • 4
  • [ 63920-75-2 ]
  • [ 63920-73-0 ]
Reference: [1] Patent: US4054661, 1977, A,
[2] Patent: US4191840, 1980, A,
[3] Patent: US4069343, 1978, A,
[4] Patent: US4154961, 1979, A,
[5] Patent: US4160100, 1979, A,
[6] Patent: US3966965, 1976, A,
  • 5
  • [ 10272-07-8 ]
  • [ 63920-73-0 ]
Reference: [1] Patent: US2013/281397, 2013, A1,
[2] Patent: WO2014/62428, 2014, A1,
[3] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 17, p. 4051 - 4055
[4] Patent: CN108484510, 2018, A,
[5] Patent: WO2008/92231, 2008, A1,
  • 6
  • [ 40891-33-6 ]
  • [ 63920-73-0 ]
Reference: [1] Patent: US2013/281397, 2013, A1,
[2] Patent: WO2008/92231, 2008, A1,
  • 7
  • [ 1599437-14-5 ]
  • [ 63920-73-0 ]
Reference: [1] Patent: WO2014/62428, 2014, A1,
  • 8
  • [ 99-10-5 ]
  • [ 63920-73-0 ]
Reference: [1] Patent: CN108484510, 2018, A,
  • 9
  • [ 1132-21-4 ]
  • [ 63920-73-0 ]
Reference: [1] Patent: CN108484510, 2018, A,
  • 10
  • [ 85657-94-9 ]
  • [ 63920-73-0 ]
Reference: [1] Patent: CN108484510, 2018, A,
  • 11
  • [ 1599437-13-4 ]
  • [ 63920-73-0 ]
Reference: [1] Patent: CN108484510, 2018, A,
  • 12
  • [ 1039948-89-4 ]
  • [ 63920-73-0 ]
  • [ 1044870-39-4 ]
YieldReaction ConditionsOperation in experiment
79.9% With toluene-4-sulfonic acid; sodium hydrogensulfite In ISOPROPYLAMIDE at 115℃; Intermediate 2 (58.74 kg), ?/,?/-dimethylacetamide (280 kg), and starting material 3 (56.00 kg) were combined and p-toluenesulfonic acid monohydrate (5.90 kg) and 1/3 of the required sodium bisulfite (24.1 kg) were added. The mixture was heated to 115 0C and stirred for 90-105 minutes before the second 1/3 of the required sodium bisulfite (24.1 kg) was added. The remaining sodium bisulfite (24.1 kg) was added after another 90-105 minutes. The reaction mixture was stirred at 115 0C until the reaction was complete as determined by HPLC (approximately 1 hour, less than 4percent of intermediate 2 remaining). The reaction mixture was cooled to 25 0C and added to water (1770 kg). The mixture was stirred at 20 0C for 6 hours to complete the crystallization. The crude material was isolated by filtration, washed with water (234 kg) and dried under vacuum to constant weight. The crude material was dissolved in ?/,?/-dimethylacetamide (252 kg) at 80 0C until all material had dissolved. The solution was cooled to 60 0C and heptane (918 kg) was slowly added over a period of 1 hour, maintaining a temperature above 35 0C.The solution was cooled to 35 0C and stirred at 35 0C for a minimum of 1 hour. The solid was isolated by filtration, washed with heptane (250 kg) and dried to constantweight under vacuum. Yield: 92.5percent; purity: 98.6percent. The dry solid (83.1 kg) was added to a 1 :1 mixture of ethanol and water (1V/1V; 1670 kg), and the mixture was heated to approximately 840C (reflux) until all material was in solution. The solution was cooled to 70 0C and polish-filtered, and then cooled to 30 0C over 2 hours. The solution was cooled to 0 0C. The mixture was stirred at 0 0C for at least 1 hour, before the material was isolated by filtration, washed with ethanol/water (1V/1V; 33 kg) and dried under vacuum to constant weight. The material was passed through a 60-mesh screen to afford 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7- dimethoxyquinazolin-4(3H)-one (4). Yield: 66.4 kg; 79.9percent.
62.7% With toluene-4-sulfonic acid; sodium hydrogensulfite In 1-methyl-pyrrolidin-2-one at 130℃; for 3 h; Inert atmosphere The intermediate H30-3 (15.2 g, 77.5 mol), H30-5 (15.06 g, 77.5 mmol), NAHSO3 (8.9 g, 85.3 mmol), P-TSA(1.34 g, 7.75 mmol), and NMP (140 mL) were added into a flask in the presence of nitrogen gas. The mixture was stirredfor 3 h at 130 °C. After the completion of the reaction detected by TLC, the mixture was extracted by adding water (450mL) and DCM (500 mL). The separated aqueous layer was extracted with DCM (4 3 400 mL). The resulting organiclayers were combined, washed with water (3 3 400 mL), dried by adding sodium sulfate, and filtered. The resultingfiltrate was distilled under reduced pressure. The resulting crude product was purified by silica gel column chromatography(eluent: dichloromethane: methanol = 80: 1) to give the intermediate H130: 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazoline-4(3H)-one (18 g, yield 62.7percent).
52% With toluene-4-sulfonic acid; sodium hydrogensulfite In N,N-dimethyl acetamide at 150℃; for 14 h; 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).
52% With toluene-4-sulfonic acid; sodium hydrogensulfite In N,N-dimethyl acetamide at 150℃; for 14 h; 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).
52% With toluene-4-sulfonic acid; sodium hydrogensulfite In N,N-dimethyl acetamide at 150℃; for 14 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).
52% With toluene-4-sulfonic acid; sodium hydrogensulfite In ISOPROPYLAMIDE at 150℃; for 14 h; 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).

Reference: [1] Patent: WO2009/158404, 2009, A1, . Location in patent: Page/Page column 16-17
[2] Patent: EP3348548, 2018, A1, . Location in patent: Paragraph 0060
[3] Patent: US2008/188467, 2008, A1, . Location in patent: Page/Page column 33
[4] Patent: US2013/281397, 2013, A1, . Location in patent: Paragraph 0477
[5] Patent: CN103319408, 2016, B, . Location in patent: Paragraph 0406-0410
[6] Patent: WO2008/92231, 2008, A1, . Location in patent: Page/Page column 63-64
  • 13
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  • [ 63920-73-0 ]
  • [ 1044870-39-4 ]
YieldReaction ConditionsOperation in experiment
39% With iodine; potassium carbonate In N,N-dimethyl-formamide at 70℃; for 17 h; 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).
39%
Stage #1: at 70℃; for 1 h;
Stage #2: With iodine; potassium carbonate In N,N-dimethyl-formamide at 70℃; for 16 h;
2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one [0476] A solution of 2-amino-4,6-dimethoxybenzamide (0.60 g, 3.06 mmol) and 4-[2-(tert-butyldimethylsilanoxy)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.
39%
Stage #1: at 70℃; for 1 h;
Stage #2: at 70℃; for 16 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).
Reference: [1] Patent: US2008/188467, 2008, A1, . Location in patent: Page/Page column 33
[2] Patent: US2013/281397, 2013, A1, . Location in patent: Paragraph 0476
[3] Patent: CN103319408, 2016, B, . Location in patent: Paragraph 0406-0410
  • 14
  • [ 63920-73-0 ]
  • [ 1044870-39-4 ]
Reference: [1] Patent: CN108484510, 2018, A,
[2] Patent: WO2008/92231, 2008, A1,
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