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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 : |
|
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 |
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 |
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 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
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 |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.0 |
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: |
* 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.
Yield | Reaction Conditions | Operation 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. |
Yield | Reaction Conditions | Operation 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. |
Yield | Reaction Conditions | Operation 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). |
Yield | Reaction Conditions | Operation 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). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With oxygen; cobalt(II) diacetate; sodium hydroxide In water monomer; ethylene glycol at 50℃; for 12h; Green chemistry; chemoselective reaction; | 2.2. Typical procedure for the Co(OAc)2-catalyzed aerobic oxidation of 1 (Table 2 in the text) Typical procedure: a mixture of substrate 1 (5.0 mmol), Co(OAc)2*4H2O (0.05 mmol, 12 mg) and NaOH (5.0 mmol, 0.2 g) in EG/H2O (5.0 mL/0.25 mL) was stirred with O2 (1.0 atm) being bubbled at 50 °C for 12 h. Hydrochloric acid (10.0 mL, 2 %) and chloroform (10.0 mL) were successively added to the reaction mixture. The chloroform phase was separated, and the aqueous phase was further extracted with chloroform (10.0 mL × 2). The combined organic layer was dried over anhydrous sodium sulfate and concentrated to give a residue, which was purified by column chromatography on silica gel (eluents: .petroleum ether/ethyl acetate, 5/1) to provide the desired products 2. 3,5-Dimethyl-4-hydroxybenzaldehyde (2a):[1,2] white solid, 0.66 g (88% yield). Thespectral data see 2.1 section. |
87% | With copper (II) acetate; ethylene glycol at 65℃; for 12h; Green chemistry; regioselective reaction; | |
85% | With 2.9-dimethyl-1,10-phenanthroline; sodium methoxide In methanol for 0.75h; |
83% | With potassium hydroxide; iodine In methanol for 2h; | |
75% | With acetic acid | 5 EXAMPLE 5 EXAMPLE 5 Into a 300-ml stainless steel Parr bomb is placed 25 g of 2,4,6-trimethylphenol, 2.0 g of 5 percent platinum on carbon and 75 ml of acetic acid. The bomb is pressurized to 250 psig with O2 and heated to 75° C. The bomb is held at this temperature for 4.5 hours. The material is filtered through celite and the acetic acid is removed by rotary evaporation. A 75 percent yield of 3,5-dimethyl-4-hydroxybenzaldehyde is obtained. This material is further purified using a toluene slurry wash (m.p. 111° C.-113° C.). The principle by-product is 2,6-dimethyl p-benzoquinone. |
70% | With potassium dichromate||potassium bichromate||K2Cr2O7||Cr2O7K2; acetic acid In methanol; water monomer for 4h; Ambient temperature; | |
17% | With air In water monomer; acetone at 20℃; Electrolysis; | |
With NX-1011; ethanol | ||
With iodic acid In ethanol | ||
83 % Chromat. | With N-Bromosuccinimide In dimethyl sulfoxide at 120℃; for 4h; | |
Multi-step reaction with 3 steps 1: 69 percent / CuCl2*2H2O; neocuproine / methanol / 1 h / 20 °C 2: 20 °C 3: 280 mg / H2O / 20 °C | ||
Multi-step reaction with 2 steps 1: 49 percent Chromat. / cobalt(III) acetate / acetic acid / 1 h / 50 °C 2: 67 percent Chromat. / cobalt(III) acetate / acetic acid / 1 h / 50 °C | ||
Multi-step reaction with 2 steps 1: 55 percent / 2,3-dichloro-5,6-dicyano-p-benzoquinone / methanol 2: 82 percent / ammonium acetate, potassium ferricyanide / H2O; methanol / 240 h / 45 °C | ||
Multi-step reaction with 2 steps 1: cobalt(II) diacetate; sodium hydroxide; oxygen / water monomer / 3 h / 50 °C / 760.05 Torr / Green chemistry 2: cobalt(II) diacetate; sodium hydroxide; oxygen / ethylene glycol; water monomer / 12 h / 50 °C / 760.05 Torr / Green chemistry | ||
With oxygen; sodium hydroxide In 2-methoxy-ethanol at 80℃; for 7h; chemoselective reaction; | 2.4. Oxidation of p-cresols General procedure: In a typical procedure, NaOH (5.4 g, 135 mmol) was first dissolvedwith 20 g EGME in a four-necked round-bottom flask, then 50 mmolsubstrate and 0.04 g catalyst (cobalt/substrate molar ratio, 0.4%) wereadded to the above solution. The flask was equipped with a condenser,a stirrer and an air-vent needle for continuous flow of 100 mL min-1 O2. The stirring speed was 600 rpm to minimize the effect of mass transfer (Fig. S1). The reaction temperature is 80 °C and the reaction time is 7 h. After the reaction, the CoOxCN was separated by an externalmagnet for reuse and the decanted reaction solution was dilutedwith water. A high performance liquid chromatography (HPLC)(Shimadzu LC-20AT) equipped with a UV detector connected to a C18reversal pillar (size: 250×4.6 mm) was used for product analysis. Amixture of methanol and water (volume ratio, 40:60) was used asmobile phase at a flow rate of 1.0 mL min-1. The column temperaturewas 40 °C and the UV detection wavelength was 230 nm. HPLC andhigh performance liquid chromatography-mass spectrum (HPLC-MS)were used to test the products and intermediates by comparison withstandard chemicals. The conversions (conv.) of p-cresols, yields (Yi) ofp-hydroxybenzaldehydes, selectivity (Si) of p-hydroxybenzaldehydesand turnover numbers (TONs) of catalysts are defined as followingequations: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With sodium tetrahydridoborate In ethanol at 20℃; | 2.General procedure for the preparation of 1a-d and 1f-1i General procedure: To a solution of 4-hydroxy or4-methoxybenzaldehyde derivatives (1.5 mmol) in anhydrous ethanol (8 mL) wasadded NaBH4 (6.0 mmol). The reaction mixture was stirred at room temperature until the TLC indicated the consumption of the starting material. An appropriate amount of water was added to the reaction, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine,dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was puried byash chromatography (petroleum ether/ethyl acetate 10:1 to 1:1) to give the products 1a-1d and 1i |
52% | With sodium tetrahydridoborate In methanol at 15 - 20℃; for 1h; | 5 EXAMPLE 5; Compound 7 To a solution of 3,5-dimethyl-4-hydroxybenzaldehyde (5.0 g, 0.33 mol) in methanol (75 mL) cooled to 15 °C was added sodium borohydride (3. 8 G, 0. 10 MOL). The cooling bath was then removed, and the reaction mixture stirred at room temperature for one hour, followed by acidification with 0.1N HC1 solution. The solvent was removed under reduced pressure and the residue taken up in water (50 mL), and extracted with DCM. The organic layer was dried (anhydrous sodium sulfate), filtered, and the solvent removed under reduced pressure to yield 7 (2.6 g, 52 %). 13C NMR (67.8 MHz, CDC13) 8 151.83, 132. 51, 127.79, 123.24, 65.20, 15.84. |
With lithium aluminium hydride; diethyl ether |
With sodium hydroxide; sodium tetrahydridoborate | ||
3.30 g | With sodium tetrahydridoborate In tetrahydrofuran at 0 - 20℃; for 0.666667h; | |
With methanol; sodium tetrahydridoborate at 0℃; for 0.75h; | 1 Sodium borohydride (378 mg, 9.99 mmol) was added in 4-5 portions to a solution of 4-hydroxy-3,5-dimethylbenzaldehyde (500 mg, 3.33 mmol) in methanol (8 mL) at 0 °C and the resulting mixture stirred at 0 °C for 45 minutes. The reaction mixture was acidified to pH 2 by the addition of 1 M HCl (10-15 mL) and the organic solvent removed under reduced pressure. The aqueous residue was extracted with CH2Cl2 (2 × 20 mL) and the combined organic extracts dried (MgSO4) and concentrated under reduced pressure to give crude diol Int-131 (600 mg), which was used in the next step without further purification. | |
With methanol; sodium tetrahydridoborate at 0℃; for 0.75h; | 1 DMPHB-C12a'bMe-bromide-2-TG (Int-135): Sodium borohydride (378 mg, 9.99 mmol) was added in 4-5 portions to a solution of 4-hydroxy-3,5-dimethylbenzaldehyde (500 mg, 3.33 mmol) in methanol (8 mL) at 0 °C and the resulting mixture stirred at 0 °C for 45 minutes. The reaction mixture was acidified to pH 2 by the addition of 1 M HCl (10-15 mL) and the organic solvent removed under reduced pressure. The aqueous residue was extracted with CH2Cl2 (2 × 20 mL) and the combined organic extracts dried (MgSO4) and concentrated under reduced pressure to give crude diol Int-131 (600 mg), which was used in the next step without further purification. | |
With methanol; sodium tetrahydridoborate at 0℃; for 0.75h; | 1 Sodium borohydride (378 mg, 9.99 mmol) was added in 4-5 portions to a solution of 4-hydroxy-3,5-dimethylbenzaldehyde (500 mg, 3.33 mmol) in methanol (8 mL) at 0 °C and the resulting mixture stirred at 0 °C for 45 minutes. The reaction mixture was acidified to pH 2 by the addition of 1 M HC1 (10-15 mL) and the organic solvent removed under reduced pressure. The aqueous residue was extracted with CH2CI2 (2 c 20 mL) and the combined organic extracts dried (MgSCri) and concentrated under reduced pressure to give crude diol lnt-131 (600 mg), which was used in the next step without further purification. | |
With sodium tetrahydridoborate In methanol at 0℃; for 0.75h; | [00639] Sodium borohydride (378 mg, 9.99 mmol) was added in 4-5 portions to a solution of 4-hydroxy-3,5-dimethylbenzaldehyde (500 mg, 3.33 mmol) in methanol (8 mL) at 0 °C and the resulting mixture stirred at 0 °C for 45 minutes. The reaction mixture was acidified to pH 2 by the addition of 1 M HC1 (10-15 mL) and the organic solvent removed under reduced pressure. The aqueous residue was extracted with CH2CI2 (2 c 20 mL) and the combined organic extracts dried (MgSCri) and concentrated under reduced pressure to give crude diol lnt-131 (600 mg), which was used in the next step without further purification. | |
With sodium tetrahydridoborate In methanol at 0℃; for 0.75h; | 1 [00584] DMPHB-C12α'βMe-bromide-2-TG (Int-135): [00585] Sodium borohydride (378 mg, 9.99 mmol) was added in 4-5 portions to a solution of 4-hydroxy-3,5-dimethylbenzaldehyde (500 mg, 3.33 mmol) in methanol (8 mL) at 0 °C and the resulting mixture stirred at 0 °C for 45 minutes. The reaction mixture was acidified to pH 2 by the addition of 1 M HCl (10-15 mL) and the organic solvent removed under reduced pressure. The aqueous residue was extracted with CH2Cl2 (2 20 mL) and the combined organic extracts dried (MgSO4) and concentrated under reduced pressure to give crude diol Int-131 (600 mg), which was used in the next step without further purification. | |
With sodium tetrahydridoborate In methanol at 0℃; for 0.75h; | 1 [00584] DMPHB-C12α'βMe-bromide-2-TG (Int-135): [00585] Sodium borohydride (378 mg, 9.99 mmol) was added in 4-5 portions to a solution of 4-hydroxy-3,5-dimethylbenzaldehyde (500 mg, 3.33 mmol) in methanol (8 mL) at 0 °C and the resulting mixture stirred at 0 °C for 45 minutes. The reaction mixture was acidified to pH 2 by the addition of 1 M HCl (10-15 mL) and the organic solvent removed under reduced pressure. The aqueous residue was extracted with CH2Cl2 (2 20 mL) and the combined organic extracts dried (MgSO4) and concentrated under reduced pressure to give crude diol Int-131 (600 mg), which was used in the next step without further purification. | |
With sodium tetrahydridoborate |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With piperidine In dichloromethane at 130℃; for 7h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Stage #1: 4-hydroxy-3,5-dimethylbenzaldehyde With potassium carbonate In acetone at 20℃; for 0.25h; Stage #2: chloromethyl methyl ether In acetone for 2h; Reflux; | |
92% | Stage #1: 4-hydroxy-3,5-dimethylbenzaldehyde With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; Inert atmosphere; Stage #2: chloromethyl methyl ether In N,N-dimethyl-formamide at 0 - 20℃; for 16h; Inert atmosphere; | 5 Example 5. Preparation of 7-(2-benzyloxy-ethoxy)-2-(4-hydroxy-3,5-dimethyl-phenyl)-5-methoxy-3H-quinazolin-4-one [0167] To a suspension of sodium hydride (2.00 g, 50.0 mmol) in anhydrous DMF (30 ml_) at 00C was added a solution of 4-hydroxy-3,5-dimethyl-benzaldehyde (5.00 g, 33.3 mmol) in anhydrous DMF (20 ml_), dropwise over a period of 30 minutes, under nitrogen. Stirring continued at room temperature for 30 minutes and the mixture was cooled to 00C. Chloromethoxymethane (5.06 mL, 66.6 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours under nitrogen. The reaction mixture was poured into water (200 mL), extracted with ethyl acetate (2 * 50 mL), dried over anhydrous Na2SO4, and concentrated. The crude compound was purified by column chromatography (SiO2, ethyl acetate / hexanes = 1:3) to afford 4-methoxymethoxy-3,5-dimethyl-benzaldehyde as colorless oil. Yield: 5.97 g (92%).[0168] To a solution of 4-methoxymethoxy-3,5-dimethyl-benzaldehyde (4.00 g, 20.6 mmol) and 2-amino-4,6-difluoro-benzamide (3.55 g, 20.6 mmol) in Λ/,Λ/-dimethylacetamide (20 mL) were added sodium hydrogen sulfite (58.5 wt%) (5.45 g, 30.9 mmol) and p-toluenesulfonic acid (0.20 g, 1.0 mmol). The reaction mixture was stirred at 1200C for 16 hours under nitrogen and cooled to room temperature. The solvent was evaporated under reduced pressure. Methanol (50 mL) and water (200 mL) were added, the separated solid was filtered, washed with water (30 mL), methanol (30 mL), hexanes (100 mL), and dried under vacuum, to afford 5,7-difluoro-2-(4-methoxymethoxy-3,5-dimethyl-phenyl)-3H-quinazolin-4-one as a white solid. Yield: 1.40 g (20%).[0169] To a solution of 5,7-difluoro-2-(4-methoxymethoxy-3,5-dimethyl- phenyl)-3H-quinazolin-4-one (1.40 g, 4.04 mmol) in anhydrous DMF (20 mL) was added a solution of sodium methoxide in methanol (25 wt%, 5.0 mL, 24 mmol). The reaction mixture was stirred at room temperature for 16 hours under nitrogen, diluted with water (100 ml_), extracted with ethyl acetate, dried over sodium sulfate, and concentrated on a rotary evaporator to afford 7-fluoro-5-methoxy-2-(4- methoxymethoxy-3,5-dimethyl-phenyl)-3H-quinazolin-4-one as a white solid. Yield: 1.1 g (76%).[017O] To a suspension of sodium hydride (0.176 g, 4.40 mmol) in anhydrous DMF (20 ml_) was added benzyloxyethanol (1.02 g, 6.70 mmol) at room temperature under nitrogen. The reaction mixture was stirred 600C for 30 minutes to get a clear solution. Then, 7-fluoro-5-methoxy-2-(4- methoxymethoxy-3,5-dimethyi-phenyl)-3H-quinazolin-4-one (0.200 g, 0.559 mmol) was added and the reaction mixture was stirred at 1050C for 16 hours under nitrogen. The reaction was diluted with water (100 ml_), extracted with ethyl acetate (100 ml_), and concentrated on a rotary evaporator. The oily residue was subjected to column chromatography (Siθ2, hexanes / ethyl acetate / methanol = 6:2:1) to afford a mixture of two components of very similar polarity. The mixture was dissolved in 50% aqueous acetic acid (60 ml_) and mixed with concentrated HCI (3 ml_). The resulting mixture was stirred at 7O0C for 1 hour and concentrated to dryness on a rotary evaporator. The residue was diluted with saturated sodium bicarbonate aqueous solution (50 mL), extracted with ethyl acetate (150 ml_), and concentrated. The residue was purified by column chromatography (SiO2, hexanes / ethyl acetate / methanol = 7:2:1) to afford the title compound as a light yellow solid. Yield: 45 mg (18%). 1H NMR (400 MHz, CDCI3): δ 9.68 (br s, 1H), 7.69 (s, 2H), 7.40-7.30 (m, 5H), 6.79 (d, 1 H), 6.50 (d, 1 H)1 4.66 (s, 2H), 4.27 (t, 2H), 3.96 (s, 3H), 3.88 (t, 2H), 2.33 (s, 6H). MS (ES+) m/z: 447.59 (M+1). |
92% | Stage #1: 4-hydroxy-3,5-dimethylbenzaldehyde With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 1h; Inert atmosphere; Stage #2: chloromethyl methyl ether In N,N-dimethyl-formamide at 20℃; for 16h; Inert atmosphere; | 5 Preparation of 7-(2-benzyloxy-ethoxy)-2-(4-hydroxy-3,5-dimethyl-phenyl)-5-methoxy-3H-quinazolin-4-one To a suspension of sodium hydride (2.00 g, 50.0 mmol) in anhydrous DMF (30 mL) at 0° C. was added a solution of 4-hydroxy-3,5-dimethyl-benzaldehyde (5.00 g, 33.3 mmol) in anhydrous DMF (20 mL), dropwise over a period of 30 minutes, under nitrogen. Stirring continued at room temperature for 30 minutes and the mixture was cooled to 0° C. Chloromethoxymethane (5.06 mL, 66.6 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours under nitrogen. The reaction mixture was poured into water (200 mL), extracted with ethyl acetate (2*50 mL), dried over anhydrous Na2SO4, and concentrated. The crude compound was purified by column chromatography (SiO2, ethyl acetate/hexanes=1:3) to afford 4-methoxymethoxy-3,5-dimethyl-benzaldehyde as colorless oil. Yield: 5.97 g (92%). |
91% | With N-ethyl-N,N-diisopropylamine at 20℃; for 8h; | |
83% | With dmap; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 3h; | |
With sodium chloride In <i>N</i>-methyl-acetamide; water | 21.a 21(a) 21(a) 3,5-dimethyl-4-methoxymethoxybenzaldehyde A solution of 9.0 g of 3,5-dimethyl-4-hydroxybenzaldehyde in 20 ml of dimethylformamide was added dropwise and whilst ice-cooling to a suspension of 3.14 g of a 55% w/w dispersion of sodium hydride in 50 ml of dimethylformamide. The mixture was then stirred for 20 minutes, after which 5.8 g of methyl chloromethyl ether were added, whilst ice-cooling. The resulting mixture was then stirred at room temperature for one hour. At the end of this time, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was then washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure to give 11.0 g of the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 17h; | |
75% | With potassium carbonate In DMF (N,N-dimethyl-formamide); dichloromethane at 20℃; for 1.5h; | 7h 4-(2'-nitrobenzyloxycarbonyloxy)-3,5-dimethylbenzaldehyde (7h) A solution of 2-nitrobenzylchloroformate (215 mg, 1 mmol) in CH2Cl2 (1 mL) was added to a stirring mixture of 4-hydroxy-3,5-dimethylbenzaldehyde (150 mg, 1 mmol) and potassium carbonate (276 mg, 2 mmol) in DMF (4 mL) at r.t. After stirring for 1.5 hours, the reaction mixture was quenched by pouring into 5% NaHCO3 (80 mL). Aqueous worktap (Et2O, MgSO4) and concentration in vacuo afforded a light yellow solid which was purified by flash chromatography (20 g, CH2Cl2) to yield 7h (247 mg, 75%) as a light yellow solid: 1H NMR (270 MHz, CDCl3) d 2.22 (s, 6H), 5.66 (s, 2H), 7.45-7.50 (in, IH), 7.53 (s, 2H), 7.66 (d, J=3.9 Hz, 2H), 8.08 (d, J=7.9 Hz, 1H); 13BC NMR (68 MHz, CDCl3) d 16.1, 67.3, 125.4, 129.0, 129.5, 130.4, 131.0, 131.6, 134.1, 134.4, 147.4, 151.9, 152.7, 191.4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 3.5h; | |
88% | With potassium carbonate In DMF (N,N-dimethyl-formamide) at 20℃; for 2h; | 7b 4-(2'-Nitrobenzyloxy)-3,5-dimethylbenzaldebyde (7b) DMF (20 mL) at r.t. was added to a stirring mixture of 4-hydroxy-3,5-dimethylbenzaldehyde (0.500 g, 3.3 mmol), potassium carbonate (0.921 g, 6.6 mmol) and 2-nitrobenzylbromide (0.719 g, 3.3 mmol) and stirring was continued for 2 hours. The reaction was diluted with 5% NaHCO3 (100 mL) and aqueous workup (Et2O, MgSO4) followed by concentration in vacuo yielded 7b (1.044 g, 88%) as a light yellow solid: 1H NMR (270 MHz, CDCl3) d 2.29 (s, 6H), 5.24 (s, 2H), 7.49 (t, J=7.4 Hz, 1H), 7.55 (s, 2H), 7.74 (t, J=7.7 Hz, 1H), 8.11 (d, J=6.5 Hz, 1H), 8.14 (d, J=7.5 Hz, 1H), 9.85 (s, 1H); 13C NMR (68 MHz, CDCI3) d 16.5, 70.2, 125.0, 128.3, 128.4, 130.9, 132.2, 132.8, 134.0, 134.3, 146.5, 160.7, 191.6. |
With potassium hydride In DMF (N,N-dimethyl-formamide) at -23℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | Stage #1: 4-hydroxy-3,5-dimethylbenzaldehyde; bromoacetic acid methyl ester With potassium carbonate In ethanol at 95℃; for 16h; Inert atmosphere; Stage #2: With sodium hydroxide In water at 20℃; for 0.5h; Stage #3: With hydrogenchloride In water | 26 Example 26. Preparation of 2-[4-(5,7-Dimethoxy-4-oxo-3,4-dihydro-quinazolin-2-yl)-2,6-dimethyl-phenoxy]-N-(4-methoxy-phenyl)-acetamide [0257] To a solution of 4-hydroxy-3,5-dimethyl-benzaldehyde (9.00 g, 60.0 mmol) in ethanol (300 mL) were added potassium carbonate (24.9 g, 180 mmol) and methyl bromoacetate (11.4 mL, 120 mmol). The reaction mixture was stirred at 95°C under nitrogen for 16 hours. The mixture was concentrated to dryness under reduced pressure. Water (150 mL) and 1 N NaOH solution (90 mL) were added to the residue. The mixture was stirred at room temperature for 30 minutes, then washed with ether. Concentrated HCI was added slowly to the aqueous solution until a large amount of white precipitate formed. The solid was filtered, washed with water, and air-dried, to give (4-formyl-2,6-dimethyl-phenoxy)- acetic acid as a white solid. Yield: 11.1 g (89%).[0258] To a solution of (4-formyl-2,6-dimethyl-phenoxy)-acetic acid (3.12 g, 15.0 mmol) and 2-amino-4,6-dimethoxy-benzamide (2.94 g, 15.0 mmol) in N,N-dimethylacetamide (50 mL) were added sodium hydrogen sulfite (58.5 wt%, 3.02 g, 16.5 mmol) and p-toluenesulfonic acid monohydrate (0.285 g, 1.50 mmol). The reaction mixture was stirred at 1200C for 17 hours under nitrogen and cooled to room temperature. The precipitate was filtered, washed with water, then methanol, and air-dried to give 1.29 g [4-(5,7-dimethoxy-4-oxo-3,4-dihydro-quinazolin-2-yl)-2,6-dimethyl-phenoxy]-acetic acid. The filtrate was concentrated to dryness and water was added. The suspension was stirred for 30 minutes and filtered. The solid was washed with water, then methanol. After air drying, 3.78 g more [4-(5,7-dimethoxy-4-oxo-3, 4-dihydro-quinazolin-2-yl)-2,6-dimethyl-phenoxy]- acetic acid was obtained. Yield: 5.07 g (88%).[0259] To a mixture of [4-(5,7-dimethoxy-4-oxo-3,4-dihydro-quinazolin-2-yl)-2,6-dimethyl-phenoxy]-acetic acid (0.400 g, 1.04 mmol), 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (EDCI; 0.240 g, 1.24 mmol), 1-hydroxybenzotriazole hydrate (HOBt; 0.17 g, 1.24 mmol) in DMF (10 ml_) was added 4-methylmorpholine (0.20 mL, 1.8 mmol). After 10 minutes, p-anisidine (0.26 g, 2.08 mmol) was added. The mixture was stirred at room temperature under nitrogen for 2.5 days. The solvent was removed under reduced pressure. Water was added, stirred for 30 minutes. The solid was filtered, washed with water, and dried in air. The crude product was purified by column chromatography (silica gel, 230-400 mesh; 5% MeOH in CH2CI2 as eluent). The product fractions were combined, concentrated to dryness. The solid was dissolved in small amount of dichloromethane, precipitate out by adding ether. The precipitate was filtered, washed with ether, dried under vacuum to afford the title compound as a white solid. Yield: 0.26 g (51%). 1H NMR (400 MHz, CDCI3): δ 10.30 (br s, 1 H), 8.52 (s, 1 H), 7.83 (s, 2H), 7.58 (dd, J = 6.8 and 2.0 Hz, 2H), 6.93 (dd, J = 6.8 and 2.0 Hz, 2H), 6.84 (d, J = 2.4 Hz, 1 H), 6.48 (d, J = 2.0 Hz, 1 H), 4.44 (s, 2H), 3.97 (s, 3H), 3.94 (s, 3H), 3.83 (s, 3H), 2.42 (s, 3H). MS (ES+) m/z: 490.55 (M+1). |
4-hydroxy-3,5-dimethylbenzaldehyde; bromoacetic acid methyl ester Stage #2: With sodium hydroxide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With copper; triethylamine In dichloromethane at 0 - 20℃; for 72h; | 28.a To a mixture of bis(4-methoxy-3-iso-propylphenyl)iodonium tetrafluoroborate (4.80 g, 9.38 mmol) and copper powder (0.79 g, 12.52 mmol) in CH2Cl2 (15.0 mL) at 0° C. was added a solution of triethylamine (0.96 mL, 6.89 mmol) and 3,5-dimethyl-4-hydroxybenzaldehyde (0.94 g, 6.26 mmol) in dichloromethane (15.0 mL). The reaction mixture was stirred at room temperature for 3 d and filtered through a Celite plug. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with acetone-hexanes (1:19) to afford 3,5-dimethyl-4-(3'-iso-propyl-4'-methoxyphenoxy)benzaldehyde as an oil (2.00 g, 100%): 1H NMR (300 MHz, DMSO-d6): δ 9.96 (s, 1H), 7.75 (s, 2H), 6.85 (m, 1H), 6.73 (m, 1H), 6.36 (m, 1H), 3.74 (s, 3H), 3.19 (m, 1H), 2.15 (s, 6H), 1.12 (d, J=6.0 Hz, 6H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=hexanes-acetone (17:3); Rf=0.51. |
100% | With copper; triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere; | |
100% | With copper; triethylamine In dichloromethane at 0 - 20℃; for 72h; | 28.a To a mixture of bis (4-methoxy-3-iso-propylphenyl) iodonium tetrafluoroborate (4.80 g, 9.38 mmol) and copper powder (0.79 g, 12.52 mmol) inCH2Cl2 (15.0 mL) at 0 C was added a solution of triethylamine (0.96 mL, 6.89 mmol) and 3,5-dimethyl-4-hydroxybenzaldehyde (0.94 g, 6.26 mmol) in dichloromethane (15.0 mL). The reaction mixture was stirred at room temperature for 3 d and filtered through a Celite plug. The solvent was removed under reduced pressure and the residue was purified by column, chromatography on silica gel, eluting with acetone-hexanes (1: 19) to afford 3,5-dimethyl-4- (3'-iso-propyl-4'-methoxyphenoxy) benzaldehyde as an oil (2.00 g, 100%):'H NMR (300 MHz, DMSO-d6) : 8 9.96 (s,1 H), 7.75 (s, 2 H), 6. 85 (m,1 H), 6.73 (m,1 H), 6.36 (m, 1 H), 3.74 (s,3 H), 3.19 (m,1 H), 2.15 (s, 6 H), 1.12 (d,J= 6. 0 Hz, 6 H) ; TLC conditions: Uniplate silica gel, 250 microns; Mobile phase = hexanes-acetone (17: 3);Rf= 0.51. |
93% | With copper bronze; triethylamine In dichloromethane at 0 - 20℃; for 16h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 15 - 20℃; for 1.08333h; | 15 EXAMPLE 15; Compound 16 To a solution of 3, 5-dimethyl-4-hydroxybenzaldehyde (1.0 g, 6.7 mmol) and 4-NITROPHENYLCHLOROFORMATE (1.35 g, 6.7 mmol) in anhydrous DCM (20 mL) cooled to 15 °C was added DIEA (1.16 mL, 6.7 mmol) dropwise over a period of 5 minutes. The cooling bath was removed, and the reaction mixture stirred at room temperature for one hour, followed by washing with 0. 1N HC1 solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent removed from the filtrate in vacuo to give 16 (1.9g, 90 %). 13C NMR (67.8 MHz, CDC13) 8 191. 03,155. 00,152. 14,149. 58,145. 60,134. 53, 131.27, 130.40, 125.41, 121.47, 16.23. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With potassium carbonate In DMF (N,N-dimethyl-formamide) at 90℃; | 4 4-(2-Fluoro-benzyloxy)-3,5-dimethyl-benzaldehyde Example 4 4-(2-Fluoro-benzyloxy)-3,5-dimethyl-benzaldehyde 0.5M Solution of 1-bromomethyl-2-fluoro-benzene (1.51 g, 8.0 mmol) in DMF was added dropwise to a suspension containing 1.1 g of 4-hydroxy-3,5-dimethyl-benzaldehyde (7.3 mmol), 1.51 g of K2CO3 (11 mmol) and 120 mg of KI (0.73 mmol) in 100 ml DMF. The reaction followed the same procedure described in Example 3. The residue was purified on silica gel, obtaining a quantitative recovery of the title compound. (1.88 g) |
With potassium carbonate; potassium iodide In DMF (N,N-dimethyl-formamide) | 4 4-(2-Fluoro-benzyloxy)-3,5-dimethyl-benzaldehyde Example 4 4-(2-Fluoro-benzyloxy)-3,5-dimethyl-benzaldehyde 0.5M Solution of 1-bromomethyl-2-fluoro-benzene (1.51 g, 8.0 mmol) in DMF was added dropwise to a suspension containing 1.1 g of 4-hydroxy-3,5-dimethyl-benzaldehyde (7.3 mmol), 1.51 g of K2CO3 (11 mmol) and 120 mg of KI (0.73 mmol) in 100 ml DMF. The reaction followed the same procedure described in Example 3. The residue was purified on silica gel, obtaining a quantitative recovery of the title compound. (1.88 g) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 90℃; | 6 3,5-Dimethyl-4-(4-trifluoromethyl-benzyloxy)-benzaldehyde Example 6 3,5-Dimethyl-4-(4-trifluoromethyl-benzyloxy)-benzaldehyde 0.5M solution of 1-bromomethyl-4-trifluoromethyl-benzene (1.9 g, 8.0 mmol) in DMF was added dropwise to a suspension of 4-hydroxy-3,5-dimethyl-benzaldehyde (930 mg, 7.3 mmol), K2CO3 (1.51 g, 11 mmol) and KI (120 mg, 0.73 mmol) in DMF (100 ml). The reaction mixture was stirred at 90°C overnight. After cooling, the solid residue was filtered off and the solvent was evaporated under vacuum. The residue was dissolved in ethyl acetate and the organic layer washed twice with NaOH 1M, dried over Na2SO4 and evaporated to dryness. The residue was purified on silica gel, obtaining 2.24 g of the title compound in a quantitative yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A 0.25 M stock solution of 2-cyano-N- (5-ethyl- [1, 3, 4] thiadiazol-2- yl)-acetamide was prepared in 1.0 M diisopropylethylamine in DMF. Benzaldehyde and other heterocyclic aldehydes were individually weighed and were dissolved to 0.25 M using a Tecan Genesis workstation. The Tecan was used to dispense 200 muL of template 1 to each reaction vessel then was used to dispense 400 L of aldehyde stock solutions to individual reaction vessels. The reaction vessels were sealed and were heated at 45-50 C, with agitation, for 18 hours. The reaction vessels were then cooled, unsealed, and 50 L of aminopropyl-functionalized silica gel (Aldrich) was dispensed to each reaction vessel. Activated 4 angstrom molecular sieves (powdered, 50 L) were then dispensed to each reaction. Reaction vessels were then sealed and were heated at 45-50 C with agitation for 3 h. Reactions were then unsealed and were filtered to remove solids. B. Sample solutions were dried in vacuo using a Genevac. Samples were dissolved in 500 pL of DMSO and 500 pL of methanol and purity was determined by LC-MS with using a combination of UV254, UV220, and ELSD detection [purity = (UV254+UV220/2)]. The HPLC conditions were: 4.6 mm x 50 mm C18 column, 10-90% acetonitrile gradient over 5 minutes (mobile phases were H20 with 0.05 % TFA and acetonitrile with 0.035 % TFA), with a flow rate of 3.5 ml/min. Samples which were <80% pure were purified using a mass directed LC-MS purification. Purified samples were concentrated in vacuo then were dissolved in DMSO and were reformatted into 96 well microtiter plates. Samples were tested for purity using LC-MS and quantity was estimated by correlating ELSD response to a standard concentration-ELSD response curve. Samples were then concentrated to dryness and were dissolved in DMSO to a final concentration of 10 uM based on ELSD quantitation. C. The following compounds were prepared in the manner described above in Steps A and B using the appropriate aldehyde in place of benzaldehyde: 2-Cyano-3- (3, 4-dimethoxy-phenyl)-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)- acrylamide ; MS (ES): 345 (MH+) ; 3- (4-Benzyloxy-phenyl)-2-cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)- acrylamide ; MS (ES) : 391 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3- (4-hydroxy-phenyl)- acrylamide ; MS (ES): 301 (MH+) ; Acetic acid 4- [2-cyano-2- (5-ethyl- [1, 3,4] thiadiazol-2-ylcarbamoyl)-vinyl]- phenyl ester; MS (ES): 343 (MH+); 2-Cyano-3- (2, 4-dichloro-phenyl)-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)- acrylamide ; MS (ES): 353 (MH+) ; 3- (2-Bromo-phenyl)-2-cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)- acrylamide ; MS (ES): 363 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3- (2-fluoro-phenyl)- acrylamide ; MS (ES): 303 (MH+) ; 3- (4-tert-Butyl-phenyl)-2-cyano-N- (5-ethyl- [1, 3, 4] thiadiazol-2-yl)- acrylamide ; MS (ES): 341 (MH+) ; 3- (2-Chloro-4-fluoro-phenyl)-2-cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)- acrylamide ; MS (ES): 337 (MH+) ; 2-Cyano-3- (2, 5-dimethyl-phenyl)-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)- acrylamide ; MS (ES): 313 (MH+) ; 2-Cyano-5- (4-methoxy-phenyl)-penta-2, 4-dienoic acid (5-ethyl- [1,3, 4] thiadiazol-2-yl)-amide ; MS (ES): 341 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3-(4-hydroxy-3, 5-dimethoxy- phenyl)-acrylamide ; MS (ES): 361 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3- (4-hydroxy-3-iodo-5- methoxy-phenyl)-acrylamide ; MS (ES): 457 (MH+) ; 2-Cyano-3- (3, 4-dihydroxy-phenyl)-N- (5-ethyl- [1, 3, 4] thiadiazol-2-yl)- acrylamide ; MS (ES): 317 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3- (4-hydroxy-3-methoxy-5- nitro-phenyl)-acrylamide ; MS (ES): 376 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yi)-3- (4-hydroxy-3-methoxy-5- nitro-phenyl)-acrylamide ; MS (ES): 376 (MH+) ; 3-(4-Benzyloxy-3,5-dimethyl-phenyl)-2-cyano-N-(5-ethyl- [1,3, 4] thiadiazol-2-yl)-acrylamide ; MS (ES): 419 (MH+) ; 2-Cyano-3- (3, 5-dibromo-2-methoxy-phenyl)-N- (5-ethyl- [1, 3,4] thiadiazol- 2-yl)-acrylamide ; MS (ES) : 471 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3, 4] thiadiazol-2-yl)-3- (4-hexyloxy-phenyl)- acrylamide ; MS (ES): 385 (MH+) ; Acetic acid 4- [2-cyano-2- (5-ethyl- [1, 3,4] thiadiazol-2-ylcarbamoyl)-vinyl]- 2, 6-dimethoxy-phenyl ester; MS (ES): 403 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yi)-3- (4-imidazol-1-yi-phenyl)- acrylamide ; MS (ES): 351 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3-(2-trifluoromethyl-phenyl)- acrylamide ; MS (ES): 353 (MH+) ; 3- (2-Chloro-3, 4-dimethoxy-phenyl)-2-cyano-N- (5-ethyl- [1, 3,4] thiadiazol- 2-yl)-acrylamide ; MS (ES): 379 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3, 4] thiadiazol-2-yl)-3- ( 1-methyl-1 H-indol-3-yl)- acrylamide ; MS (ES): 338 (MH+) ; 2-Cyano-3- (2, 6-dichloro-phenyl)-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)- acrylamide ; MS (ES): 353 (MH+) ; 2-Cyano-3-(4-dimethylamino-2-nitro-phenyl)-N-(5-ethyl-[1, 3,4] thiadiazol- 2-yl)-acrylamide ; MS (ES): 373 (MH+) ; 2-Cyano-N-(5-ethyl-[1, 3,4] thiadiazol-2-yl)-3- (2-iodo-phe... |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With hydrogenchloride In ethanol at 20℃; for 1 - 6h; | 1.1; 2.1 EXAMPLES; 1-Description of the General Synthetic Methods; General Method 1:; Synthesis of hydroxy-1,3-diphenylprop-2-en-1-ones; One molar-equivalent of hydroxy-acetophenone (or the sulfated analog of same) and 1 molar-equivalent of aldehyde, or 1 molar-equivalent of hydroxy-benzaldehyde (or the sulfated analog of same) and 1 molar-equivalent of ketone are dissolved in an ethanol solution saturated with gaseous hydrochloric acid. The mixture is stirred at room temperature for 1 to 6 hours and the solvent is eliminated by vacuum evaporation. The hydroxy-1,3-diphenylprop-2-en-1-one is purified by silica gel chromatography or by recrystallization.; Synthesis of the Chemical Precursor:; 1-[4-chlorophenyl]-3-[3,5-dimethyl-4-hydroxyphenyl]prop-2-en-1-one (Compound 1); This compound was synthesized from 4-chloroacetophenone and 3,5-dimethyl-4-hydroxybenzaldehyde according to general method 1 described hereinabove. Purification was by silica gel chromatography (cyclohexane/ethyl acetate 95:5). Yield: 91% 1H NMR CDCl3 δ ppm: 2.30 (s, 6H), 7.32 (s, 2H), 7.34 (d, J=15.25 Hz, 1H), 7.47 (d, J=8.86 Hz, 2H), 7.75 (d, J=15.26 Hz, 1H), 7.97 (d, J=8.86 Hz, 2H). |
67% | With hydrogenchloride In methanol at 20℃; for 24h; Inert atmosphere; | 4.1.4 General produce C for the preparation of 17, 19-32, 35-40 General procedure: To a solution of 4 M HCl in methanol were added 1a or 1d-l (1.0 equiv.) and 2b or 2e-o (1.0 equiv.). The solution was stirred at room temperature for 24 h. The forming precipitate was filtered and dried to obtain target compounds. |
With hydrogenchloride In ethanol at 20℃; for 6h; | 1-[4-chlorophenyl]-3-[3,5-dimethyl-4-hydroxyphenyl]prop-2-en-1-one 1-[4-chlorophenyl]-3-[3,5-dimethyl-4-hydroxyphenyl]prop-2-en-1-one This compound was synthesised from 4-chloroacetophenone and 3,5-dimethyl-4-hydroxybenzaldehyde according to general method 1 described earlier. Purification was by chromatography on silica gel (elution:cyclohexane/ethyl acetate 95:5). 1H NMR CDCl3 δ ppm: 2.30 (s, 6H), 7.32 (s, 2H), 7.34 (d, J=15.25 Hz, 1H), 7.47 (d, J=8.86 Hz, 2H), 7.75 (d, J=15.26 Hz, 1H), 7.97 (d, J=8.86 Hz, 2H). |
With hydrogenchloride In ethanol at 20℃; for 6h; | 1 1-[4-chlorophenyl]-3-[3.5-dimethyl-4-hydroxyphenyl]prop-2-en-1-one General Method 1: Synthesis of 1,3-diphenylprop-2-en-1-ones in Acidic Medium: The ketone (1 eq) and the aldehyde (1 eq) were dissolved in ethanol solution saturated with gaseous hydrochloric acid. The reaction was stirred at room temperature for 6 hours and the solvent was then eliminated by vacuum evaporation. 1,3-diphenylprop-2-en-1-one was purified by chromatography on silica gel; This compound was synthesized from 4-chloroacetophenone and 3,5-dimethyl-4-hydroxybenzaldehyde according to general method 1 described earlier. Purification was by chromatography on silica gel (elution: cyclohexane/ethyl acetate 95:5). 1H NMR CDCl3 δ ppm: 2.30 (s, 6H), 7.32 (s, 2H), 7.34 (d, J=15.25 Hz, 1H), 7.47 (d, J=8.86 Hz, 2H), 7.75 (d, J=15.26 Hz, 1 H), 7.97 (d, J=8.86 Hz, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With pyridine In dichloromethane at 0 - 20℃; for 2h; | |
55% | With triethylamine In dichloromethane at -78 - 20℃; for 14h; Inert atmosphere; | |
53% | Stage #1: 4-hydroxy-3,5-dimethylbenzaldehyde With triethylamine In dichloromethane at -78℃; for 0.5h; Inert atmosphere; Stage #2: trifluoromethylsulfonic anhydride In dichloromethane at -78℃; for 2h; Inert atmosphere; | General Procedure for Trifluoromethanesulfonate Synthesis General procedure: Triethylamine (4.04 g, 40 mmol) was added to a solution ofphenol (13 mmol) in anhydrous CH2Cl2 (13 mL) at -78 °Cunder argon, and the solution stirred for 30 min.Trifluoromethanesulfonic anhydride (2.5 mL, 15 mmol, 1.1equiv) was added dropwise via a syringe pump (7.7 mL/h).The reaction was left to stir for a further 2 h. The reactionmixture was diluted with CH2Cl2 (15 mL) and washed withsat. NaHCO3 (20 mL), brine (20 mL), and H2O (20 mL),dried (MgSO4), filtered, and concentrated to give thetrifluoromethanesulfonate which was purified by columnchromatography. |
52% | With pyridine at 0 - 20℃; for 20.1667h; | 50.A Preparation 50; 1-(2,6-Dimethyl-4'-trifluoromethyl-biphenyl-4-yl)-3-methyl-butan-1-ol; Step A. Trifluoro-methanesulfonic acid 4-formyl-2,6-dimethyl-phenyl ester; To a solution of 4-Hydroxy-3,5-dimethyl-benzaldehyde (4.5 g, 30 mmol) in pyridine (20 mL) at 0 °C was slowly added triflic anhydride (10 g, 36 mmol). The resulting mixture was stirred at 0 °C for 10min and then allowed to warm to room temperature and stirred for 20h. The resulting mixture was poured into water and extracted with ether, washed with water, IN HCI, brine, dried over MgS04, concentrated and purified with column chromatography to afford 4.4 g (52%) of the titled compound as colorless oil |
52% | With pyridine In dichloromethane at 20℃; for 2.33333h; Cooling with ice; | |
52% | In pyridine at 0 - 20℃; for 20h; | 1.A Trifluoro-methanesulfonic acid 4-formyl-2,6-dimethyl-phenyl ester To a solution of 4-hydroxy-3,5-dimethyl-benzaldehyde (4.5 g, 30 mmol) in pyridine (20 ml) at 0 0C is slowly added triflic anhydride (10 g, 36 mmol). The resulting mixture is stirred at 0 0C for 10 min and then allowed to warm to room temperature and stirred for 20 h. The resulting mixture is poured into water and extracted with ether. The organic portion is washed with water, IN HCl, brine, dried over MgSO4, and concentrated. The resulting residue is purified by silica gel column chromatography, eluting withEtOAc/hexanes to afford 4.4 g (52%) of the titled compound as a colorless oil. 1H-NMR |
With pyridine In dichloromethane at 0 - 20℃; for 2h; | A.a Building Block A; a); To a solution of 4-hydroxy-3,5-dιmethyl-benzaldehyde (5.0 g, 33.3 mmol) in DCM (50 ml_) and pyridine (8 ml_), tϖfluoromethanesulfonic anhydride (6 ml_, 36.6 mmol) is slowly added at 00C. Upon complete addition, stirring is continued for 2 h at rt. The reaction mixture is diluted with EA and washed three times with water. The separated organic layer is dried over MgSO4, filtered and evaporated The crude product is purified by CC on silica gel eluting with heptane:EA 4 1 to give trifluoro- methanesulfonic acid 4-formyl-2,6-dimethyl-phenyl ester (5.3 g) as a slightly yellow solid; LC-MS: tR = 1 04 mm; 1 H NMR (CDCI3): δ 9.97 (s, 1 H), 7.66 (s, 2H), 2.48 (s, 6H). | |
With pyridine In dichloromethane at 0 - 20℃; for 2h; | a To a solution of 4-hydroxy-3,5-dimethyl-benzaldehyde (5.0 g, 33.3 mmol) in DCM (50 mL) and pyridine (8 mL), trifluoromethanesulfonic anhydride (6 mL, 36.6 mmol) is slowly added at 0° C. Upon complete addition, stirring is continued for 2 h at rt. The reaction mixture is diluted with EA and washed three times with water. The separated organic layer is dried over MgSO4, filtered and evaporated. The crude product is purified by CC on silica gel eluting with heptane:EA 4:1 to give trifluoro-methanesulfonic acid 4-formyl-2,6-dimethyl-phenyl ester (5.3 g) as a slightly yellow solid; LC-MS: tR=1.04 min; 1H NMR (CDCl3): δ 9.97 (s, 1H), 7.66 (s, 2H), 2.48 (s, 6H). | |
With pyridine In dichloromethane at 0 - 20℃; for 2.33h; | 235.a To an ice-cooled solution of 4-hydroxy-3,5-dimethylbenzaldehyde (6.0 g, 40 mmol) in DCM (60 mL) and pyridine (10 mL), trifluoromethanesulfonic acid anhydride (12.4 g, 44 mmol) is added over a period of 20 min. Upon complete addition, the ice bath is removed and the reaction is stirred for further 2 h at rt. The mixture is diluted with EA (200 mL), washed three times with water, dried over MgSO4, filtered and evaporated. The residue is purified by flash chromatography on silica gel eluting with heptane:EA 4:1 to give trifluoro-methanesulfonic acid 4-formyl-2,6-dimethyl-phenyl ester (5.9 g) as a colourless oil; LC-MS: tR=1.04 min. | |
With pyridine In dichloromethane at 0 - 20℃; for 2h; | 3.a To a solution of 4-hydroxy-3,5-dimethyl-benzaldehyde (5.0 g, 33.3 mmol) in DCM (50 ml_) and pyridine (8 ml_), trifluoromethanesulfonic anhydride (6 ml_, 36.6 mmol) is slowly added at 0°C. Upon complete addition, stirring is continued for 2 h at rt.The reaction mixture is diluted with EA and washed three times with water. The separated organic layer is dried over MgSO4, filtered and evaporated. The crude product is purified by CC on silica gel eluting with heptane:EA 4:1 to give trifluoro- methanesulfonic acid 4-formyl-2,6-dimethyl-phenyl ester (5.3 g) as a slightly yellow solid; LC-MS: tR = 1.04 min; 1H NMR (CDCI3): δ 9.97 (s, 1 H), 7.66 (s, 2H), 2.48 (s,6H). | |
2.17 g | In pyridine; toluene at 0 - 35℃; for 0.5h; | 18.A A) 4-formyl-2,6-dimethylphenyl trifluoromethanesulfonate To a solution of 4-hydroxy-3,5-dimethylbenzaldehyde (2 g) in pyridine (30 mL) was added a solution (5 mL) of trifluoromethanesulfonic acid anhydride (2.92 mL) in toluene at 0°C. The reaction mixture was stirred at room temperature for 30 min, concentrated, and then azeotropically distilled with toluene. To the residue was added 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.17 g). 1H NMR (300 MHz, DMSO-d6) δ 2.43 (6H, s), 7.85 (2H, s), 9.98 (1H, s). |
With pyridine In dichloromethane for 1h; | ||
With pyridine In dichloromethane at 5 - 20℃; for 2h; | 11.a a) To a cold solution (5°C) of 3,5-diemthyl-4-hydroxybenzaldehyde (2.5 g, 16.6 mmol) in DCM (25 ml_) and pyridine (3.8 ml_), trifluoromethanesulfonic acid anhydride (3 ml_) is slolwly added. Upon complete addition, the mixture is warmed to rt and stirred for 2 h. The mixture is diluted with EA (150 ml_) and washed with water (2x100 ml_) The solvent of the organic phase is evaporated and the crude product is purified by CC on silica gel eluting with heptane:EA 3:1 to give trifluoromethanesulfonic acid 4-formyl-2,6-dimethyl-phenyl ester (3.13 g) as a colourless liquid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With potassium carbonate In acetonitrile at 20℃; for 16h; Heating / reflux; | 3.3.1 Example 3-3; Ethyl 2-((2,6-dimethyl-4-hydroxycarbonylmethyl)phenoxy)-2-methylpropanoate; This acid was synthesized in 9 steps: Step 1; 3,5-dimethyl-4-benzyloxybenzaldehyde; 3,5-dimethyl-4-hydroxybenzaldehyde (50.0 g; 0.333 mol) was solubilized in acetonitrile (600 ml) and potassium carbonate (92.0 g; 0.666 mol) was added. Benzyl bromide (39.6 ml; 0.333 mol) was slowly poured into the mixture under vigourous stirring at room temperature. The crude was refluxed for 16 h. Salts were filtered, washed with acetonitrile, and the filtrate was evaporated. The residue was taken in ethyl acetate, washed with 1M NaOH and NaClsat. The resulting organic layer was dried with magnesium sulfate (MgSO4) and evaporated. The resulting oil was used without further purification. Yield: 99% |
99% | With potassium carbonate In acetone at 50℃; for 2.5h; | |
95% | Stage #1: 4-hydroxy-3,5-dimethylbenzaldehyde With sodium hydride In N,N-dimethyl-formamide at 20℃; for 1h; Stage #2: benzyl bromide In N,N-dimethyl-formamide at 20℃; for 16h; Stage #3: With acetic acid In water; N,N-dimethyl-formamide | 1 Example 1. Preparation of 5-(2-dimethylamino-ethoxy)-2(4-hydroxy-3,5-dimethylphenyl)-7-methoxy-3H-quinazolin-4-one[0153] To a solution of 3,5-dimethyl-4-hydroxybenzaldehyde (10.0 g, 66.6 mmol) in anhydrous DMF (20 ml_) was added NaH (4.00 g, 99.9 mmol) in portions and the mixture was stirred for 1 hour at room temperature. Benzyl bromide (9.5 ml_, 80 mmol) was added dropwise and stirred for 16 hours at room temperature. Water was added, the mixture was acidified with acetic acid to pH approximately 4-5, and the product was isolated by extraction with ethyl acetate. The solvent was evaporated in vacuo and the residue was purified by column chromatography (silica gel 230-400 mesh; 2-5% ethyl acetate/hexane as eluent) to give 4-benzyloxy-3,5-dimethyl-benzaldehyde as white solid. Yield: 15.2 g (95%). [0154] A mixture of 2-amino-4,6-difluorobenzamide (2.13 g, 12.4 mmol), 4- benzyloxy-3,5-dimethylbenzaldehyde (2.98 g, 12.4 mmol), NaHSO3 (2.50 g, 13.6 mmol) and p-toluene sulfonic acid (0.236 g, 1.24 mmol) in /V,/V-dimethylacetamide (20 ml_) was stirred at 110-120 0C for 16 hours. The solvent was evaporated in vacuo, water was added and the precipitated solid was filtered off, washed with water and ether to give 2-(4-benzyloxy-3,5- dimethylphenyl)-5,7-difluoro-3H-quinazolin-4-one as a light yellow solid. Yield: 1.99 g (41%). [0155] To a solution of 2-dimethylaminoethanol (180 mg, 2.03 mmol) in DMF (2 ml_) was added NaH (61 mg, 1.5 mmol) at 00C. The reaction mixture was stirred at room temperature for 30 minutes. Then, 2-(4-benzyloxy-3,5- dimethylphenyl)-5,7-difluoro-3H-quinazolin-4-one (200 mg, 0.510 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over Na2SO4, and concentrated in vacuo to give product 2-(4-bezyloxy-3,5-dimethyl phenyl)-5-(2-dimethylamino-ethoxy)-7-fluoro-3H-quinazolin-4-one. Yield: 220 mg (93%).[0156] To a solution of 2-(4-bezyloxy-3,5-dimethylphenyl)-5-(2- dimethylaminoethoxy)-7-fluoro-3H-quinazolin-4-one (220 mg, 0.470 mmol) in DMF (3 ml_) was added 25% (w/w) sodium methoxide in methanol (205 mg, 3.81 mmol). The reaction mixture was heated at 95°C for 4 hours. The reaction mixture was cooled to the room temperature, diluted with water, and extracted with ethyl acetate. The combined organic layer was washed with water, brine, dried over anhydrous Na2SO4, and concentrated in vacuo to give crude product, which was purified by column chromatography (silica gel 230-400 mesh; 5% NH3 in methanol/ CH2CI2 as eluent) to give pure product 2-(4-bezyloxy-3,5-dimethylphenyl)-5-(2-dimethylamino-ethoxy)-7-methoxy-3H-quinazolin-4-one. Yield: 110 mg (49%).[0157] To a solution of 2-(4-bezyloxy-3,5-dimethylphenyl)-5-(2-dimethylaminoethoxy)-7-methoxy-3H-quinazolin-4-one (110 mg, 0.23 mmol) in methanol (5 ml_) and THF (5 mL) was added Pd/C (50 mg, 10% on charcoal). The reaction mixture was hydrogenated for 2 hours at 50 psi at room temperature. The mixture was filtered through celite and solvent was evaporated in vacuo to give crude product, which was purified by column chromatography (silica gel 230-400 mesh; 5% NH3 in methanol/CH2CI2 as eluent) to give the title compound as a light brown solid. Yield: 70 mg (78%). 1H NMR (400 MHz, CDCI3): δ 7.58 (s, 2H), 6.80 (s, 1 H), 6.40 (S1 1 H), 4.20 (t, 2H), 3.90 (s, 3H), 2.90 (t, 2H), 2.40 (s, 3H), 2.25 (s, 3H). MS (ES+) m/z: 384.09 (M+1). |
95% | Stage #1: 4-hydroxy-3,5-dimethylbenzaldehyde With sodium hydride In N,N-dimethyl-formamide at 20℃; for 1h; Stage #2: benzyl bromide In N,N-dimethyl-formamide at 20℃; for 16h; | 1 To a solution of 3,5-dimethyl-4-hydroxybenzaldehyde (10.0 g, 66.6 mmol) in anhydrous DMF (20 mL) was added NaH (4.00 g, 99.9 mmol) in portions and the mixture was stirred for 1 hour at room temperature. Benzyl bromide (9.5 mL, 80 mmol) was added dropwise and stirred for 16 hours at room temperature. Water was added, the mixture was acidified with acetic acid to pH approximately 4-5, and the product was isolated by extraction with ethyl acetate. The solvent was evaporated in vacuo and the residue was purified by column chromatography (silica gel 230-400 mesh; 2-5% ethyl acetate/hexane as eluent) to give 4-benzyloxy-3,5-dimethyl-benzaldehyde as white solid. Yield: 15.2 g (95%) |
95% | Stage #1: 4-hydroxy-3,5-dimethylbenzaldehyde With potassium carbonate In N,N-dimethyl-formamide at 0℃; Stage #2: benzyl bromide In N,N-dimethyl-formamide at 0 - 20℃; for 0.4h; | 3.2.2. Synthesis of 3,5-Dimethyl-4-benzyloxybenzaldehyde 2b K2CO3 (12.0 mmol, 2.0 eq) was added to a solution of 3,5-dimethyl-4-hydroxybenzaldehyde 2(6.0 mmol, 1.0 eq) in DMF (dimethyl formamide) (40 mL), which was stirred at 0 °C. Then, BrBn(6.6 mmol, 1.1 eq) was added dropwise and the mixture was allowed to increase in temperature toroom temperature. The end of reaction was monitored by TLC about 4.5 h, then water was added(50 mL). The solution was then extracted with EA (ethyl acetate) (20 mL x 3).The combined organicphase was washed with water (20 mL x 3) and brine (20 mL x 3), and dried over anhydrous Na2SO4after filtration. The solvent was removed under reduced pressure to get the crude product, which waspurified through flash column chromatography to aord compound 2b (white solid; yield 95%). Otherdata can be found in Reference [13]. |
95% | With potassium carbonate In N,N-dimethyl-formamide at 0 - 20℃; | 1.2 (2) Synthesis of compound 2b: Dissolve 3,5-dimethyl p-hydroxybenzaldehyde (6 mmol, 1.0 eq), K2CO3 (12 mmol, 2.0 eq) in anhydrous DMF (40 mL), and lower the temperature to 0 ° C. BrBn (6.6 mmol, 1.1 eq) was then added dropwise. After the dropwise addition was completed, the temperature was slowly raised to room temperature.The reaction was monitored by TLC. After the reaction was completed, 50 mL of water was added, EA 20 mL × 3 extraction, the organic layers were combined, washed three times with 50 mL of water, washed three times with 20 mL of saturated brine, dried over anhydrous Na2SO4, and filtered. The EA was removed under reduced pressure to obtain compound 2b, yield 95% . |
90% | With caesium carbonate In acetone at 20℃; Inert atmosphere; | |
88% | With potassium carbonate; sodium iodide In acetone at 50℃; | |
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 16h; | Typical procedure for synthesis of compound 4a. General procedure: To a mixture of 3-hydroxy-4-methoxybenzaldehyde (3.0 g, 19.7 mmol) and potassium carbonate (10.9 g, 78.8 mmol) in DMF (30 mL) was added benzyl bromide (4.7 mL, 39.4 mmol) and the reaction mixture was stirred at room temperature for 16 h. The reaction solution was filtered to remove inorganic salts, and the filtrate was diluted with water (200 mL), extracted three times with ethyl acetate and washed with brine. The combined organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrated residue was purified by silica-gel column chromatography (hexane/ethyl acetate = 5:1) to give 4.7 g of benzylated compound. To a mixture of magnesium turnings (0.75 g, 0.031 mol) in THF (5 mL) at room temperature was slowly added a solution of 4-methoxybenzylchloride (1.6 g, 10.2 mmol) in THF (10 mL). The reaction solution was refluxed with heating for one hour and then cooled down in a 0 °C water bath. The ashy solution was extracted by using a syringe, which was used as a Grignard reagent. To a solution of the benzylated aldehyde (0.82 g, 3.4 mmol) in THF (15 mL) at 0 °C was added the Grignard reagent slowly, and the reaction mixture was stirred at room temperature for 1 h. Saturated ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate threetimes and washed with brine. Combined organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrated residue was purified by silica-gel column chromatography (hexane/ethyl acetate = 5:1), to give 1.2 g of alcoholic compound. To a mixture of the alcoholic compound (1.2 g, 3.3 mmol), 4-methylmorpholine N-oxide (0.57 g, 4.9 mmol) and anhydrous powdered 4 Å molecular sieves (1.64 g) in dichloromethane (10 mL) was added tetrapropylammonium perruthenate (57 mg). The reaction mixture wasstirred for 30 min, passed through a short silica-gel pad by washing with ethyl acetate, and concentrated to give 1.1 g (88% in three-steps) of compound 2. To a solution of compound 2 (1.26 g, 3.5 mmol) in toluene (10 mL) was added dimethylformamide dimethylacetal (DMFDMA) (1.2 g, 10 mmol). The reaction mixture was refluxed for 16 h at 135 °C. The reaction solution was cooled to 0 °C, concentrated and purified by silica-gel column chromatography(hexane/ethyl acetate = 1:2) to give 1.35 g (93%) of compound 3. To a solution of compound 3 (1.12 g, 2.7 mmol) in methanol (35 mL) was added sodium carbonate (190 mg, 1.7 mmol) and NH2OH HCl (1.9 g, 27.0 mmol). The mixturewas adjusted to be pH 4-5 using acetic acid (1.0 mL) and then heated in a heavy-wall screw capped tube at 115 °C for 2 h. The reaction mixture was cooled to room temperature and methanol was removed under reducedpressure. The residue was extracted with methylene chloride and water, and the organic layer washed with brine, dried over Na2SO4, concentrated and purified by silica-gel column chromatography (hexane/ethyl acetate = 5:1) to give 1.0 g (97%) of isoxazole compound 4a |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With diethylazodicarboxylate; In tetrahydrofuran; hexane; | To a stirring, 0 C. solution of 3,5-dimethyl-4-hydroxybenzaldehyde (1.5018 g, 10 mmol), <strong>[146667-84-7]N-Boc-3-piperidineethanol</strong> (2.153 g, 10 mmol), and triphenylphosphene (2.964 g, 11.3 mmol) in 40 mL THF, was added dropwise over 10 min 1.78 mL (11.3 mmol) DEAD the mixture was mixed slowly and allowed to warm to ambient temperature and stirred for 12 hours. The mixture was concentrated in vacuo, and Hexane/DCM was added to precipitate out triphenylphosphene oxide, which was filtered off. The filtrate was concentrated in vacuo, and the residue was flash chromatographed on silica gel, the appropriate fractions combined to give the desired boc-amino ether. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.3 g (16%) | With triethylamine In acetic anhydride | R.1 2-(4-Acetoxy-3,5-dimethylbenzylidene)-3,4-dihydro-3-oxo-2H-1,4-benzothiazine (Reference compound No. 1-1) REFERENCE EXAMPLE 1 2-(4-Acetoxy-3,5-dimethylbenzylidene)-3,4-dihydro-3-oxo-2H-1,4-benzothiazine (Reference compound No. 1-1) Triethylamine (33.74 ml) was added to a suspension of 3,4-dihydro-3-oxo-2H-1,4-benzothiazine (4.0 g) and 3,5-dimethyl-4-hydroxybenzaldehyde (3.64 g) in acetic anhydride (114.2 ml). After the addition, the mixture was refluxed for 19 hours under nitrogen atmosphere. The reaction mixture was poured into 1N hydrochloric acid and the whole was extracted with ethyl acetate. The organic layer was washed with 1N sodium hydroxide and saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The oily residue was purified by silica gel column chromatography to give 1.3 g (16%) of the titled compound as crystals. mp 231°-234° C. IR (KBr, cm-1) 3177, 3036, 2978, 1751, 1665, 1592, 1571, 1488, 1437, 1427, 1370, 1229, 1206, 1142, 1045 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With Cs2CO3 In acetonitrile at 80℃; | |
42.9% | With potassium carbonate In acetonitrile at 25 - 80℃; for 16h; Large scale; | 1.1 Step 1: Preparation of Compound B At 25° C., acetonitrile (30 L) was added into a 50 L reactor, start stirring, and then Compound A (2.00 kg, 13.32 mol, 1.0 eq), ethyl bromoisobutyrate (7.79 kg, 39.95 mol, 3.0 eq) and potassium carbonate (5.52 kg, 39.95 mol, 3.0 eq) were added. The reaction solution was stirred at 80° C. for 16 h. The reaction temperature was cooled to 25° C., and then filtered. The filtrate was concentrated under reduced pressure. The resultant residue was dissolved in ethyl acetate (5 L). The filter cake was washed with ethyl acetate (5 L×2), and the ethyl acetate solutions were combined. The combined organic phases were washed with aq. NaOH (1 mol/L, 5 L/time) until showed that no spot of raw material A appeared in the organic phase by TLC (petroleum ether: ethyl acetate=5:1). The organic phase was washed with aqueous saturated solution of sodium chloride (5 L×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, to give 1.51 kg of compound B, yield: 42.9%.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.85 (s, 1H), 7.50 (s, 2H), 4.31-4.23 (m, 2H), 2.25 (s, 6H), 1.45 (s, 6H), 1.33 (t, J=7.2 Hz, 1H). |
37% | Stage #1: 4-hydroxy-3,5-dimethylbenzaldehyde With potassium carbonate In acetone for 0.5h; Heating / reflux; Stage #2: ethyl 2-bromoisobutyrate for 65h; Heating / reflux; | 66 ethyl 2-(4-formyl-2,6-dimethylphenoxy)-2-methylpropanoate A solution of 8.16g (0.053 mol) of 4-hydroxy-3, 5-dimethylbenzaldehyde and 14.72g (0.106mol) of K2CO3 in80 mL of acetone was refluxed for 30 min. Then, 12 mL (0.08 mol) of ethyl 2-bromo-2-methylpropanoate was added to the reaction mixture, which was stirred at reflux for 65h. 3 eq of K2CO3 and 3.5 eq of bromo derivative were added progressively during reflux. The resulting mixture was filtered off, washed with acetone and evaporated to dryness. The residue was diluted in CH2CI2, washed with NaOH (1N) ; an emulsion appeared that was filtered through celite, washed with water, filtered again through celite, dried onMgS04 and evaporated to dryness to a dark oil, which was purified by flash chromatography(CH2CI2 100%) to give a dark oil (5.3g). Yield : 37% 1H NMR (DMSO= 2.51) 8 : 9.87 (s, CHO); 7.60 (s, 2H); 4.20 (quad, 2H); 2.21 (s, 6H); 1.42 (s, 6H); 1.26 (t, 3H) |
25.7% | With potassium carbonate; potassium iodide In dimethyl sulfoxide at 25 - 110℃; for 16h; | |
With Cs2CO3 In N,N-dimethyl-formamide at 80℃; for 12h; | 12 Ethyl 2-(4-formyl-2,6-dimethylphenoxy)-2-methylpropanoate 3,5-Dimethyl-4-hydroxybenzaldehyde (5.0 g) was dissolved in N,N-dimethylformamide (20 ml), and cesium carbonate (10 g) and ethyl 2-bromo-2-methylpropanoate (10 ml) were added thereto and the resulting solution was stirred at 80°C for 12 hours. The temperature was allowed to elevate to room temperature, and ethyl acetate (200 ml) and water (40 ml) were added to the solution. The organic layer separated was collected, washed with saturated brine, and dried over anhydrous sodium sulfate. This was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane = 1/3) to obtain the entitled compound (6.2 g) as a pale yellow oily substance. 1H-NMR (400 MHz, CDCl3) δ: 1.35 (3H, t, J=7.2 Hz), 1.50 (6H, s), 2.31 (6H, s), 4.30 (2H, q, J=7.2 Hz), 7.52 (2H, s), 9.85 (1H, s). | |
With Cs2CO3 In N,N-dimethyl-formamide at 80℃; for 12h; | ||
With Cs2CO3 In N,N-dimethyl-formamide at 80℃; | ||
With potassium carbonate; potassium iodide In dimethyl sulfoxide at 130℃; for 4h; | 25.3; 26.3; 79.1 Step 3: Compound 25-c Potassium carbonate (110.44 g, 799.05 mmol, 3.00 eq), ethyl 2-bromo-isobutyrate (207.81 g, 1.07 mol, 156.25 mL, 4.00 eq) and potassium iodide (44.21 g, 266.35 mmol, 1.00 eq) was added into a solution of Compound 1-b (40.00 g, 266.35 mmol, 1.00 eq) in dimethylsulfoxide (400.00 mL) at 20°C. The mixture was stirred at 130°C. for 4 h. Water (1 L) was added into the mixture, and extracted with ethyl acetate (200 mL6). The combined organic phase was washed with water (1 L) and saturated brine (1 L), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether:ethyl acetate=100:0-100:50) to give Compound 25-c . 1H NMR (400 MHz, CDCl3) δ ppm 9.85 (s, 1H), 7.50 (s, 2H), 4.31-4.23 (m, 2H), 2.25 (s, 6H), 1.45 (s, 6H), 1.33 (t, J=7.2 Hz, 1H). | |
With Cs2CO3 at 95℃; for 48h; | 3 Example- 3: Preparation of Ethyl 2-(4-formyl-2, 6-dimethylphenoxy)-2-methylpropanoate To a solution of 4-hydroxy-3, 5-dimethylbenzaldehyde (5.0 g, 0.033 mol] in methyl isobutyl ketone (100 mL], CS2CO3 (21.69 g, 0.066 mol] and ethyl bromoisobutyrate (12.99 g, 0.066 mol] were added. Reaction mixture was stirred at 95 °C for 48 h.Reaction mixture was cooled to ambient temperature and then filtered. The filtrate was concentrated under reduced pressure. The residue obtained was dissolved in ethylacetate (100 mL] and then washed with water (100 mL] The ethyl acetate layer was concentrated under reduced pressure. Residue obtained (8.3 g, crude] was used in the next step without purification | |
With Cs2CO3 In acetonitrile at 80℃; for 36h; | A round-bottomed flask was charged with 3,5-dimethyl-4-hydroxybenzaldehyde (A, 1.0 equiv.) and ethyl 2-bromoisobutyrate (3.0 equiv.), caesium carbonate (3.0 equiv.),solved in acetonitrile. The reaction mixture was stirred at 80 °C for36 h. After the reaction was completed (monitored by TLC), themixture was diluted by water and extracted by ethyl acetate. Thecombined organic layer was washed with brine, dried over anhydroussodium sulfate and concentrated under the reduced pressure.The corresponding compound B was used in the next step withoutfurther purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16.8% | With caesium carbonate; In acetonitrile; for 4h;Reflux; Inert atmosphere; | Compound 1 (3.0 g, 20 mmol) was added to a 100 mL single-necked flask equipped with magnetic stirring.And acetonitrile (20mL),Stir and dissolve,Add compound 2 (8.96 g, 40 mmol)And cesium carbonate (Cs2CO3, 13g, 40mmol),The reaction mixture was heated to reflux for 4 hours under N2.Cool to room temperature,Add ethyl acetate (30 mL),filter,The filtrate is concentrated,The residue was separated into a white solid (yield: 980 mg).The yield was 16.8%. |
With potassium carbonate; potassium iodide; In dimethyl sulfoxide; at 110℃; for 16h;Inert atmosphere; | Under nitrogen protection, a solution of Compound 1-b (20.00 g, 133.18 mmol, 1.00 eq), tert-butyl 2-bromo-isobutyrate (118.86 g, 532.72 mmol, 99.05 mL, 4.00 eq), potassium carbonate (55.22 g, 399.54 mmol, 3.00 eq) and potassium iodide (2.21 g, 13.32 mmol, 0.10 eq) in dimethylsulfoxide (250.00 mL) was stirred at 110C. for 16 h. The mixture was filtered, and ethyl acetate/water (1:1, 300 mL) was added into the filtrate. The organic phase was washed with water (2300 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography (11.8%, ethyl acetate/petroleum ether) to give Compound 44-a . 1H NMR (400 MHz, CDCl3) delta ppm 9.89 (s, 1H), 7.48 (s, 2H), 2.26 (s, 6H), 1.47 (s, 9H), 1.42 (s, 6H). |
Yield | Reaction Conditions | Operation in experiment |
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76% | Stage #1: 4-hydroxy-3,5-dimethylbenzaldehyde With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 1h; Stage #2: 2-Bromoethyl methyl ether In N,N-dimethyl-formamide; mineral oil at 20℃; for 72h; | 73 To a solution of 3,5-dimethyl-4-hydroxy benzaldehyde (2.0 g, 13.33 mmol) in DMF was added NaH (640 mg, 16.0 mmol, 60% in oil) and the mixture was stirred for 1 h at room temperature. A solution of 1-bromo-2-methoxy ethane (1.85 g, 13.33 mmol) was added and the mixture was stirred for 72 h at room temperature. The reaction mixture was quenched by addition of saturated NH4Cl solution and diluted with water. The product was extracted with ethyl acetate. The combined organic layers were washed with water, brine and dried over Na2SO4. Upon removal of solvent, it gave 2.1 g of 4-(2-methoxy ethoxy)-3,5-dimethyl benzaldehyde (76 yield). To a solution of 2-amino-4,6-dimethoxy-benzamide (200 mg, 1.02 mmol) and 4-(2-methoxy ethoxy)-3,5-dimethyl benzaldehyde (212 mg, 1.02 mmol) in N,N-dimethyl acetamide (10 mL), NaHSO3 (199 mg, 1.12 mmol) and p-TSA (22 mg, 0.102 mmol) were added and the reaction mixture was heated at 150° C. for 3 h. Cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was diluted with water and the solid was collected to give the crude product. The crude product was purified by chromatography using 2% MeOH in CH2Cl2 to give 5,7-dimethoxy-2-(4-(2-methoxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one (170 mg, 43%). Selected data: MS (ES) m/z: 385.10; MP 201-202° C |
Stage #1: 4-hydroxy-3,5-dimethylbenzaldehyde With sodium hydride In N,N-dimethyl-formamide at 20℃; for 1h; Stage #2: 2-Bromoethyl methyl ether In N,N-dimethyl-formamide at 20℃; for 72h; | 79 To a solution of 3,5-dimethyl-4-hydroxy benzaldehyde (2.0 g, 13.33 mmol) in DMF was added NaH (640 mg, 16.0 mmol, 60% in oil) and the mixture was stirred for 1 h at room temperature. A solution of 1-bromo-2-methoxy ethane (1.85 g, 13.33 mmol) was added and the mixture was stirred for 72 h at room temperature. The reaction mixture was quenched by addition of saturated NH4Cl solution and diluted with water. The product was extracted with ethyl acetate. The combined organic layers were washed with water, brine and dried over Na2SO4. Upon removal of solvent, it gave 2.1 g of 4-(2-methoxy ethoxy)-3,5-dimethyl benzaldehyde (76 yield). To a solution of 2-amino-4,6-dimethoxybenzamide (200 mg, 1.02 mmol) and 4-(2-methoxy ethoxy)-3,5-dimethyl benzaldehyde (212 mg, 1.02 mmol) in N,N-dimethyl acetamide (10 mL), NaHSO3 (199 mg, 1.12 mmol) and p-TSA (22 mg, 0.102 mmol) were added and the reaction mixture was heated at 150° C. for 3 h. Cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was diluted with water and the solid was collected to give the crude product. The crude product was purified by chromatography using 2% MeOH in CH2Cl2 to give 5,7-dimethoxy-2-(4-(2-methoxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one (170 mg, 43%). Selected data: MS (ES) m/z: 385.10; MP 201-202° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | Stage #1: 4-hydroxy-3,5-dimethylbenzaldehyde With sodium hydride In N,N-dimethyl-formamide for 0.333333h; Stage #2: 2-(2-bromoethyl)isoindoline-1,3-dione In N,N-dimethyl-formamide at 65℃; for 5h; Stage #3: With acetic acid In water | 37 Example 37. Preparation of N-{2-[4-(5,7-dimethoxy-4-oxo-3,4-dihydro-pyrido[2,3-d]pyrimidin-2-yl)-2,6-dimethyl-phenoxy]-ethyl}-acetamide [0283] To a solution of 4-hydroxy-3,5-dimethyl-benzaldehyde (15.0 g, 0.10 mol) in anhydrous DMF (30 ml_) was added 60% sodium hydride (4.80 g, 0.12 mol) and the reaction mixture was kept stirring for 20 minutes. 2-(2-Bromo-ethyl)-isoindole-1,3-dione (25.4 g, 0.10 mol) in anhydrous DMF (30 ml_) was added drop-wise. The reaction mixture was heated to 65°C for 5 hours. Acetic acid (3 ml_) was added, DMF was removed, and the residue was poured into water (150 ml_), and extracted with dichloromethane (200 ml_). The crude compound was purified by column chromatography (silica gel 230-400 mesh; eluting with ethyl acetate and hexane 1 :1) to give 4-[2-(1,3-dioxo-1,3-dihydro- isoindol-2-yl)-ethoxy]-3,5-dimethyl-benzaldehyde. Yield: 11.0 g (34%).[0284] To a solution of 2-amino-4,6-dimethoxy-nicotinamide (0.40 g, 2.02 mmol, and 4-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethoxy]-3,5-dimethyl-benzaldehyde (0.65 g, 2.02 mmol) in N,N-dimethylacetamide (30 ml_) was added NaHSO3 (58.5 wt%, 0.40 g, 2.20 mol) and p-TSA (0.12 g, 6.00 mmol). The reaction mixture was heated to 145°C for 16 hours, and then cooled to room temperature. Solvent was removed under reduced pressure. Aqueous sodium bicarbonate solution (50 ml_) was added and the solid separated was filtered and washed with ether (50 ml_). Crude compound was purified by column chromatography (silica gel, 230-400 mesh; methanol, ethyl acetate and dichloromethane 5:20:75) to give 2-{2-[4-(5,7-dimethoxy-4-oxo-3,4-dihydro-pyrido[2,3-d]pyrimidin-2-yl)-2,6-dimethyl-phenoxy]-ethyl}-isoindole-1,3-dione as a light yellow solid. Yield: 0.43 g (43%).[0285] Hydrazine hydrate (0.2 ml_, 4.1 mmol) was added to a solution of 2- {2-[4-(5,7-dimethoxy-4-oxo-3,4-dihydro-pyrido[2,3-d]pyrimidin-2-yl)-2,6-dimethyl- phenoxy]-ethyl}-isoindole-1,3-dione (0.43 g, 0.86 mmol) in ethanol (10 ml_). The reaction mixture was heated to 700C for 4 hours, solvent was removed, and the residue was purified by column chromatography (silica gel, 230-400 mesh; eluting with 5% 7 N ammonia in methanol and dichloromethane) to give 2-[4-(2-amino-ethoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-pyrido[2,3-d]pyrimidin-4-one as a white solid. Yield: 0.22 g (69%). [0286] To a solution of 2-[4-(2-amino-ethoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-pyrido[2,3-d]pyrimidin-4-one (0.21 g, 0.56 mmol) in pyridine (4 mL) and dichloromethane (10 mL) was added acetyl chloride (51 mg, 0.65 mmol), and the reaction mixture was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure, the residue was poured into water (50 mL) and stirred for 30 minutes. The solid separated was filtered and washed with cold water and ether, and then dried under vacuum to give the title compound as a white solid. Yield: 0.19 g (81%). 1H NMR (400 MHz, DMSO-d6): δ 8.15 (s, 1H), 7.90 (s, 2H), 6.36 (s, 1H), 3.93 (s, 3H), 3.88 (s, 3H)1 3.79 (t, J = 5.6 Hz, 3H), 3.42 (q, J = 5.6Hz, 2H), 2.28 (s, 6H), 1.84 (s, 3H). MS (ES) m/z: 411.15 (M-1). |
34% | With sodium hydride In N,N-dimethyl-formamide at 65℃; for 5h; | 31; 37 To a solution of 4-hydroxy-3,5-dimethyl-benzaldehyde (15.0 g, 0.10 mol) in anhydrous DMF (30 mL) was added 60% sodium hydride (4.80 g, 0.12 mol) and the reaction mixture was kept stirring for 20 minutes. 2-(2-Bromo-ethyl)isoindole-1,3-dione (25.4 g, 0.10 mol) in anhydrous DMF (30 mL) was added drop-wise. The reaction mixture was heated to 65° C. for 5 hours. Acetic acid (3 mL) was added, DMF was removed, and the residue was poured into water (150 mL), and extracted with dichloromethane (200 mL). The crude compound was purified by column chromatography (silica gel 230-400 mesh; eluting with ethyl acetate and hexane 1:1) to give 4-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethoxy]-3,5-dimethyl-benzaldehyde. Yield: 11.0 g (34%) |
23% | With potassium carbonate; sodium iodide In N,N-dimethyl-formamide at 80℃; for 2.5h; | 99 A mixture of 3,5-dimethyl-4-hydroxybenzaldehyde (0.600 g, 4.00 mmol), N-(2-bromoethyl)-phthalimide (1.22 g, 4.80 mmol), K2CO3 (0.829 g, 6.00 mmol), Nal (3.00 g, 20.0 mmol) in DMF (40.0 mL) was heated at 80° C. for 2.5 h. The reaction was cooled to room temperature, diluted with EtOAc (200 mL), washed with 1 M NaOH (2×100 mL), 1 M HCl (2×100 mL), brine (75 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The residue was chromatographed on silica gel (40 g, hexanes/EtOAc) to provide the expected ether (0.300 g, 23%) as a yellow solid. A mixture of the above ether (0.293 g, 0.907 mmol), 2-amino-4,6-dimethoxybenzamide (0.178 g, 0.907 mmol), NaHSO3 (94%, 0.100 g, 0.907 mmol), and p-TsOH.H2O (0.0173 g, 0.0907 mmol) in DMA (11.3 mL) was stirred at reflux for 1.5 h then cooled to room temperature. The mixture was diluted with EtOAc (250 mL), washed with saturated aqueous ammonium chloride (3×75 mL) and brine (75 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The residue was chromatographed on silica gel (40 g, CH2Cl2/CH3OH) to provide the expected product (0.075 g, 17%) as a light yellow solid. A mixture of the above compound (0.213 g, 0.426 mmol) and 2 M methylamine in THF (25.0 mL) was stirred at room temperature for 17 h. The volatiles were removed under vacuum and the residue was chromatographed on silica gel to provide compound N1-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-N2-methylphthalamide (0.0493 g, 22%) and compound 2-(4-(2-aminoethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.0360 g, 23%) as white solids. Selected data for N1-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-N2-methylphthalamide: 1H NMR (300 MHz, DMSO-d6) δ 11.80 (s, 1H), 8.51 (t, J=5.57 Hz, 1H), 8.18 (q, J=4.57 Hz, 1H), 7.89 (s, 2H), 7.53-7.42 (m, 4H), 6.74 (d, J=2.31 Hz, 1H), 6.52 (d, J=2.29 Hz, 1H), 3.96-3.80 (m, 8H), 3.61 (q, J=5.73 Hz, 2H), 2.71 (d, J=4.62 Hz, 3H), 2.32 (s, 6H); MS (APCl) m/z 531 [M+H]+. Selected data for 2-(4-(2-aminoethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one: 1H NMR (300 MHz, DMSO-d6) δ 7.90 (s, 2H), 6.74 (d, J=2.31 Hz, 1H), 6.51 (d, J=2.32 Hz, 1H), 3.88 (s, 3H), 3.85 (s, 3H), 3.77 (t, J=5.76 Hz, 2H), 2.91 (t, J=5.75 Hz, 2H), 2.30 (s, 6H); MS (APCl) m/z 370 [M+H]+. |
23% | With potassium carbonate; sodium iodide In N,N-dimethyl-formamide at 80℃; for 2.5h; | 43 Example 43. Preparation of N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)propane-2-sulfonamide [0301] A mixture of 3,5-dimethyl-4-hydroxybenzaldehyde (0.600 g, 4.00 mmol), N-(2-bromoethyl)-phthalimide (1.22 g, 4.80 mmol), K2CO3 (0.829 g, 6.00 mmol), NaI (3.00 g, 20.0 mmol) in DMF (40.0 ml_) was heated at 800C for 2.5 hours. The reaction was cooled to room temperature, diluted with EtOAc (200 ml_), washed with 1 M NaOH (2 x 100 ml_), 1 M HCI (2 * 100 ml_), brine (75 ml_), dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was chromatographed on silica gel (40 g, hexanes/EtOAc) to provide the expected ether (0.300 g, 23%) as a yellow solid. A mixture of this ether (0.293 g, 0.907 mmol), 2-amino-4,6-dimethoxybenzamide (0.178 g, 0.907 mmol), NaHSO3 (94%, 0.100 g, 0.907 mmol), and p-TsOHΗ2O (0.0173 g, 0.0907 mmol) in DMA (11.3 ml_) was stirred at reflux for 1.5 hours, then cooled to room temperature. The mixture was diluted with EtOAc (250 ml_), washed with saturated aqueous ammonium chloride (3 * 75 ml_), them brine (75 ml_), dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was chromatographed on silica gel (40 g, CH2CI2/CH3OH) to provide the expected product (0.075 g, 17%) as a light yellow solid. A mixture of the above compound (0.213 g, 0.426 mmol) and 2 M methylamine in THF (25.0 ml_) was stirred at room temperature for 17 hours. The volatiles were removed under vacuum and 2-(4-(2-aminoethoxy)- 3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one was isolated (0.036 g, 23%) as a white solid.[0302] A mixture of 2-(4-(2-aminoethoxy)-3,5-dimethylphenyl)-5,7- dimethoxyquinazolin-4(3H)-one (0.125 g, 0.338 mmol), 2-propylsulfonyl chloride (0.040 mt_, 0.36 mmol), and DBU (0.100 ml_, 0.67 mmol) in THF (2.5 ml_) was stirred at 600C for 18 hours. Then, the mixture was cooled to room temperature and purified by silica gel chromatography, eluting with 92:7:1 CHCI3/MeOH/concentrated NH4OH. The mixture was further purified by reverse- phase HPLC, eluting with 10% to 90% CH3CN in H2O with 0.1% TFA, to afford the desired product. The product was freeze-dried from CH3CN/H2O to afford the title compound (0.080 g, 50%) as a white solid. 1H NMR (300 MHz, DMSO-Cf6: δ 11.85 (S1 1 H), 8.09 (s, 2H), 7.33 (t, J = 6.0 Hz, 1 H), 6.74 (d, J = 2.3 Hz, 1 H), 6.52 (d, J = 2.3 Hz, 1H), 3.89 (s, 3H), 3.82-3.86 (m, 5H), 3.21-3.39 (m, 3H), 2.31 (s, 6H), 1.26 (d, J = 6.8 Hz, 6H). APCI MS m/z 476 [M+H]+. |
23% | With potassium carbonate; sodium iodide In N,N-dimethyl-formamide at 80℃; for 2.5h; | 93 Example 93 A mixture of 3,5-dimethyl-4-hydroxybenzaldehyde (0.600 g, 4.00 mmol), N-(2-bromoethyl)-phthalimide (1.22 g, 4.80 mmol), K2CO3 (0.829 g, 6.00 mmol), NaI (3.00 g, 20.0 mmol) in DMF (40.0 mL) was heated at 80° C. for 2.5 h. The reaction was cooled to room temperature, diluted with EtOAc (200 mL), washed with 1 M NaOH (2×100 mL), 1 M HCl (2×100 mL), brine (75 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The residue was chromatographed on silica gel (40 g, hexanes/EtOAc) to provide the expected ether (0.300 g, 23%) as a yellow solid. A mixture of the above ether (0.293 g, 0.907 mmol), 2-amino-4,6-dimethoxybenzamide (0.178 g, 0.907 mmol), NaHSO3 (94%, 0.100 g, 0.907 mmol), and p-TsOH.H2O (0.0173 g, 0.0907 mmol) in DMA (11.3 mL) was stirred at reflux for 1.5 h then cooled to room temperature. The mixture was diluted with EtOAc (250 mL), washed with saturated aqueous ammonium chloride (3×75 mL) and brine (75 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The residue was chromatographed on silica gel (40 g, CH2Cl2/CH3OH) to provide the expected product (0.075 g, 17%) as a light yellow solid. A mixture of the above compound (0.213 g, 0.426 mmol) and 2 M methylamine in THF (25.0 mL) was stirred at room temperature for 17 h. The volatiles were removed under vacuum and the residue was chromatographed on silica gel to provide compound N1-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-N2-methylphthalamide (0.0493 g, 22%) and compound 2-(4-(2-aminoethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.0360 g, 23%) as white solids. Selected data for N1-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-N2-methylphthalamide: 1H NMR (300 MHz, DMSO-d6) δ 11.80 (s, 1H), 8.51 (t, J=5.57 Hz, 1H), 8.18 (q, J=4.57 Hz, 1H), 7.89 (s, 2H), 7.53-7.42 (m, 4H), 6.74 (d, J=2.31 Hz, 1H), 6.52 (d, J=2.29 Hz, 1H), 3.96-3.80 (m, 8H), 3.61 (q, J=5.73 Hz, 2H), 2.71 (d, J=4.62 Hz, 3H), 2.32 (s, 6H); MS (APCI) m/z 531 [M+H]+. Selected data for 2-(4-(2-aminoethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one: 1H NMR (300 MHz, DMSO-d6) δ 7.90 (s, 2H), 6.74 (d, J=2.31 Hz, 1H), 6.51 (d, J=2.32 Hz, 1H), 3.88 (s, 3H), 3.85 (s, 3H), 3.77 (t, J=5.76 Hz, 2H), 2.91 (t, J=5.75 Hz, 2H), 2.30 (s, 6H); MS (APCI) m/z 370 [M+H]+. |
23% | With potassium carbonate; sodium iodide In N,N-dimethyl-formamide at 80℃; for 2.5h; | 18 At 80 °C 3,5-dimethyl-4-hydroxybenzaldehyde(0.600g, 4.00mmol), N- (2- bromoethyl) - phthalimide(1.22g, 4.80mmol), K 2CO 3(0.829g, 6.00mmol), NaI (3.00g, 20.0mmol) was heated (40.0mL) in a mixtureof DMF for 2.5 hours. The reaction was cooled to room temperature, dilutedwith EtOAc (200mL), 1M NaOH (2 × 100mL), 1M HCl (2 × 100mL), brine (75mL),washed with, dried over sodium sulfate, filtered, and concentrated in vacuo.The residue was purified on silica gel (4Og, hexanes / EtOAc) chromatographedon to give the desired etheras a yellow solid (0.300g, 23%). Under the above reflux ether(0.293g, 0.907mmol), 2-amino-4,6-dimethoxybenzene-carboxamide (0.178g, 0.907mmol), NaHSO 3(940.100g0.907mmol) and p-TsOH·H 2O (0.0173g, 0.0907mmol) was added and stirredfor 1.5 hours in DMA (11.3 mL), thencooled to room temperature. The mixture was diluted with EtOAc (250mL), washedwith saturated aqueous ammonium chloride solution (3 × 75mL) and brine (75mL),dried over sodium sulfate, filtered, and concentrated in vacuo. The residue waschromatographed on silica (40g, CH 2Cl 2/CH 3OH in chromatography, to obtainthe desired product as a lightyellow solid (0.075g, 17%)) on.Mixtures of the abovecompounds at roomtemperature (0.213g, 0.426mmol) and 2M methylamine(25.0 mL) in THFwas stirred for 17 hours.The volatiles were removed in vacuo, the residue was chromatographed on silicagel to give a whitesolid compound N1- (2- (4- (5,7-dimethoxy-4-oxo-3,4-bis hydrogen quinazolin-2-yl) -2,6-dimethylphenoxy) ethyl)-N2-methyl-phthalic acid diamide (0.0493g, 22%) and compound 2- (4- (2 - aminoethoxy) -3,5-dimethyl-phenyl)-5,7-dimethoxy-quinazolin -4 (3H) - one (0.0360g, 23%). |
23% | With potassium carbonate; sodium iodide In N,N-dimethyl-formamide at 80℃; for 2.5h; | 18; 21 A mixture of 3,5-dimethyl-4-hydroxybenzaldehyde (0.600 g, 4.00 mmol), N-(2-bromoethyHl)-phthalfmide (1.22 g, 4.80 mmol), K2CO3 (0.829 g, 6.00 mmol), NaI (3.00 g, 20.0 mmol) In DMF (40.0 mL) was heated at 80°C for 2.5 h. The reaction was cooled to room temperature, diluted with EtOAc (200 mL), washed with 1 M NaOH (2x100 mL), 1 M HCI (2x100 mL), brine (75 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The residue was chromatographed on silica gel (40 g, hexanes/EtOAc) to provide the expected ether (0.300 g, 23%) as a yellow solid. A mixture of the above ether (0.293 g, 0.907 mmol), 2-amino-4,6-dimethoxybenzamide (0.178 g, 0.907 mmol), NaHSO3 (94%, 0.100 g, 0.907 mmol), and />-TsOH-H2O (0.0173 g, 0.0907 mmol) in DMA (11.3 mL) was stirred at reflux for 1.5 h then cooled to room temperature. The mixture was diluted with EtOAc (250 mL), washed with saturated aqueous ammonium chloride (3x75 mL) and brine (75 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The residue was chromatographed on silica gel (40 g, CH2CI2ZCHaOH) to provide the expected product (0.075 g. 17%) as a light yellow solid. A mixture of the above compound (0.213 g, 0.426 mmol) and 2 M methylamine in THF (25.0 mL) was stirred at room temperature for 17 h. The volatiles were removed under vacuum and the residue was chromatographed on silica gel to provide compound N1-(2-(4-(5,7-dimethoxy-4-oxo-3,4- dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-N2'methylphthalamldβ (0.0493 g, 22%) and compound 2-(4-(2-aminoethoxy)-3,5-dirnethylphenyl)-5,7- dimethoxyquinazolin-4(3H)-one (0,0360 g, 23%) as white solids. Selected data for N1-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazo]in-2-yl)-2,6- dimethylphenoxy)ethyi)-N2-methylphthalamide: 1H NMR (300 MHz, DMSO-cfe) δ 11.80 (s, 1H), 8.51 (t, J = 5.57 Hz, 1H), 8.18 (q, J = 4.57 Hz, 1H), 7.89 (s, 2H), 7.53-7.42 (m, 4H), 6.74 (d, J - 2.31 Hz, 1H), 6.52 (d, J = 2.29 Hz, 1 H), 3.96-3.80 (m, 8H), 3.61 (q, J = 5.73 Hz, 2H), 2.71 (d, J = 4.62 Hz, 3H), 2.32 (s, 6H); MS (APCI) m/z 531 [M+H]+. Selected data for 2-(4-(2-aminoethoxy)^3,5- dimethylphenylj-5,7-dimethoxyquinazolin-4(3H)-one: 1H NMR (300 MHz, DMSO- de) δ 7.90 (S, 2H), 6.74 (d, J = 2.31 Hz, 1H), 6.51 (d, J = 2.32 Hz, 1H). 3.88 (S, 3H), 3.85 (s, 3H), 3.77 (t, J = 5.76 Hz, 2H), 2.91 (t, J « 5.75 Hz, 2H), 2.30 (s, 6H);MS (APCI) m/z 370 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With potassium carbonate; In ethanol; for 24.0h;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, 39%) 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; 50% ethyl acetate in hexane as eluent) to give 33.3 g (95%) 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; 5% methanol in CH2Cl2 as eluent) to give 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (33 g, 52%). |
95% | With potassium carbonate; In ethanol; for 24.0h;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; 50% ethyl acetate in hexane as eluent) to give 33.3 g (95%) 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; 5% methanol in CH2Cl2 as eluent) to give 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (33 g, 52%). |
95% | With potassium carbonate; In ethanol; for 24.0h; | 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, 39%). 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 50% hexanes in ethyl acetate as eluent) to afford 33.3g (95%) 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 25% methanol as eluent) to afford 2- (4- (2-hydroxyethoxy) -3,5-dimethyl-phenyl)-5,7-dimethoxy-quinazoline -4 (3H) - one (33g, 52%). |
95% | With potassium carbonate; In ethanol; for 24.0h;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 lambda/,/V-dimethyl formamide (20 mL) was stirred at 70C 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 70C 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, 39%) as a white solid. Selected data: 229-231C.[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; 50% ethyl acetate in hexane as eluent) to give 33.3 g (95%) 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 150C 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 % methanol in CHzCI2 as eluent) to give 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7- dimethoxyquinazolin-4(3H)-one (33 g, 52%). |
94% | With potassium carbonate; In ethanol; for 24.0h;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 94%. |
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 60.0h; | 3,5-dimethyl-4-hydroxybenzaldehyde (3,5-dimethyl-4-hydroxybenzaldehyde, 13.8 g, 91.9 mmol),2-chloroethanol (15.0 g, 187 mmol)Then, N, N-dimethylformamide (DMF) (130 mL) was added to potassium carbonate (24.2 g, 175 mmol), and the mixture was stirred at 100 C. for 2.5 days.Raw material (Rf: 0.6) by TLC (ethyl acetate / hexane = 1/2 (v / v))After confirming disappearance of the solvent, the solvent was distilled off. After dissolving the residue in dichloromethane and removing inorganic salts by filtration,Washing (1M HClaq. ? 2 times aqueous sodium bicarbonate ? saturated saline)This gave crude product 21 (14.8 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With toluene-4-sulfonic acid; sodium hydrogensulfite; In N,N-dimethyl acetamide; at 20 - 150℃; for 3h; | To a solution of <strong>[5004-88-6]2-amino-4,5-dimethoxybenzamide</strong> (0.157 g, 0.8 mmol) in N,N-dimethylacetamide (5 mL) were added 3,5-dimethyl-4-hydroxybenzaldehyde (0.120 g, 0.8 mmol), sodium hydrogen sulphite (58.5%, 0.156 g, 0.88 mmol) and p-toluenesulfonic acid (15 mg, 0.08 mmol). The reaction mixture was stirred at 150 C. for 3 h. The reaction mixture was cooled to room temperature and water (40 mL) was added. A white precipitate was formed and filtered off, washed with water and a small amount of methanol and dried under vacuum to give 2-(4-hydroxy-3,5-dimethylphenyl)-6,7-dimethoxyquinazolin-4(3H)-one (0.230 g, 88% yield) as an off-white solid. Selected data: MS (ES) m/z: 327.12; MP>300 C. |
88% | With toluene-4-sulfonic acid; sodium hydrogensulfite; In N,N-dimethyl acetamide; at 150℃; for 3h; | Example 47 2-(4-hydroxy-3,5-dimethylphenyl)-6,7-dimethoxyquinazolin-4(3H)-one To a solution of <strong>[5004-88-6]2-amino-4,5-dimethoxybenzamide</strong> (0.157 g, 0.8 mmol) in N,N-dimethylacetamide (5 mL) were added 3,5-dimethyl-4-hydroxybenzaldehyde (0.120 g, 0.8 mmol), sodium hydrogen sulphite (58.5%, 0.156 g, 0.88 mmol) and p-toluenesulfonic acid (15 mg, 0.08 mmol). The reaction mixture was stirred at 150 C. for 3 h. The reaction mixture was cooled to room temperature and water (40 mL) was added. A white precipitate was formed and filtered off, washed with water and a small amount of methanol and dried under vacuum to give 2-(4-hydroxy-3,5-dimethylphenyl)-6,7-dimethoxyquinazolin-4(3H)-one (0.230 g, 88% yield) as an off-white solid. Selected data: MS (ES) m/z: 327.12; MP >300 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With toluene-4-sulfonic acid; sodium hydrogensulfite; In N,N-dimethyl acetamide; at 120℃; for 16h; | Aniline 12 (37 mg, 0.188 mmol) and4-hydroxy-3,5-dimethylbenzaldehyde (13a)(28.3 mg, 0.188 mmol) were dissolved inDMAc (1.0 mL) and treated with sodiumhydrogen sulfite (23.5mg, 0.23 mmol) and PTSA (7.2 mg, 0.04 mmol).The reactionmixture was stirred at 120 C for 16 h. Water was added tothereaction, and the precipitated solid was collected by filtrationto giveRVX-OH (49 mg, 79%). |
75% | With sodium hydrogen sulfate; toluene-4-sulfonic acid; In N,N-dimethyl-formamide; at 120℃; for 16h; | Compound 8 (1.96 g, 10 mmol) was added to a 100 mL single-mouth bottle.Add N,N-dimethylformamide 30mL to dissolve it.At the same time, compound 9A, 3,5-dimethyl-4-hydroxybenzaldehyde (1.65 g, 11 mmol), was added.Sodium bisulfite (0.95 g, 5 mmol),P-toluenesulfonic acid monohydrate (1.25g, 12mmol),After stirring evenly,Warm the system to 120 C,The reaction was refluxed for 16 hours.After the reaction is over,Add 20 mL of water to the reaction system.Extract three times with ethyl acetate (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 methylene chloride / methanol,Volume ratio 20:1),The compound 10A (2.45 g, yield 75%) was obtained as a pale yellow solid. |
75% | With sodium hydrogen sulfate; toluene-4-sulfonic acid; In N,N-dimethyl-formamide; at 120℃; for 16h; | General procedure: NaHSO3 (0.95 g5 mmol) and toluene-4-sulfonic acid (1.25 g, 12 mmol) added to a solution of 13 (1.96 g, 10 mmol) and 14 (2.13 g, 11 mmol) in DMF (30 mL), followed by warm to 120 C and reflux for 16 h. The resulting mixture was added water (20 mL), extracted using ethyl acetate, then RVX-208 (2.78g, 75 %, Mp: 594.2 ) as yellow solid was obtained after organic phase was dried overnight, filtered, vacuum distillated, purified by column chromatography (40:1, CH2Cl2/CH3OH). |
51% | With iodine; potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 12h; | 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, 98%), 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, 79%) as a yellow-green solid. To a heated solution (external temp 70 C.) of the isatin (162 g, 0.78 mol) in aqueous NaOH (40%, 1.5 L) was added H2O2 (35%, 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 (37%, 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, 55%). 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, 50%) 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 <strong>[63920-73-0]2-amino-4,6-dimethoxybenzamide</strong> (46.7 g, 57%) as a brown solid.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, 51%) as a white solid. Selected data: MP 291-293 C. |
51% | With iodine; potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 12h; | 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, 51%) as a white solid. Selected data: MP 291-293 C |
51% | With iodine; potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 12h; | 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 10C 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, 98%). 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, 79%). After 2 Hour to isatin (162g,0.78mol) was heated in aqueous NaOH solution(40%, 1.5L) in (externalTemperature 70 C) was slowly added to H 2 O 2(35%, 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 (37%, 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, 55%). 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, 50%), 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, 57%).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, 51%). Selected data:MP291-293 C. |
51% | With iodine; potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 12h; | 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 0C. HCI gas (227 g) was bubbled through the solution over 45 min. After 45 min at 10C, the mixture was filtered, washed with isopropylacetate (4 L), and dried overnight on high vacuum at 45C to give the hydrochloride (242.3 g, 98%), 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 (170C external <n="58"/>temperature), and the oxalyl chloride was distilled from the reaction mixture. The flask was cooled to 0C 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, 79%) as a yellow-green solid. To a heated solution (external temp 70C) of the isatin (162 g, 0.78 mol) in aqueous NaOH (40%, 1.5 L) was added H2O2 (35%, 405 mL) slowly over 2 h. After the addition of each portion of H2O2, the internal reaction temperature (initially 64C) increased (to a maximum temp of 80C). After the addition was complete, the foaming reaction mixture was then stirred for an additional 2 h at 70C, and the mixture was allowed to stir overnight while cooling to RT. The mixture was heated to 70C. Additional H2O2 (75 mL) was added, and the mixture was stirred at 70C for a further 2 h until the reaction was complete. After cooling to 10C (bath temperature), aqueous Na2S2O3 (150 mL, saturated) was added. The mixture was brought to pH 8 with HCI (37%, 1.6 L) and pH 6 with acetic acid (glacial, 75 mL), without allowing the reaction mixture to warm to greater than 40C. Filtration of the reaction mixture and washing with water (4 L) gave the expected amino acid as a tan solid (83.7 g, 55%). 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, 50%) 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 <strong>[63920-73-0]2-amino-4,6-dimethoxybenzamide</strong> (46.7 g,57%) 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 80C 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, 51%) as a white solid. Selected data: MP 291-293C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 18h; | 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, 95%).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: >99% pure. |
61% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 18h; | 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 (50muL, 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 (61%) 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. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With potassium carbonate; In N,N-dimethyl-formamide; at 110℃; | To a solution of 3, 5-dimethyl-4-hydroxybenzaldehyde (1.50 g, 10 mmol) in DMF (30 mL) was added ethylene carbonate (0.88 g, 10 mmol) and K2CO3, and warmed to 110 for refluxing overnight. The reaction mixture then was added water (20 mL), extracted for 3 times with CHCl3, and organic phase was dried overnight, filtered, vacuum distillated, purified by column chromatography (2:1, petroleum ether/ethyl acetate) to afford 14 (1.86 g, 96 %) as yellow oil liquid. 1H NMR (600 MHz, CDCl3) delta: 9.88 (s, 1H), 7.57 (s, 2H), 5.30 (s, 1H), 4.00-3.98 (m, 2H), 3.96 (d, J = 4.9, 3.5 Hz, 2H), 2.36 (s, 6H). MS (ESI) m/z: 217.1 [M + Na]+. |
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 5% 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, 78.8%). 1H-NMR (DMSO-d6): delta 9.82 (1 H), 7.54 (2H), 4.96 (1 H), 3.85 (2H), 3.74 (2H), 2.29 (6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98.9% | With pyridine In dichloromethane at 0 - 20℃; for 16h; | 56 Example 56. Preparation of 2-[4-(3-hydroxy-propyl)-3,5-dimethoxyphenyl]-5,7- dimethoxy-3H-quinazolin-4-one [0322] To a stirred solution of 4-hydroxy-3,5-dimethoxylbenzaldehyde (5.87 g, 32.2 mmol) in CH2CI2 (50 ml_) and pyridine (8.6 ml_) was added trifluoromethanesulfonic anhydride (10.0 g, 35.4 mmol) at 00C. After the addition was complete, stirring was continued for 16 hours at room temperature. The reaction mixture was diluted with ethyl acetate (150 ml_) and washed with water (3 x 100 ml_). The separated organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product, trifluoromethanesulfonic acid 4-formyl-2,6-dimethoxyphenyl ester, was used in the next step without further purification. Yield: 10.0 g (98.9%).[0323] To a stirred solution of trifluoromethanesulfonic acid 4-formyl-2,6- dimethoxyphenyl ester (8.00 g, 25.4 mmol) in anhydrous DMF (80 ml_) under nitrogen at room temperature were sequentially added triethylamine (5.14 g, 50.8 mmol), methyl acrylate (21.9 g, 254.0 mmol), 1,3-bis-(diphenylphosphino)- propane (0.84 g, 2.03 mmol), and palladium acetate (0.40 g, 1.77 mmol). The reaction mixture was stirred at 115°C for 16 hours. DMF was removed under reduced pressure and the residue was taken in ethyl acetate (200 mL) and washed with 1 N HCI solution (2 * 50 mL), and saturated sodium bicarbonate solution (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (silica gel 230-400 mesh; eluting with hexane / ethyl acetate = 3:1) to give 3-(4- formyl-2,6-dimethoxyphenyl)-acrylic acid methyl ester. Yield: 4.0 g (62%).[0324] To a solution of 3-(4-formyl-2,6-dimethoxyphenyl)-acrylic acid methyl ester (5.00 g, 20.0 mmol) in methanol (80 mL), 1.5 N sodium hydroxide (45 mL) was added. The suspension was stirred at room temperature for 16 hours. Methanol was evaporated and acetic acid (4.0 mL) was added. The aqueous layer was extracted with dichloromethane (200 mL) then acidified, to pH 3, with 2 N HCI. The solid was filtered and further washed with cold water (100 mL) to obtain 3-(4-formyl-2,6-dimethoxyphenyl)-acrylic acid as a yellow solid. Yield: 4.20 g (89%).[0325] To a solution of 3-(4-formyl-2,6-dimethoxyphenyl)-acrylic acid (4.20 g, 17.7 mmol) and N,N-diisopropylethylamine (3.5 mL) in ethanol (80 mL) were added Pd/C (400 mg, 10 wt%). The suspension was vigorously stirred under 1 bar of hydrogen pressure for 16 hours. The mixture was filtered through a celite pad and the filtrate was evaporated. The residue was poured into chilled 1 N HCI (200 mL), the solid was filtered, and further washed with cold water (100 mL) to give a mixture of 3-(4-formyl-2,6-dimethoxyphenyl)-propionic acid and 3-(4- hydroxymethyl-2,6-dimethoxyphenyl)-propionic acid as a white solid. Yield: 3.30 g. [0326] To a suspension of LiAIH4 (1.00 g, 26.3 mmol) in anhydrous THF (40 ml_) was added dropwise a solution of a mixture of 3-(4-formyl-2,6-dimethoxyphenyl)-propionic acid and 3-(4-hydroxymethyl-2,6-dimethoxyphenyl)-propionic acid (3.30 g, 13.8 mmol). After the addition was complete, the reaction mixture was stirred at reflux for 2 hours. The suspension was diluted with THF (20 iτiL) and another portion of LiAIH4 (0.60 g, 15.8 mmol) was added. The mixture was refluxed for an additional 1 hour. The reaction was cooled to room temperature, carefully quenched with aqueous saturated NH4CI solution (8 mL), acidified to pH 1-2 with 2 N HCI, and extracted with ethyl acetate (200 mL). The organic phase was dried over sodium sulfate, filtered and concentrated to provide 3-(4-hydroxymethyl-2,6-dimethoxyphenyl)-propan-1-ol as a colorless crystalline solid. Yield: 3.08 g (98.7%).[0327] To a solution of 3-(4-hydroxymethyl-2,6-dimethoxyphenyl)-propan-1-ol (3.08 g, 13.6 mmol) in ethanol (50 mL) was added activated MnO2 (4.15 g, 47.6 mmol) and the resulting suspension was stirred at reflux for 16 hours. The reaction mixture was filtered through a celite pad and the filtrate was concentrated. The residue was purified by column chromatography (silica gel 230- 400 mesh; eluting with 2:1 hexane and ethyl acetate) to give 4-(3-hydroxy-propyl)- 3,5-dimethoxybenzaldehyde. Yield: 1.10 g (36%).[0328] To a solution of 2-amino-4,6-dimethoxy-benzamide (0.35 g, 1.78 mmol) and 4-(3-hydroxy-propyl)-3,5-dimethylbenzaldehyde (0.40 g, 1.78 mmol) in N,N-dimethylacetamide (8 mL) were added NaHSO3 (0.35 g, 1.96 mmol) and p-TSA (34 mg, 0.18 mmol) and the reaction mixture was heated at 115-1200C for 5 hours, then cooled to room temperature. N,N-dimethylacetamide was removed under reduced pressure. The residue was diluted with water (50 mL) and the pH was adjusted to 7 by adding sodium bicarbonate solution. The solid was collected and washed with ether and further mixed with methanol (30 mL) and stirred for 1 hour, filtered, and dried under vacuum to give the title compound as a white solid. Yield: 0.25 g (35%). 1H NMR (400 MHz, CDCI3): 5 11.13 (s, 1H), 7.30 (s, 2H), 6.86 (d, J = 2.4 Hz, 1H), 6.47 (d, J = 2.4 Hz, 1 H), 3.98 (s, 6H), 3.95 (s, 3H), 3.94 (s, 3H), 3.52 (m, 2H), 2.86 (t, J = 6.6 Hz 2H), 2.27 (t, J = 6.6 Hz, 1 H), 1.81 (m, 2H). MS (ES+) m/z: 401.49 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With sodium hydride; potassium iodide In N,N-dimethyl-formamide at 70℃; for 14h; | 15 Example 15. Preparation of 5,7-difluoro-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazoIin-4(3H)-one [0207] A mixture of 3,5-dimethoxy-4-hydroxybenzaldehyde (10 g, 66.67 mmol), (2-bromoethoxy)-dimethyl-tert-butylsilane (15 ml_, 70 mmol), potassium iodide (1.1 g, 6.67 mmol), and sodium hydride (4.00 g, 100 mmol) in DMF (150 ml_) was heated and stirred at 7O0C for 14 hours. The reaction was then cooled and quenched by addition of water (100 ml_). The mixture was extracted with EtOAc (3 * 100 ml_) and concentrated on a rotary evaporator. The resulting residue was purified by column (Siθ2, hexanes/EtOAc = 6:1) to yield 4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,5-dimethyl-benzaldehyde (15.4 g, 75%). [0208] A solution of 2-amino-4,6-difluorobenzoic acid (0.5 g, 2.9 mmol), EDCI HCI (0.887 g, 4.62 mmol), HOBt (0.975 g, 7.22 mmol), and triethylamine (1.6 ml_, 11.552 mmol) in THF (50 ml_) was stirred at room temperature for 1 hour. Ammonium hydroxide (50% aqueous, 10 ml_) was then added to the reaction mixture. The resulting mixture was stirred at room temperature for 6 hours. The reaction was quenched by adding water (50 ml_), extracted with DCM (3 * 100 mL), and concentrated on a rotary evaporator to afford 2-amino-4,6-difluorobenzamide (0.25 g, 50%).[0209] A mixture of 2-amino-4,6-difluoro benzamide (0.25 g, 1.45 mmol), 4- [2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,5-dimethyl-benzaldehyde (0.448 g, 1.45 mmol), sodium hydrogensulfite (0.26 g, 1.45 mmol) and p-toluenesulfonic acid (0.276 g, 1.45 mmol) in N,N-dimethyl acetamide (10 mL) was stirred at 155°C for 14 hours. The reaction mixture was cooled to room temperature, diluted with water (50 mL), extracted with EtOAc (3 * 100 mL), and concentrated on a rotary evaporator, to afford impure product. The residue was re-dissolved in THF (20 mL) and mixed with TBAF in THF (10 mL, 10 mmol). The reaction mixture was stirred at room temperature for 3 hours and concentrated on a rotary evaporator to afford an oily residue. Further purification by column (Siθ2, EtOAc/DCM = 3:1) yielded a light yellow solid. This solid was diluted with MeOH (10 ml_) to make a slurry. The solid was collected by filtration and washed with MeOH to afford the title compound as a light yellow solid (49 mg, 5% overall yield). |
71% | With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 16h; | 20 To a solution of 4-hydroxy-3,5-dimethyl-benzaldehyde (1.00 g, 6.70 mmol) in DMF (20 mL) was added cesium carbonate (8.70 g, 26.6 mmol) followed by (2-bromo-ethoxy)-tert-butyl-dimethyl-silane (2.9 mL, 13 mmol). The reaction mixture was stirred at room temperature for 16 hours. Water was added and the product was extracted with ethyl acetate. The solvent was evaporated in vacuo to obtain 4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,5-dimethyl-benzaldehyde as a colorless oil. It was contaminated with (2-bromo-ethoxy)-tert-butyl-dimethyl-silane, but was used in the next step without further purification. Yield: 2.5 g (71%) |
With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 16h; | 23 Example 23. Preparation of 7-(2-benzyloxy-ethoxy)-2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-5-methoxy-3H-quinazolin-4-one [0246] To a solution of 4-hydroxy-3,5-dimethyl-benzaldehyde (1.00 g, 6.70 mmol) in DMF (20 mL) was added cesium carbonate (8.70 g, 26.6 mmol) followed by (2-bromo-ethoxy)-tert-butyl-dimethyl-silane (2.9 mL, 13 mmol). The reaction mixture was stirred at room temperature for 16 hours. Water was added and the product was extracted with ethyl acetate. The solvent was evaporated in vacuo to obtain 4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,5-dimethyl-benzaldehyde as a colorless oil. It was contaminated with (2-bromo-ethoxy)-tert-butyl-dimethyl-silane, but was used in the next step without further purification. Yield: 2.5 g (71%).[0247] To a stirred solution of 2-amino-4,6-difluoro-benzamide (0.50 g, 2.9 mmol) and 4-[2-(teff-butyl-dimethyl-silanyloxy)-ethoxy]-3,5-dimethyl- benzaldehyde (1.3 g, 2.9 mmol) in Λ/./V-dimethylacetamide (10 mL) were added sodium hydrogen sulfite (0.60 g, 3.5 mmol) and p-toluenesulfonic acid (0.1 g, 0.6 mmol) and the reaction mixture was stirred at 1200C for 16 hours. The solvent was evaporated in vacuo, water was added, and the precipitated solid was filtered off to obtain 2-{4-[2-(terf-butyl-dimethyl-silanyloxy)-ethoxy]-3,5-dimethyl-phenyl}- 5,7-difluoro-3H-quinazolin-4-one as a yellow solid, which was used in the next step without further purification. Yield: 0.490 g (36%).[0248] To a suspension of 2-{4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,5-dimethyl-phenyl}-5,7-difluoro-3H-quinazolin-4-one (0.490 g, 1.06 mmol) in DMF (3 mL) was added sodium methoxide in methanol (2.3 mL, 11 mmol) and the reaction mixture was stirred at room temperature for 16 hours. Water was added, the mixture was acidified with acetic acid, to pH approximately 4-5, and the precipitated solid was filtered off to obtain 7-fluoro-2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-5-methoxy-3H-quinazolin-4-one as a white solid. Yield: 0.21 g (55%). [0249] To a solution of 7-fluoro-2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-5-methoxy-3H-quinazolin-4-one (0.21 g, 0.59 mmol) in THF (12 ml_) was added imidazole (80 mg, 1.2 mmol), followed by ferf-butyldiphenylsilyl chloride (0.20 ml_, 0.65 mmol). The reaction mixture was stirred at room temperature for 16 hours. Saturated NH4CI aqueous solution was added and the product was extracted with ethyl acetate. The solvent was evaporated in vacuo and the residue was purified by column chromatography (silica gel; 230-400 mesh; eluting with 5- 10% ethyl acetate / CH2CI2) to afford 2-{4-[2-(tert-butyl-diphenyl-silanyloxy)-ethoxy]-3,5-dimethyl-phenyl}-7-fluoro-5-methoxy-3H-quinazolin-4-one. Yield: 0.36 g (quantitative).[0250] To a solution of 2-benzyloxy-ethanol (3 ml_) in dimethyl sulfoxide (3 ml_) was added sodium hydride (0.24 g, 6.0 mmol) in portions and the reaction mixture was stirred at room temperature for 45 minutes. To this mixture was added 2-{4-[2-(tert-butyl-diphenyl-silanyloxy)-ethoxy]-3,5-dimethyl-phenyl}-7-fluoro-5-methoxy-3H-quinazolin-4-one (0.36 g, 0.60 mmol) and the reaction mixture was heated at 700C for 16 hours. Water was added, and the mixture was acidified with acetic acid, to pH approximately 4-5, and the precipitated solid was filtered off to obtain a crude product, which was purified by preparative HPLC to obtain the title compound as a white solid. Yield: 0.12 g (42%). 1H NMR (400 MHz, DMSO-de): δ 11.83 (s, 1 H), 7.89 (s, 2H), 7.37 (m, 5H), 6.75 (s, 1 H), 6.53 (s, 1H), 4.91 (s, 1H), 4.58 (s, 2H), 4.30 (s, 2H), 3.84-3.73 (m, 9H), 2.31 (s, 6H). MS (ES+) m/z: 491.55 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With iodine In ethanol for 4h; Inert atmosphere; Reflux; | |
68% | With toluene-4-sulfonic acid; sodium hydrogensulfite In N,N-dimethyl acetamide at 135℃; for 2.5h; | 10 Example 10. Preparation of 2-(4-hydroxy-3,5-dimethylphenyl)-6-((4-methylpiperazin-1-yl)methyl)quinazolin-4(3H)-one [018O] A solution of 2-amino-5-bromobenzamide (12.0 g, 55.8 mmol) and 4-hydroxy-3,5-dimethylbenzaldehyde (8.4 g, 55.8 mmol) in DMA (200 ml_) was treated with NaHSO3 (7.7 g, 72.5 mmol) and p-TsOH (1.1 g, 5.6 mmol). The reaction was heated at 135°C for 2.5 hours, at which time, H2O (10 ml_) and CH2CI2 (100 ml_) were added and the solids were collected by filtration. The solids were washed with CH2CI2 and dried in vacuo to afford 6-bromo-2-(4-hydroxy-3,5-dimethylphenyl)quinazolin-4(3H)-one (13.1 g, 68%).[0181 ] A solution of 6-bromo-2-(4-hydroxy-3,5-dimethylphenyl)quinazolin-4(3H)-one (2.0 g, 5.8 mmol) in DMF (20 mL) was treated with vinyltributyltin (2.6 mL, 8.70 mmol), Pd(PPh3)4 (0.670 g, 0.58 mmol), and LiCI (0.730 g, 17.4 mmol). The reaction was stirred at reflux for 30 minutes, then concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with 30% to 100% of 92:7:1 CHCI3/MeOH/concentrated NH4OH in CH2CI2, to afford 2-(4-hydroxy-3,5-dimethylphenyl)-6-vinylquinazolin-4(3H)-one (0.780 g, 46%). [0182] To a suspension of 2-(4-hydroxy-3,5-dimethylphenyl)-6- vinylquinazolin-4(3H)-one (0.500 g, 1.70 mmol) in THF (30 mL) and H2O (10 mL) was added NaIO4 (1.09 g, 5.10 mmol), followed by OsO4 (0.2 mL, 0.017 mmol). The reaction was stirred overnight, then concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with 92:7:1 to 6:3:1 CHCI3/MeOH/ concentrated NH4OH to afford 2-(4-hydroxy-3,5-dimethylphenyl)-4- oxo-3,4-dihydroquinazoline-6-carbaldehyde (0.475 g, 95%). [0183] To a solution of 2-(4-hydroxy-3,5-dimethylphenyl)-4-oxo-3,4-dihydroquinazoline-6-carbaldehyde (0.115 g, 0.40 mmol) in DCE/CH2CI2 (1 :1 , 15 mL) was added 1-methylpiperazine (0.13 mL, 1.20 mmol) and NaBH(OAc)3 (0.250 g, 1.20 mmol). The reaction stirred at room temperature overnight. After this time, the mixture was concentrated in vacuo and purified by flash chromatography on silica gel eluting with 92:7:1 CHCI3/MeOH/concentrated NH4OH to afford the title compound (0.036 g, 25%) as a white solid: 1H NMR (300 MHz, DMSO-Cf6): δ11.63 (br s, 1 H), 8.77 (br s, 1 H), 8.00 (s, 1 H), 7.85 (s, 2H), 7.65-7.69 (m, 2H), 3.57(s, 2H), 2.15-2.39 (m, 17H); APCI MS m/z 377 [M-H]-. |
68% | With sodium hydrogen sulfate; toluene-4-sulfonic acid In N,N-dimethyl acetamide at 135℃; for 2.5h; | 10 A solution of 2-amino-5-bromobenzamide (12.0 g, 55.8 mmol) and 4-hydroxy-3,5-dimethylbenzaldehyde (8.4 g, 55.8 mmol) in DMA (200 mL) was treated with NaHSO3 (7.7 g, 72.5 mmol) and p-TsOH (1.1 g, 5.6 mmol). The reaction was heated at 135° C. for 2.5 hours, at which time, H2O (10 mL) and CH2Cl2 (100 mL) were added and the solids were collected by filtration. The solids were washed with CH2Cl2 and dried in vacuo to afford 6-bromo-2-(4-hydroxy-3,5-dimethylphenyl)quinazolin-4(3H)-one (13.1 g, 68%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With sodium hydride In N,N-dimethyl-formamide; mineral oil at 65℃; | 12 To a solution of 4-hydroxy-3,5-dimethylbenzaldehyde (6.84 g, 0.0455 mol) in anhydrous DMF (15 mL) was added NaH in mineral oil (60%, 2.23 g, 0.0558 mol). (2-Bromo-ethyoxymethyl)-benzene (10.0 g, 0.0465 mol) was added and the reaction was kept at 65° C. overnight. The reaction mixture was poured into water and extracted with dichloromethane to yield (4-(2-benzyloxy-ethoxy)-3,5-dimethylbenzaldehyde (10.5 g, 81%), which was used for next step reaction without further purification |
With sodium hydride In N,N-dimethyl-formamide; mineral oil at 65℃; | 13 Example 13. Preparation of 2-(4-(2-(benzyloxy)ethoxy)-3,5-dimethylphenyl)-5,7-dimethoxypyrido[2,3-d]pyrimidin-4(3H)-one [0196] A mixture of dimethyl acetone-1,3-dicarboxylate (200 g 1.148 mol), cyanamide (48.3 g, 1.148 mol), and Ni(acac)2 (14.75 g, 0.0574 mol) in dioxane (200 mL) was heated to reflux in a 1-L flask with a reflux condenser. The reaction mixture was heated at reflux for 16 hours and then cooled to room temperature. The precipitate was filtered off, and the solid was mixed with methanol (200 mL), stirred for 30 minutes, and filtered again to give methyl 2-amino-4-hydroxy-6-oxo-1,6-dihydropyridine-3-carboxylate (93 g, 44%). [0197] In a 1-L flask with a reflux condenser was added methyl 2-amino-4- hydroxy-6-oxo-1,6-dihydropyridine-3-carboxylate (93.0 g, 0.505 mol) and POCI3 (425 ml_) and the reaction mixture was heated to reflux for 35 minutes. About 300 ml_ POCI3 was evaporated under vacuum. The residue was poured into ice and water (400 ml_), which was further neutralized with KOH to pH approximately 6-7. The precipitate was filtered off and extracted with ethyl acetate (2 x 300 ml_). The organic solution was concentrated and passed through a column, eluting with hexane:ethyl acetate 4:1 , to give methyl 2-amino-4,6-dichloropyridine-3-carboxylate (22.5 g, 20.1%).[0198] In a 500-mL flask with a reflux condenser was added methyl 2- amino-4.6-dichloropyridine-3-carboxylate (22.5 g, 0.101 mol) and 25 wt% sodium methoxide in methanol (88 mL, 0.407 mol), together with methanol (20 ml_). The mixture was heated to reflux for 5 hours, then cooled to room temperature. Acetic acid (15 mL) was added to the mixture and pH was adjusted to approximatley 7. Methanol was removed and the residue was poured into water (100 mL). The precipitated solid was filtered and further rinsed with water (3 * 200 mL) to give methyl 2-amino-4, 6-dimethoxypyridine-3-carboxylate (18.5 g, 86.4%).[0199] In a 500-mL flask with a reflux condenser was added methyl 2-amino-4,6-dimethoxypyridine-3-carboxylate (18.5 g, 0.0872 mol), potassium hydroxide (19.5 g, 0.349 mol) in water (80 mL) and ethanol (100 mL). The mixture was heated to 800C for 16 hours. The solvent was removed and aqueous HCI was used to adjust the pH to 6. The water was removed by freeze drying. The obtained solid was extracted with methanol to yield 2-amino-4,6-dimethoxy-nicotinic acid (17.2 g, 100%).[0200] 2-Amino-4,6-dimethoxy-nicotinic acid (17.2 g, 0.0872 mol) was added to THF (110 mL). 1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (21.73 g, 0.113 mol), 1-hydroxybenzotriazole hydrate (12.96 g, 0.0959 mol) and 4-methyl morpholine (9.7 g, 0.0959 mol) were then added to the suspension. After stirring for 10 minutes at room temperature, 50% v/v ammonium hydroxide (18.3 g, 0.262 mol) was added. The reaction mixture was kept at room temperature for 16 hours. THF was removed and the residue was poured into cold water (100 mL). The precipitate was filtered off and washed with cold water to yield 2-amino-4,6-dimethoxy-nicotinamide (10.8 g, 62.3%). [0201] To a solution of 4-hydroxy-3,5-dimethylbenzaldehyde (6.84 g, 0.0455 mol) in anhydrous DMF (15 ml_) was added NaH in mineral oil (60%, 2.23 g, 0.0558 mol). (2-Bromo-ethyoxymethyl)-benzene (10.0 g, 0.0465 mol) was added and the reaction was kept at 65°C overnight. The reaction mixture was poured into water and extracted with dichloromethane to yield (4-(2-benzyloxy-ethoxy)-3,5-dimethylbenzaldehyde (10.5 g, 81%), which was used for next step reaction without further purification.[0202] To a solution of 2-amino-4,6-dimethoxy-nicotinamide (2.55 g, 12.9 mmol) and 4-(2-benzyloxy-ethoxy)-3,5-dimethylbenzaldehyde (3.68 g, 12.9 mmol) in N,N-dimethyl acetamide (20 ml_), were added NaHSO3 (2.52 g, 14.2 mmol) and p-TSA (1.98 g, 10.4 mmol). The reaction mixture was heated at 1500C for 14 hours. The reaction mixture was cooled to room temperature. The solvent was removed under reduced pressure. The residue was diluted with water and the solid was collected and further washed with methanol. The crude product was purified by column chromatography (silica gel 230-400 mesh; 2% methanol in CH2CI2 as eluent) to give the title compound as an off-white solid (0.88 g, 14.7%). MP 204.5-205.90C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With hydrogenchloride In methanol; water at 0 - 40℃; for 16h; Large scale; | 2 Example 2: Preparation of GFT505 Intermediate IV A mixture of 4-mercaptoacetophenone (19 Kg, 114 mol), 3,5-dimethyl-4-hydroxybenzaldehyde (17.1 Kg, 114 mol)(4 mol / L), stirred at 20 to 30 ° C for 3 hours, cooled to 0 to 10 ° C, stirred for 1 hour, left offThe heart was dried at 40 ° C for 12 hours to give 31.6 kg of GFT505 intermediate (IV) as a yellow solid in 93% yield |
With hydrogenchloride In ethanol at 20℃; for 6h; | 1 Example 1 : Comparative Synthesis of Compounds of General Formula (lh); Materials & MethodsSynthesis of the Compounds of General Formula (la) in Acidic MediumCpd. 1 a and Cpd. 4a have been synthesized. 4'-methylthioacetophenone (1 equivalent) and 3,5-dimethyl-4-hydroxybenzaldehyde (1 equivalent) were dissolved in ethanol solution saturated with gaseous hydrochloric acid. Reaction was stirred at room temperature for 6 hours and solvent was eliminated by vacuum evaporation. Compounds were purified by chromatography on silica gel (elution in cyclohexane/ethyl acetate).Cpd. 2a and Cpd. 3a have been synthesized and purified similarly to Cpd. 1 a, using 4'-methylthioacetophenone and either 3,5-diethyl-4-hydroxybenzaldehyde or 3,5- diisopropyl-4-hydroxybenzaldehyde, respectively, as starting materials.Cpd. 5a and Cpd. 6a have been synthesized and purified similarly to Cpd. 1 a, using 3,5-dimethyl-4-hydroxybenzaldehyde and either 4'-trifluoromethoxyacetophenone or 4'- chloroacetophenone, respectively as starting materials.Synthesis of the Compounds of General Formula (lb) by Phase Transfer Catalysis (PTC) The PTC reactions were performed using AAG1 (tert-butyl obromoisobutyrate,Sigma-Aldrich ref.17455), AAG2 (tert-butyl 2-methyl-2-(methylsulfonyloxy) propanoate), or AAG3 (ethyl 2-methyl-2-(methylsulfonyloxy) propanoate) as alkylating agent.Each PTC reaction was performed under nitrogen atmosphere using 10 g of a compound of General Formula (la), 1 .5 equiv. of potassium carbonate, in presence of tetra-n-butylammonium hydrogen sulfate (nBu4NHS04; compound of General Formula (III), at the amount corresponding to 10% of compound of General Formula (la)). The reactants were mixed in 100 mL of solvent (50 % water / 50% toluene) and the mixture was heated up to 80°C before adding 1 .0 equivalent of AAG1 , AAG2, or AAG3. The mixture was then kept under reflux for 22 hours, 1 .0 equivalent of potassium carbonate and a 2nd aliquot of 1 .0 equivalent of AAG1 , AAG2, or AAG3 were added. After that the mixture was kept under reflux for further 22 hours, 1 .0 equivalent of potassium carbonate and a 3rd 1 .0 equivalent of AAG1 , AAG2, or AAG3 were added. The mixture was kept under reflux for further 22 hours, the mixture was then returned to room temperature and 50 mL of ethyl acetate were added. After decantation and washing twice with water (50 mL) and brine (50 mL), the organic layer was evaporated to dryness. The solid residue was purified by chromatography over silica gel (for Cpd. 2b, 3b, and 4b) or crystallized in 20 mL of diisopropyl ether (for Cpd. 1 b, 5b, and 6b). In the latter case after reflux for 1 hour, the mixture was cooled to 0°C with ice bath and kept at this temperature for 1 hour. Solid material was collected, washed with cold diisopropyl ether and dried under vacuum. | |
With hydrogenchloride In methanol at 20℃; for 16h; | 1.1 Step 1: Compound 1-c A solution of Compound 1-a (5.00 g, 30.08 mmol, 1.00 eq) and Compound 1-b (4.52 g, 30.08 mmol, 1.00 eq) in HCl/MeOH (4 N, 40.01 mL, 5.32 eq) was stirred at 20°C. for 16 h. The reaction mixture was concentrated under reduced pressure to give a crude product. The crude product was washed with dichloromethane/MeOH solution (1:1, 50 mL) to give Compound 1-c . MS m/z (ESI): 298.9 [M+1]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With caesium carbonate In N,N-dimethyl-formamide | 75 To a solution of 4-hydroxy-3,5-dimethyl benzaldehyde (5.0 g, 33.29 mmol) in DMF (30 mL) were added 3-bromo propan-1-ol (5.56 g, 39.95 mmol) and Cs2CO3 (16.24 g, 50.0 mmol). Then, the reaction mixture was stirred at room temperature for 48 hours. Then, water was added and the products were extracted with ethyl acetate (2*250 mL). The combined organic phase was washed with water (100 mL), then brine (100 mL), and dried over anhydrous Na2SO4. Removal of solvent gave 4-(3-hydroxypropoxy)-3,5-dimethyl benzaldehyde as a colorless liquid. Yield: 5.38 g (77%) |
77% | With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 48h; | 77 Example 77 Preparation of 2-(3,5-Dimethyl-4-(3-(pyrrolidin-1-yl)propoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one To a solution of 4-hydroxy-3,5-dimethyl benzaldehyde (5.0 g, 33.29 mmol) in DMF (30 mL) were added 3-bromo propan-1-ol (5.56 g, 39.95 mmol) and Cs2CO3 (16.24 g, 50.0 mmol). Then, the reaction mixture was stirred at room temperature for 48 hours. Then, water was added and the products were extracted with ethyl acetate (2*250 mL). The combined organic phase was washed with water (100 mL), then brine (100 mL), and dried over anhydrous Na2SO4. Removal of solvent gave 4-(3-hydroxypropoxy)-3,5-dimethyl benzaldehyde as a colorless liquid. Yield: 5.38 g (77%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5% | To a solution of 4-hydroxy-3,5-dimethylbenzaldehyde (2.65 g, 17.7 mmol) in DMF (100 mL) was added K2CO3 (3.66 g, 26.6 mmol). The mixture was stirred at room temperature under nitrogen for 30 minutes. Then, a solution of <strong>[72479-05-1](S)-5-(bromomethyl)pyrrolidin-2-one</strong> (3.15 g, 17.7 mmol) in DMF (100 mL) was added, and the mixture heated at reflux for 16 hours. The mixture was then concentrated, ethyl acetate (250 mL) added, and the organic phase washed sequentially with water (2*150 mL), and brine (200 mL), dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with 100% ethyl acetate to 10% MeOH/ethyl acetate, followed by a second chromatography, eluting with 1:1 CH2Cl2/92:71 CHCl3/MeOH/concentrated NH4OH to 100% 92:7:1 CHCl3/MeOH/concentrated NH4OH, to afford (S)-3,5-dimethyl-4-((5-oxopyrrolidin-2-yl)methoxy)benzaldehyde as a white solid (0.200 g, 5%) | |
5% | To a solution of 4-hydroxy-3,5-dimethylbenzaldehyde (2.65 g, 17.7 mmol) in DMF (100 mL) was added K2CO3 (3.66 g, 26.6 mmol). The mixture was stirred at room temperature under nitrogen for 30 minutes. Then, a solution of <strong>[72479-05-1](S)-5-(bromomethyl)pyrrolidin-2-one</strong> (3.15 g, 17.7 mmol) in DMF (100 mL) was added, and the mixture heated at reflux for 16 hours. The mixture was then concentrated, ethyl acetate (250 mL) added, and the organic phase washed sequentially with water (2*150 mL), and brine (200 mL), dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with 100% ethyl acetate to 10% MeOH/ethyl acetate, followed by a second chromatography, eluting with 1:1 CH2Cl2/92:7:1 CHCl3/MeOH/concentrated NH4OH to 100% 92:7:1 CHCl3/MeOH/concentrated NH4OH, to afford (S)-3,5-dimethyl-4-((5-oxopyrrolidin-2-yl)methoxy)benzaldehyde as a white solid (0.200 g, 5%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19% | With toluene-4-sulfonic acid; sodium hydrogensulfite; In N,N-dimethyl acetamide; at 155℃; for 16h; | To a round-bottomed flask were added <strong>[16313-65-8]2-amino-5-nitro-benzamide</strong> (0.681 g, 3.76 mmol), 4-hydroxy-3,5-dimethyl-benzaldehyde (0.565 g, 3.76 mmol), sodium bisulfite (0.747 g, 4.2 mmol), p-toluenesulfonic acid, monohydrate (0.072 g, 0.376 mmol) and N,N-dimethylacetamide (60 mL). The reaction mixture was refluxed at 155 C. for 16 h before being cooled to room temperature. Water was added and the precipitated solid was filtered off, washed with water and methanol to obtain a crude which was purified by column chromatography (silica gel (50 g) employing 1-20% methanol in dichloromethane as eluents, to obtain 2-(4-hydroxy-3,5-dimethyl-phenyl)-6-nitro-3H-quinazolin-4-one (0.220 g, 19%). The compound 2-(4-hydroxy-3,5-dimethyl-phenyl)-6-nitro-3H-quinazolin-4-one (0.220 g, 0.71 mmol) was hydrogenated in dimethyl formamide (20 mL) using palladium on activated carbon (0.076 g, 0.071 mmol) at room temperature for 14 h. The solvent was evaporated and the crude was purified by column chromatography (silica gel 25 g) employing 1-5% methanol in dichloromethane as eluents to obtain 6-amino-2-(4-hydroxy-3,5-dimethyl-phenyl)-3H-quinazolin-4-one (0.132 g). The compound 6-amino-2-(4-hydroxy-3,5-dimethyl-phenyl)-3H-quinazolin-4-one was dissolved in pyridine under nitrogen. Acetic anhydride was added at room temperature and stirred for 4 h. Pyridine was removed and the residue was dried. Methanol was added to the flask and a solution of potassium carbonate in water was added and stirred for 4 h. The solvent was removed, acidified with 1 N hydrochloric acid and the precipitated solid was filtered off and dried to obtain N-(2-(4-hydroxy-3,5-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)acetamide (0.037 g, 17%). Selected data: MS (ES) m/z: 324.1; MP 336.5 C. (decomposed). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | Stage #1: 2.6-dimethylphenol With aluminum (III) chloride In dichloromethane at 20℃; for 0.166667h; Inert atmosphere; Stage #2: Dichloromethyl methyl ether In dichloromethane at 20℃; for 0.166667h; Inert atmosphere; | General Procedure for Formylation General procedure: Aluminium trichloride (4.82 g, 36 mmol) was added to asolution of phenol (33 mmol) in anhydrous CH2Cl2 (50 mL)under argon, and the solution was stirred for 10 min.Dichloromethyl methyl ether (3.3 mL, 36 mmol) was addeddropwise via a syringe pump (7.7 mL/h). The reaction wasleft to stir for a further 10 min before cold H2O (200 mL) wasadded slowly. After stirring for a further 10 min, the organiclayer was separated and washed with brine (100 mL) andH2O (150 mL), dried over MgSO4, filtered, and concentratedto give the aldehyde which was purified by columnchromatography. |
Stage #1: 2.6-dimethylphenol With aluminum (III) chloride In dichloromethane at 0℃; for 0.166667h; Inert atmosphere; Stage #2: Dichloromethyl methyl ether In dichloromethane for 0.5h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With pyridine; In methanol; at 100℃; for 0.5h;Microwave irradiation; | General procedure: A suspension of indolinone (0.3mmol), aldehyde (0.3mmol) and pyridine (30muL) in methanol (1mL) were heated under microwave irradiation at 100 C for 30 minutes. The reaction mixture was cooled to room temperature and the resulting precipitate was removed by filtration, carefully washed with methanol and dried in vacuo. When no precipitate was observed methanol was removed under vacuum and the residue was purified by silica gel chromatography to give the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With dmap; triethylamine In dichloromethane at 20℃; | |
60% | With 1H-imidazole In dichloromethane at 0 - 20℃; for 4.5h; | 109.1 Step 1. Synthesis of 4-(tert-butyl-dimethyl-silanyloxy)-3,5-dimethyl-benzaldehyde Step 1. Synthesis of 4-(tert-butyl-dimethyl-silanyloxy)-3,5-dimethyl-benzaldehyde To a solution of 3,5-dimethyl-4-hydroxybenzaldehyde (600 mg, 4.00 mmol) and TBDMSCl (900 mg, 6.00 mmol) in 10 mL of CH2Cl2 was added imidazole (544 mg, 8.00 mmol) in one portion at 0° C. The reaction mixture was stirred at room temperature for 4.5 h then partitioned between CH2Cl2 (50 mL) and H2O (20 mL). The organic layer was dried over MgSO4 then concentrated to give a crude product. The crude product was purified by flash chromatography (ethyl acetate:hexane=1:8) to give the desired product as a colorless viscous liquid (600 mg, 60%). 1H NMR (CDCl3, 300 MHz) δ 9.83 (s, 1H), 7.53 (s, 2H), 2.27 (s, 6H), 1.03 (s, 9H), 0.23 (s, 6H). |
With triethylamine In dichloromethane at 0 - 20℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | Stage #1: 4-hydroxy-3,5-dimethylbenzaldehyde With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 0.25h; Stage #2: 2,4-dichlorothieno[3,2-d]pyrimidine In N,N-dimethyl-formamide at 20℃; for 1h; | 3 Example 3: preparation of (E) -3- (4 - ((2-chlorothieno [3,2-d] pyrimidin-4-yl) oxy) -3,5-dimethylphenyl) acrylonitrile 4-hydroxy-3,5-dimethylbenzaldehyde (4.02 g, 26.7 mmol) and potassium carbonate (5.04 g, 36.6 mmol) were weighed(5.0 g, 24.4 mmol) was added to a solution of 150 mL of N, N-dimethylformamide (DMF) at room temperature for 15 minutes and then 2,4-dichlorothieno [3,2-d] pyrimidineContinue stirring at room temperature for 1 h (TLC detection reaction finished). At this time a large amount of white solid was formed, slowly adding 250 mL of ice water thereto, filtering, drying in a vacuum oven and then recrystallizing in chloroform to give the compound 4 - ((2-chlorothieno [3, 2-d] pyrimidin-4-yl) oxy) -3,5-dimethylbenzyl 14, 95.0% yield |
95% | Stage #1: 4-hydroxy-3,5-dimethylbenzaldehyde With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 0.25h; Stage #2: 2,4-dichlorothieno[3,2-d]pyrimidine In N,N-dimethyl-formamide at 20℃; for 1h; | 3 Weighing 4-hydroxy-3,5-dimethylbenzaldehyde (4.02 g, 26.7 mmol) and potassium carbonate (5.04 g, 36.6 mmol) in 150 mL of N,N-dimethylformamide (DMF), Stir at room temperature for 15 minutes.Then, 2,4-dichlorothieno[3,2-d]pyrimidine (5.0 g, 24.4 mmol) was added and the mixture was stirred at room temperature for 1 h (TLC detection reaction was completed).At this time, a large amount of white solid was formed, and 250 mL of ice water was slowly added thereto, filtered, and dried in a vacuum drying oven.It is then recrystallized from chloroform to give the compound 4-((2-chlorothieno[3,2-d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzaldehyde 14 as a white solid.Yield 95.0%, |
91.3% | Stage #1: 2,4-dichlorothieno[3,2-d]pyrimidine With potassium carbonate In N,N-dimethyl-formamide at 25℃; for 0.25h; Stage #2: 4-hydroxy-3,5-dimethylbenzaldehyde In N,N-dimethyl-formamide for 1.5h; |
90% | Stage #1: 4-hydroxy-3,5-dimethylbenzaldehyde With potassium carbonate In N,N-dimethyl-formamide at 25℃; for 0.25h; Stage #2: 2,4-dichlorothieno[3,2-d]pyrimidine In N,N-dimethyl-formamide at 25℃; for 1.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.7% | 4-hydroxy-3,5-dimethylbenzaldehyde (4.02 g, 26.7 mmol) and potassium carbonate (5.04 g, 36.6 mmol) were weighed150 mL of N, N-dimethylformamide (DMF), stirred at room temperature for 15 minutes, and then 2,4-dichlorothieno [2,3-d] pyrimidine (5.0 g, 24.4 mmol) was added and the mixture was stirred at room temperature 1h (TLC detection reaction finished). At this time a large amount of white solid was formed, and 250 mL of ice water was slowly added thereto, filtered, dried in a vacuum oven and then recrystallized from chloroform to give the title compound as a white solid4 - ((2-chlorothieno [2,3-d] pyrimidin-4-yl) oxy) -3,5-dimethylbenzaldehyde 14. Yield92.7percent. | |
92.7% | Weighing 4-hydroxy-3,5-dimethylbenzaldehyde (4.02 g, 26.7 mmol) and potassium carbonate (5.04 g, 36.6 mmol) in 150 mL of N,N-dimethylformamide (DMF), Stir at room temperature for 15 minutes.Then, <strong>[18740-39-1]2,4-dichlorothieno[2,3-d]pyrimidine</strong> (5.0 g, 24.4 mmol) was added and the mixture was stirred at room temperature for 1 h (TLC detection reaction was completed).At this time, a large amount of white solid was formed, and 250 mL of ice water was slowly added thereto, filtered, and dried in a vacuum drying oven.It is then recrystallized from chloroform to give the compound 4-((2-chlorothieno[2,3-d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzaldehyde 14 as a white solid.The yield was 92.7percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With potassium carbonate In acetonitrile at 80℃; for 24h; | ethyl 4-(4-formyl-2,6-dimethylphenoxy)butanoate (14aa) General procedure: 4-hydroxy-3,5-dimethylbenzaldehyde(13a)(1.5 g, 10 mmol) and ethyl4-bromobutanoate (1.95g, 10mmol) were dissolved in acetonitrile (100 mL) andtreated with K2CO3 (5.52g, 40mmol). The reaction mixturewas stirred at 80 °C for 24 h.Water was added to thereaction,and the aqueouslayer was extracted with EA (3 × 20 mL). The organic layers were combined,washed with water (3 × 25 mL),dried over anhydrous Na2SO4,and concentrated in vacuo to give compound 14aa(1.87g,71%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With potassium carbonate In acetonitrile at 80℃; for 24h; | ethyl 4-(4-formyl-2,6-dimethylphenoxy)butanoate (14aa) 4-hydroxy-3,5-dimethylbenzaldehyde(13a)(1.5 g, 10 mmol) and ethyl4-bromobutanoate (1.95g, 10mmol) were dissolved in acetonitrile (100 mL) andtreated with K2CO3 (5.52g, 40mmol). The reaction mixturewas stirred at 80 °C for 24 h.Water was added to thereaction,and the aqueouslayer was extracted with EA (3 × 20 mL). The organic layers were combined,washed with water (3 × 25 mL),dried over anhydrous Na2SO4,and concentrated in vacuo to give compound 14aa(1.87g,71%). |
With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 80℃; for 4h; | 4.2.1 Synthesis of intermediate 3 To a solution of 4-hydroxy-3,5-dimethylbenzaldehyde (1) (25mmol) in DMF (60mL), K2CO3 (50mmol) and catalytic amount potassium iodide were added, and the resulting mixture was allowed to warm up for 4h at 80°C. Upon the starting material was consumed completely, the hot reaction suspension was poured into 50mL water, extracted with dichloromethane (3×50mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate and brine, and then dried over anhydrous sodium sulfate. After removing the solvent under reduced pressure to give the crude oil. The crude oil was purified by silica sel flash chromatography (dichloromethane/methanol 50:1) as a colorless oil, yield 82-93% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With potassium carbonate; In acetonitrile; at 80℃; for 24h; | General procedure: 4-hydroxy-3,5-dimethylbenzaldehyde(13a)(1.5 g, 10 mmol) and ethyl4-bromobutanoate (1.95g, 10mmol) were dissolved in acetonitrile (100 mL) andtreated with K2CO3 (5.52g, 40mmol). The reaction mixturewas stirred at 80 C for 24 h.Water was added to thereaction,and the aqueouslayer was extracted with EA (3 × 20 mL). The organic layers were combined,washed with water (3 × 25 mL),dried over anhydrous Na2SO4,and concentrated in vacuo to give compound 14aa(1.87g,71%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With potassium carbonate In acetonitrile at 80℃; for 24h; | ethyl 4-(4-formyl-2,6-dimethylphenoxy)butanoate (14aa) General procedure: 4-hydroxy-3,5-dimethylbenzaldehyde(13a)(1.5 g, 10 mmol) and ethyl4-bromobutanoate (1.95g, 10mmol) were dissolved in acetonitrile (100 mL) andtreated with K2CO3 (5.52g, 40mmol). The reaction mixturewas stirred at 80 °C for 24 h.Water was added to thereaction,and the aqueouslayer was extracted with EA (3 × 20 mL). The organic layers were combined,washed with water (3 × 25 mL),dried over anhydrous Na2SO4,and concentrated in vacuo to give compound 14aa(1.87g,71%). |
With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 80℃; for 4h; | 4.2.1 Synthesis of intermediate 3 To a solution of 4-hydroxy-3,5-dimethylbenzaldehyde (1) (25mmol) in DMF (60mL), K2CO3 (50mmol) and catalytic amount potassium iodide were added, and the resulting mixture was allowed to warm up for 4h at 80°C. Upon the starting material was consumed completely, the hot reaction suspension was poured into 50mL water, extracted with dichloromethane (3×50mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate and brine, and then dried over anhydrous sodium sulfate. After removing the solvent under reduced pressure to give the crude oil. The crude oil was purified by silica sel flash chromatography (dichloromethane/methanol 50:1) as a colorless oil, yield 82-93% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.9% | With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 100℃; for 12h; | In a 250 mL single-necked flask, Intermediate 1 (5.5 g, 16 mmol) was added successively,3,5-dimethyl-4-hydroxybenzaldehyde (2.1 g, 14 mmol), potassium iodide (83 mg, 0.5 mmol)Anhydrous potassium carbonate (4.4 g, 32 mmol) and 150 mL of N, N-dimethylformamide were allowed to react at 100 ° C for 12 h,TLC did not detect 3,5-dimethyl-4-hydroxybenzaldehyde, washed with water and extracted with ethyl acetate,Dried over anhydrous sodium sulfate, filtered, evaporated to dryness to remove the solvent,Compound 8 (4.5 g) was obtained by silica gel column chromatography using ethyl acetate / petroleum ether (1: 1) as developing solvent. Colorless mucous product. Yield 94.9% |
With potassium carbonate In N,N-dimethyl-formamide | ||
With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 100℃; for 12h; |
With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 100℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Three 2000 mL glass reactors equipped with a stirring device were charged with 1 mol hexachlorocyclotriphosphazene and 200 mL acetone,p-Toluenethiol4mol,While stirring, nitrogen is passed through, heated to 60C, and 20% sodium hydroxide solution is added dropwise to the pH neutrality for 60 minutes. The temperature is maintained at 60C, the reaction is stirred for 4 hours, and then 2 mol is added.3,5-Dimethyl-4-hydroxybenzaldehyde,The reaction was continued for 4 hours, followed by the addition of 4 mol of <strong>[119138-29-3]4-hydroxymethyl-3-methoxyphenol</strong>, and the reaction was continued for 4 hours. After the reaction, the inorganic components and water in the system were physically removed, the solvent in the system was distilled off, and the structure was precipitated with methanol to obtain a structure. Phosphazenes as shown below: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With potassium carbonate In ethanol at 85℃; for 12h; | 3.1 Example 3 (1) At room temperature,Combine potassium carbonate (2mol) with 3,5-dimethyl-4-hydroxybenzaldehyde (1mol),Dissolved in ethanol (58mol), after adding 3-bromo-1-propene (3mol),Adjust the temperature to 85°C, and after a period of reaction (12h),The reaction was complete as monitored by TLC.The reaction was quenched with deionized water; extracted at least three times with ethyl acetate,The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure,Use petroleum ether and ethyl acetate (V/V) mixed solvent volume ratio to be 8:1 as mobile phase, carry out column chromatography,Product 1 was obtained, yield: 90%. |
With potassium carbonate In propan-2-one at 70℃; for 5h; | Synthesis of 4-(Allyloxy)-3,5-dimethylbenzaldehyde (ZL0463). To a soluton of 4- hydroxy-3,5-dimethylbenzaldehyde (1.5 g, 10 mmol) and K2CO3 (2.07g, 15 mmol) in 40 mL acetone, 3-bromoprop-l-ene (1.21 g, 10 mmol) was added. After stirring at 70 °C for 5 h, the mixture was poured into H2O and extracted by EA. The organic extract was washed with saturated NaHCCb (aq), brine and dried over anhydrous Na2S04. The resulting solution was evaporated, and the residue was put into next step directly. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With potassium carbonate; In methanol; at 79℃; for 8.0h; | 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 80%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With sulfuric acid In ethanol at 20℃; for 5h; | 20.20c Step 20c: Preparation of ((E)-3-(4-hydroxy-3,5-dimethylphenyl)-1-(4-(methylthio)benzofuran-2-yl)prop-2-en-1-one) (Compound 0904-60): To 1-(4-(methylthio)benzofuran-2-yl)ethan-1-one (0903-60) (148 mg, 0.718 mmol, 1.0 eq.)And 4-hydroxy-3,5-dimethylbenzaldehyde (108 mg, 0.718 mmol, 1.0 eq.)Concentrated sulfuric acid (2 mL) was slowly added dropwise to the ethanol solution (8 ml), and the mixture was reacted at room temperature for 5 hours.The reaction solution was diluted with water (30 mL) and then extracted with ethyl acetate (30mL×3).The extract was dried over anhydrous sodium sulfate.Concentrated to give a yellow solid(E)-3-(4-hydroxy-3,5-dimethylphenyl)-1-(4-(methylthio)benzofuran-2-yl)prop-2-en-1-one(217 mg, yield: 89%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With sulfuric acid In ethanol at 20℃; for 15h; | 27.27b Step 27b: Preparation of ((E)-1-(3-ethyl-6-(methylthio)benzofuran-2-yl)-3-(4-hydroxy-3,5-dimethylphenyl)prop-2-en-1-one) (Compound 1004-63): 1-(3-ethyl-6-(methylthio)benzofuran-2-yl)ethan-1-one(1003-63) (0.7 g, 2.98 mol, 1.0 equivalent)Soluble in absolute ethanol (10ml),Additional 4-hydroxy-3,5-dimethylbenzaldehyde (0.447 g, 2.98 mmol, 1.0 eq.) was added.Concentrated sulfuric acid (2 ml) was added thereto under stirring at room temperature for 15 hours.After completion of the reaction, it was diluted with ethyl acetate (50 ml), and washed with a half-saturated brine (50 ml × 3).The organic phase was dried over anhydrous sodium sulfate and concentrated.Purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1)Obtaining a yellow solid product(E)-1-(3-ethyl-6-(methylthio)benzofuran-2-yl)-3-(4-hydroxy-3,5-dimethylphenyl)prop-2-ene 1-ketone(0.95 g, yield: 87%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With sulfuric acid In ethanol at 20℃; for 15h; | 28.28b Step 28b: Preparation of ((E)-3-(4-hydroxy-3,5-dimethylphenyl)-1-(3-isopropyl-6-(methylthio)benzofuran-2-yl)prop-2-en-1-one) (Compound 1004-64): 1-(3-isopropyl-6-(methylthio)benzofuran-2-yl)ethan-1-one(1003-64) (0.71 g, 2.86 mol, 1.0 eq.) was dissolved in anhydrous ethanol (20 mL).Additional 4-hydroxy-3,5-dimethylbenzaldehyde (0.472 g, 3.146 mmol, 1.1 eq.) was added.Concentrated sulfuric acid (3 ml) was added to the reaction under stirring at room temperature for 15 hours.After the reaction was completed, it was diluted with ethyl acetate (50 ml).Washed with half-saturated saline (50ml × 3),The organic phase was dried over anhydrous sodium sulfate and concentrated.Purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1)Obtaining a yellow solid product(E)-3-(4-Hydroxy-3,5-dimethylphenyl)-1-(3-isopropyl-6-(methylthio)benzofuran-2-yl)propan-2- En-1-one(0.95 g, yield: 87%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With sulfuric acid In ethanol at 20℃; | 29.29b Step 29b: Preparation of ((E)-3-(4-hydroxy-3,5-dimethylphenyl)-1-(6-(methylthio)-3-(trifluoromethyl)benzofuran-2-yl)prop-2-en-1-one)(1004-73). To a solution of concentrated sulfuric acid (2 ml) in ethanol (10 ml) was added 1-(6-(methylthio)-3-(trifluoromethyl)benzofuran-2-yl)ethan-1-one slowly.(1003-73 (0.274 g, 1.0 mmol, 1.0 eq.)And 4-hydroxy-3,5-dimethylbenzaldehyde (0.151 g, 1.0 mmol, 1.0 eq),Stir at room temperature overnight.The reaction solution was filtered, and ethyl acetate (2 ml×2) and water(20ml × 2) washing,Vacuum drying to give a yellow solid product(E)-3-(4-hydroxy-3,5-dimethylphenyl)-1-(6-(methylthio)-3-(trifluoromethyl)benzofuran-2-yl)propane -2-en-1-one(0.35 g, yield: 86%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With sulfuric acid In 1,4-dioxane at 20℃; for 72h; | 7.7e Step 7e: Preparation of ((E)-3-(4-hydroxy-3,5-dimethylphenyl)-1-(2-methyl-4-(methylthio)benzofuran-7-yl)prop-2-en-1-one) (Compound 0205-14): To 1-(2-methyl-4-(methylthio)benzofuran-7-yl)ethan-1-one (0204-14)(0.44g, 2.0mmol, 1.0 equivalents)And 4-hydroxy-3,5-dimethylbenzaldehyde (0.33 g, 2.2 mmol, 1.1 equivalents)Concentrated sulfuric acid (2 ml) was slowly added to the dioxane solution (10 ml).The reaction was stirred at room temperature for 3 days.The reaction mixture was diluted with ethyl acetate (150 ml) and washed with brineThe organic phase is dried,The residue was purified by silica gel column chromatography(eluent: 100% dichloromethane)Obtaining a yellow solid product(E)-3-(4-hydroxy-3,5-dimethylphenyl)1-(2-methyl-4-(methylthio)benzofuran-7-yl)prop-2-en-1-one (0.74 g, yield: 100%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With potassium carbonate In acetonitrile at 20℃; Reflux; | Methyl 2-(4-formyl-2,6-dimethylphenoxy)-2-methylpropanoate(4a). To a solution of 4-hydroxy-3,5-dimethylbenzaldehyde (1.0 g, 6.7mmol) and methyl 2-bromo-2-methylpropanoate (7.23 g, 39.95 mmol)in acetonitrile (50 ml) was added K2CO3 (9.2 g, 66.59 mmol) at roomtemperature. The reaction mixture was heated to refilux with stirring for8 h. Then the reaction mixture was cooled to room temperature followedby filtration and the filtrate was concentrated under vacuum. The residuewas purified by silica gel column chromatography using a mixtureof petroleum ether/ethyl acetate (1:20, v/v) as eluent to afford Methyl 2-(4-formyl-2,6-dimethylphenoxy)-2-methylpropanoate (1.34 g, 80%)as ayellow oil. |
With potassium carbonate In acetonitrile for 6h; Reflux; | A Preparation of methyl 2-(4-formyl-2,6-dimethylphenoxy)-2-methylpropanoate according to WO2004/005233 4-hydroxy-3,5-dimethylbenzaldehyde (150 mg; 1.0 mmol) was dissolved in acetonitrile (5 mL), potassium carbonate (691 mg; 5.0 mmol; 5 equiv.) and a solution of methyl 2-bromo-2-methylpropanoate (543 mg; 3.0 mmol; 3 equiv.) in acetonitrile (5 mL) were added. The reaction mixture was briskly stirred under reflux for 3 hrs, then the second portion of methyl 2-bromo-2-methylpropanoate (543 mg; 3.0 mmol; 3 equiv.) was added and the reaction mixture was stirred for additional 3 hrs. LC-MS analysis showed almost complete conversion to methyl 2-(4-formyl-2,6- dimethylphenoxy)-2-methylpropanoate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With hydrogenchloride In 1,4-dioxane for 30h; | 1.1 Step 1: 1-[4-methylthiophenyl]-(E)-3-[3,5-dimethyl-4-hydroxyphenyl]prop-2-en-1-one (Intermediate 1) Step 1: 1-[4-methylthiophenyl]-(E)-3-[3,5-dimethyl-4-hydroxyphenyl]prop-2-en-1-one (Intermediate 1) 4-methylacetophenone (20 g, 0.12 mol, 1 eq) and 3,5-dimethyl-4-hydroxybenzaldehyde (18 g, 0.12 mol, 1 eq) are solubilised in 300 ml of 4N HCl in dioxane. The reaction medium is stirred for 30 hours and then the solvents are evaporated. Purification by hot recrystallisation in 70 ml of isopropanol and 12 ml of water: 30 g (yellow solid, yield: 92%). Raw formula: C18H18O2S ESI-MS m/z=299.18 [M+H]+ 1H NMR DMSO-d6 δ ppm: 2.18 (s, 6H), 2.53 (s, 3H), 7.36 (d, J=8.5 Hz, 2H), 7.47 (s, 2H), 7.57 (d, J=15.5 Hz, 1H), 7.69 (d, J=15.5 Hz, 1H), 8.05 (d, J=8.5 Hz, 2H), 8.93 (s, 1 H) |
92% | With hydrogenchloride In ethanol; water at 20℃; | 1 Example 1: (E)-2,6-Dimethyl-4-(3-(4-(methylthio)phenyl)-3-oxoprop-1-en-1-yl)phenol (compound II) Preparation Add 4-methylthioacetophenone (83g), 3,5-dimethyl-4-hydroxybenzaldehyde (75g) and ethanol (100mL) into the reaction flask, and add 10M hydrogen chloride in ethanol (100mL) to it After stirring at room temperature overnight, the temperature was lowered to 0°C and the stirring was continued for 5 hours. After filtration and drying, 137 g of compound II was obtained with a yield of 92%. |
81.81% | With hydrogenchloride In ethanol at -5℃; for 12h; | 1-5; 1 Example 1 To a 500 ml three-necked flask was added 200 ml of a saturated solution of hydrogen chloride in ethanol, 3,5-dimethyl-4-hydroxybenzaldehyde (5 g, 33.33 mmol), 4-methylthioacetophenone (5.54 g, 33.33 mmol). After stirring at -5 ° C for 12 hours, the reaction was completed by TLC, and the reaction was stopped. After suction filtration, 8.14 g of a yellow powdery solid was obtained; mp: 148 to 149 ° C, yield 81.81%. |
77% | With hydrogenchloride In methanol at 20℃; for 24h; Inert atmosphere; | 4.1.4 General produce C for the preparation of 17, 19-32, 35-40 General procedure: To a solution of 4 M HCl in methanol were added 1a or 1d-l (1.0 equiv.) and 2b or 2e-o (1.0 equiv.). The solution was stirred at room temperature for 24 h. The forming precipitate was filtered and dried to obtain target compounds. |
106 g | With hydrogenchloride In ethanol | 1 Example- 1: Preparation of (E)-3-(4-hydroxy-3, 5-dimethylphenyl)-l-(4-(methylthio)phenyl)prop-2-en-l-one To a saturated ethanolic HC1 solution, 3, 5-dimethyl-4-hydroxy benzaldehyde (58.0 g, 0.386 mol] and 4-methylthiolacetophenone (70.6 g, 0.42 mol] were added. The reaction mixture was stirred till starting material disappears on thin layer chromatography (TLC] Thereafter the reaction mixture was concentrated under reduced pressure, diluted with methanol (200 mL], stirred and then filtered. The wet solid obtained was dried under vacuum to give (E]-3-(4-hydroxy-3, 5- dimethylphenyl]-l-(4-(methylthio] phenyl]prop-2-en-l-one (106.0 g] |
16 g | With hydrogenchloride In isopropyl alcohol at 0 - 30℃; for 24h; | 1 Example 1: Preparation of (2E)-3-(4-hydroxy-3,5-dimethylphenyl)-l-[4-(methylsulfanyl)phenyl]prop-2-en-l-one (IV) A solution of 4'-(methylthio)acetophenone (lO.Og, 0.06mol) and 4-hydroxy-3,5- dimethylbenzaldehyde (9.0 g, 0.06mol) in saturated hydrogen chloride isopropanol (lOOml) was stirred at about 0°C to about 5°C for about 6h; then raised the temperature to about 20°C to about 30°C and stirred for about l8h. After completion of the reaction, water was added to the reaction mass and stirred for about 2h to about 3h. The precipitated solid was filtered and recrystallized from isopropanol to afford (2E)-3-(4-hydroxy-3,5-dimethylphenyl)-l-[4- (methylsulfanyl)phenyl]prop-2-en-l-one as a yellow solid (compound IV; l6.0g) m/z = 299 (M+l) NMR CDCh d ppm: 2.30 (6H), 2.55 (3H), 7.31 (4H), 7.4 (1H), 7.75 (1H), 7.97 (2H). |
With sulfuric acid In methanol at 20℃; for 16h; | 4.1.3. General synthetic procedure for intermediates 3d-f General procedure: 2d (1 equiv) and 3-Fluoro-4-hydroxybenzaldehyde (3-Chloro-4-hydroxybenzaldehydeor 4-Hydroxy-3-methylbenzaldehyde) (1 equiv)were dissolved in MeOH, and H2SO4 (0.05 equiv) was added dropwiseto the mixture. The mixture was stirred at room temperature for 16 h.The solution was concentrated to give the crude product. Water (20 mL)was added to the crude product and extracted with ethyl acetate(3 × 10 mL). After the solvent was concentrated under reduced pressure,it was purified by column chromatography to afford to 3d (3e or3f). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With potassium carbonate; potassium iodide In ethyl acetate at 70℃; for 5h; | General procedure for the synthesis of 6, 7, 8, 9, 16, 17, 18, and 25 General procedure: A suspension of 5, 15 or 28 (6.55mmol) and the corresponding benzaldehydes (6.55mmol) including potassium carbonate (13.10mmol), and potassium iodide (7.86mmol) was heated at 70°C for 5h. The solvent was evaporated, the residue was dissolved in ethyl acetate (50mL), washed with saturated aqueous NaHCO3 solution (2×20mL), water (2×20mL), and brine (2×10mL), dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by flash column chromatography using ethyl acetate/ petroleum ether as an eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With hydrogenchloride; In methanol; at 20 - 30℃; for 3h; | The compound 3570mg (3 · 82mmol), 3,5-dimethyl-4-hydroxybenzaldehyde 574mg (3 · 82mmol) was added to OmL hydrogen chloride methanol solution (4mo 1 / L), stirred at 20~30 C for 3h, The temperature was lowered to 0 C, and the solid was precipitated, filtered and dried to give compound 4 963mg, yield 90%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With hydrogenchloride In methanol; water at 20 - 30℃; for 3h; | Add 120 mg (0.56 mmol) of compound 4 and 85 mg (0.56 mmol) of 3,5-dimethyl-4-hydroxybenzaldehyde to 2 mL of a hydrogen chloride methanol solution (4 mol / L).Stir at 20 30 °C for 3 hours, reduce the temperature to 0 ,The precipitated solid was filtered and dried to give compound 5 176mg, yield 90% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With potassium carbonate In N,N-dimethyl-formamide at 120℃; for 5h; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With piperidine In toluene at 80℃; for 2h; Schlenk technique; Molecular sieve; Inert atmosphere; | Standard procedure D: formation of HTIs via piperidine catalysed aldol condensations General procedure: An oven dried Schlenk flask was charged with the thioindoxyl (1.00 equiv), the aldehyde (equivalents are given individually) and molecular sieves (4 Å) under an atmosphere of nitrogen. Dry benzene or toluene and piperidine (few drops) were added and the solution was heated to 80 °C for the time indicated individually. After cooling to room temperature, a saturated aqueous solution of NH4Cl was added, the phases were separated and the aqueous layer was extracted with DCM. The combined organic extracts were dried over Na2SO4 and evaporated. Purification was accomplished as stated to yield the hemithioindigo. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid; In methanol; at 20℃; for 16h; | General procedure: 2a-c (or 4a) (1 equiv) and 4-hydroxy-3,5-dimethylbenzaldehyde (or4-hydroxybenzaldehyde) (1 equiv) were dissolved in MeOH, and H2SO4(0.05 equiv) was added dropwise to the mixture. The mixture wasstirred at room temperature for 16 h. The solution was concentrated togive the crude product. Water (20 mL) was added to the crude productand extracted with ethyl acetate (3 × 10 mL). After the solvent wasconcentrated under reduced pressure, it was purified by column chromatographyto afford to 3a-c (or 5a). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid In methanol at 20℃; for 16h; | 4.1.2. General synthetic procedure for intermediates 3a-c and 5a General procedure: 2a-c (or 4a) (1 equiv) and 4-hydroxy-3,5-dimethylbenzaldehyde (or4-hydroxybenzaldehyde) (1 equiv) were dissolved in MeOH, and H2SO4(0.05 equiv) was added dropwise to the mixture. The mixture wasstirred at room temperature for 16 h. The solution was concentrated togive the crude product. Water (20 mL) was added to the crude productand extracted with ethyl acetate (3 × 10 mL). After the solvent wasconcentrated under reduced pressure, it was purified by column chromatographyto afford to 3a-c (or 5a). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With ammonium acetate In methanol at 20℃; | 3.2.2. General Synthetic Procedure for 2-(3,5-dialkyl-4-hydroxyphenyl)-4-aryl-1-hydroxy-4,4-dimethyl-2,5-dihydro-1H-imidazoles 20a-s. General procedure: Ammonium acetate (2.78 g, 36 mmol) and corresponding 3,5-dialkyl-4-hydroxybenzaldehyde 23(6.2 mmol) were successively added to a solution of 2-hydroxylamino ketone 25a-c [58] as hydrochlorideor its free base 25d [59] (6 mmol) in methanol (5 mL) (or in absolute EtOH in the case of the synthesisof 20p-s). The reaction mixture was diluted with 5 mL of the corresponding alcohol and stirred for6-12 h until the full conversion of 2-hydroxylamino ketone (TLC control). The resultant suspensionwas kept for 12 h at 20 C and 3 h at 0 C; the formed precipitate was filtered o; washed with coldalcohol (2 4 mL), water (10 mL), and again cold alcohol (3 mL); and air dried at rt. In the case of 20r,a combined alcohol filtrate was evaporated; the residue was mixed with 25 mL of water and kept for48 h at 0 C. The formed precipitate was filtered o and air dried at rt, thereby giving an additionalamount of 20r. To obtain 20q from the reaction mixture, the solution was evaporated, and the residuewas mixed with water (40 mL) and incubated for 24 h at 0 C. The formed precipitate was filtered o,washed with water, and air dried until constant weight. To prepare an analytical sample, the driedprecipitate was washed thoroughly with 20 mL of CHCl3 to remove traces of starting benzaldehydeand 4H-imidazole 3-oxide and dried finally at 80 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With ammonium acetate In methanol at 20℃; | 3.2.2. General Synthetic Procedure for 2-(3,5-dialkyl-4-hydroxyphenyl)-4-aryl-1-hydroxy-4,4-dimethyl-2,5-dihydro-1H-imidazoles 20a-s. General procedure: Ammonium acetate (2.78 g, 36 mmol) and corresponding 3,5-dialkyl-4-hydroxybenzaldehyde 23(6.2 mmol) were successively added to a solution of 2-hydroxylamino ketone 25a-c [58] as hydrochlorideor its free base 25d [59] (6 mmol) in methanol (5 mL) (or in absolute EtOH in the case of the synthesisof 20p-s). The reaction mixture was diluted with 5 mL of the corresponding alcohol and stirred for6-12 h until the full conversion of 2-hydroxylamino ketone (TLC control). The resultant suspensionwas kept for 12 h at 20 C and 3 h at 0 C; the formed precipitate was filtered o; washed with coldalcohol (2 4 mL), water (10 mL), and again cold alcohol (3 mL); and air dried at rt. In the case of 20r,a combined alcohol filtrate was evaporated; the residue was mixed with 25 mL of water and kept for48 h at 0 C. The formed precipitate was filtered o and air dried at rt, thereby giving an additionalamount of 20r. To obtain 20q from the reaction mixture, the solution was evaporated, and the residuewas mixed with water (40 mL) and incubated for 24 h at 0 C. The formed precipitate was filtered o,washed with water, and air dried until constant weight. To prepare an analytical sample, the driedprecipitate was washed thoroughly with 20 mL of CHCl3 to remove traces of starting benzaldehydeand 4H-imidazole 3-oxide and dried finally at 80 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With ammonium acetate In methanol at 20℃; | 3.2.2. General Synthetic Procedure for 2-(3,5-dialkyl-4-hydroxyphenyl)-4-aryl-1-hydroxy-4,4-dimethyl-2,5-dihydro-1H-imidazoles 20a-s. General procedure: Ammonium acetate (2.78 g, 36 mmol) and corresponding 3,5-dialkyl-4-hydroxybenzaldehyde 23(6.2 mmol) were successively added to a solution of 2-hydroxylamino ketone 25a-c [58] as hydrochlorideor its free base 25d [59] (6 mmol) in methanol (5 mL) (or in absolute EtOH in the case of the synthesisof 20p-s). The reaction mixture was diluted with 5 mL of the corresponding alcohol and stirred for6-12 h until the full conversion of 2-hydroxylamino ketone (TLC control). The resultant suspensionwas kept for 12 h at 20 C and 3 h at 0 C; the formed precipitate was filtered o; washed with coldalcohol (2 4 mL), water (10 mL), and again cold alcohol (3 mL); and air dried at rt. In the case of 20r,a combined alcohol filtrate was evaporated; the residue was mixed with 25 mL of water and kept for48 h at 0 C. The formed precipitate was filtered o and air dried at rt, thereby giving an additionalamount of 20r. To obtain 20q from the reaction mixture, the solution was evaporated, and the residuewas mixed with water (40 mL) and incubated for 24 h at 0 C. The formed precipitate was filtered o,washed with water, and air dried until constant weight. To prepare an analytical sample, the driedprecipitate was washed thoroughly with 20 mL of CHCl3 to remove traces of starting benzaldehydeand 4H-imidazole 3-oxide and dried finally at 80 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With ammonium acetate In ethanol at 20℃; | 3.2.2. General Synthetic Procedure for 2-(3,5-dialkyl-4-hydroxyphenyl)-4-aryl-1-hydroxy-4,4-dimethyl-2,5-dihydro-1H-imidazoles 20a-s. General procedure: Ammonium acetate (2.78 g, 36 mmol) and corresponding 3,5-dialkyl-4-hydroxybenzaldehyde 23(6.2 mmol) were successively added to a solution of 2-hydroxylamino ketone 25a-c [58] as hydrochlorideor its free base 25d [59] (6 mmol) in methanol (5 mL) (or in absolute EtOH in the case of the synthesisof 20p-s). The reaction mixture was diluted with 5 mL of the corresponding alcohol and stirred for6-12 h until the full conversion of 2-hydroxylamino ketone (TLC control). The resultant suspensionwas kept for 12 h at 20 C and 3 h at 0 C; the formed precipitate was filtered o; washed with coldalcohol (2 4 mL), water (10 mL), and again cold alcohol (3 mL); and air dried at rt. In the case of 20r,a combined alcohol filtrate was evaporated; the residue was mixed with 25 mL of water and kept for48 h at 0 C. The formed precipitate was filtered o and air dried at rt, thereby giving an additionalamount of 20r. To obtain 20q from the reaction mixture, the solution was evaporated, and the residuewas mixed with water (40 mL) and incubated for 24 h at 0 C. The formed precipitate was filtered o,washed with water, and air dried until constant weight. To prepare an analytical sample, the driedprecipitate was washed thoroughly with 20 mL of CHCl3 to remove traces of starting benzaldehydeand 4H-imidazole 3-oxide and dried finally at 80 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With piperidine In methanol at 75℃; for 4h; | 4.1.2. Fluoroponytailed BM hydroiodides (3a-e and 4a-e) General procedure: 1-(1H,1H,2H,2H-Perfluorooctyl)picolinium iodide and an equimolaramount of the 4-hydroxybenzaldehyde derivative were dissolved in asuitable amount of MeOH. After addition of a catalytic amount ofpiperidine, the solution was refluxed for 4 h at 75 C. Subsequently, thesolvent was removed and the raw product purified by applying differentwashing and precipitation protocols with varying solvents. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 2h; | 1 DMPHB-C8b'bMe-bromide-2-TG-oleate (Int-181): 4-(Dimethylamino)pyridine (DMAP, 0.431 g, 2.33 mmol) and EDC•HCl (1.35 g, 4.66 mmol) were added to a solution of Int-176 (3.0 g, 2.44 mmol) and 4-hydroxy-3,5-dimethyl benzaldehyde (0.533 g, 2.33 mmol) in CH2Cl2 (30 mL), and the reaction mixture was stirred at rt for 2h. The reaction mixture was concentrated under reduced pressure to afford Int-179 (3.5 g, quantitative), which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) d 9.94(s, 1H), 7.62 (s, 2H), 5.36 (d, J = 16.8 Hz, 5H), 4.33(dd, J = 7.6, 6.0 Hz, 2H), 4.19 (dd, J = 7.8, 5.5 Hz, 2H), 2.66 (m, 1H), 2.47 (m, 2H), 2.37 (t, J = 7.2 Hz, 5H), 2.18 (s, 6H) 2.02(m, 8H) 1.63 (m, 4H), 1.31 (m, 46H), 1.10(d, J =6.9 Hz, 3H), 0.98 (d, J = 6.8 Hz, 3H), 0.92 (t, J = 6.8 Hz, 6H). |
100% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 2h; | 1 4-(Dimethylamino)pyridine (DMAP, 0.431 g, 2.33 mmol) and EDOHC1 (1.35 g, 4.66 mmol) were added to a solution of Int-176 (3.0 g, 2.44 mmol) and 4-hydroxy-3, 5 -dimethyl benzaldehyde (0.533 g, 2.33 mmol) in CH2CI2 (30 mL), and the reaction mixture was stirred at rt for 2h. The reaction mixture was concentrated under reduced pressure to afford Int-179 (3.5 g, quantitative), which was used in the next step without further purification. 'H NMR (400 MHz, CDCh) d 9.94(s, 1H), 7.62 (s, 2H), 5.36 (d, J = 16.8 Hz, 5H), 4.33(dd, J= 7.6, 6.0 Hz, 2H), 4.19 (dd, J= 7.8, 5.5 Hz, 2H), 2.66 (m, 1H), 2.47 (m, 2H), 2.37 (t, J= 7.2 Hz, 5H), 2.18 (s, 6H) 2.02(m, 8H) 1.63 (m, 4H), 1.31 (m, 46H), 1.10(d, 7=6.9 Hz, 3H), 0.98 (d, 7= 6.8 Hz, 3H), 0.92 (t, J= 6.8 Hz, 6H). |
100% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 2h; | 1 [00649] 4-(Dimethylamino)pyridine (DMAP, 0.431 g, 2.33 mmol) and EDC*HCl (1.35 g, 4.66 mmol) were added to a solution of Int-176 (3.0 g, 2.44 mmol) and 4-hydroxy-3,5-dimethyl benzaldehyde (0.533 g, 2.33 mmol) in CH2Cl2 (30 mL), and the reaction mixture was stirred at rt for 2 h. The reaction mixture was concentrated under reduced pressure to afford Int-179 (3.5 g, quantitative), which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 9.94(s, 1H), 7.62 (s, 2H), 5.36 (d, J = 16.8 Hz, 5H), 4.33(dd, J = 7.6, 6.0 Hz, 2H), 4.19 (dd, J = 7.8, 5.5 Hz, 2H), 2.66 (m, 1H), 2.47 (m, 2H), 2.37 (t, J = 7.2 Hz, 5H), 2.18 (s, 6H) 2.02(m, 8H) 1.63 (m, 4H), 1.31 (m, 46H), 1.10(d, J =6.9 Hz, 3H), 0.98 (d, J = 6.8 Hz, 3H), 0.92 (t, J = 6.8 Hz, 6H). |
100% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 2h; | 1 [00649] 4-(Dimethylamino)pyridine (DMAP, 0.431 g, 2.33 mmol) and EDC*HCl (1.35 g, 4.66 mmol) were added to a solution of Int-176 (3.0 g, 2.44 mmol) and 4-hydroxy-3,5-dimethyl benzaldehyde (0.533 g, 2.33 mmol) in CH2Cl2 (30 mL), and the reaction mixture was stirred at rt for 2 h. The reaction mixture was concentrated under reduced pressure to afford Int-179 (3.5 g, quantitative), which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 9.94(s, 1H), 7.62 (s, 2H), 5.36 (d, J = 16.8 Hz, 5H), 4.33(dd, J = 7.6, 6.0 Hz, 2H), 4.19 (dd, J = 7.8, 5.5 Hz, 2H), 2.66 (m, 1H), 2.47 (m, 2H), 2.37 (t, J = 7.2 Hz, 5H), 2.18 (s, 6H) 2.02(m, 8H) 1.63 (m, 4H), 1.31 (m, 46H), 1.10(d, J =6.9 Hz, 3H), 0.98 (d, J = 6.8 Hz, 3H), 0.92 (t, J = 6.8 Hz, 6H). |
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 2h; | [00697] 4-(Dimethylamino)pyridine (DMAP, 0.431 g, 2.33 mmol) and EDOHC1 (1.35 g, 4.66 mmol) were added to a solution of Int-176 (3.0 g, 2.44 mmol) and 4-hydroxy-3, 5 -dimethyl benzaldehyde (0.533 g, 2.33 mmol) in CH2CI2 (30 mL), and the reaction mixture was stirred at rt for 2h. The reaction mixture was concentrated under reduced pressure to afford Int-179 (3.5 g, quantitative), which was used in the next step without further purification. 'H NMR (400 MHz, CDCh) d 9.94(s, 1H), 7.62 (s, 2H), 5.36 (d, J = 16.8 Hz, 5H), 4.33(dd, J= 7.6, 6.0 Hz, 2H), 4.19 (dd, J= 7.8, 5.5 Hz, 2H), 2.66 (m, 1H), 2.47 (m, 2H), 2.37 (t, J= 7.2 Hz, 5H), 2.18 (s, 6H) 2.02(m, 8H) 1.63 (m, 4H), 1.31 (m, 46H), 1.10(d, 7=6.9 Hz, 3H), 0.98 (d, 7= 6.8 Hz, 3H), 0.92 (t, J= 6.8 Hz, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45.5% | Stage #1: 4-hydroxy-3,5-dimethylbenzaldehyde With sodium hydroxide In tetrahydrofuran Stage #2: 2-bromo-2-methylpropionic acid; 4-(Methylthio)acetophenone With sodium hydroxide In tetrahydrofuran; propan-1-ol at 50℃; for 2h; | 2 Comparative Example 2: Prepare GFT-505 with reference to WO2019025017 method 3,5-Dimethyl-4-hydroxybenzaldehyde (300mg, 2mmol) was dissolved in tetrahydrofuran (6mL), sodium hydroxide (360mg, 9mmol) was added and stirred well until a yellow-green phenol sodium salt was formed. After adding n-propanol (2mL) to the suspension, the temperature was raised to 50°C; 2-bromoisobutyric acid (1002mg, 6mmol) and 4-methylthioacetophenone (332mg, 2mmol) were dissolved in 2mL of tetrahydrofuran. The mixed solution was slowly dropped into the above sodium salt suspension, and reacted at 50°C for 2 hours. 1M sodium hydroxide solution (10 mL) was added to the reaction solution, the reaction mixture was heated up and the tetrahydrofuran was evaporated; 1M hydrochloric acid was added to the residue. After the resulting mixture was extracted with methyl tert-butyl ether, it was washed with 1M sodium carbonate solution. Add appropriate amount of sodium chloride to the mixed solution to ensure that the final product sodium salt precipitates. The collected sodium salt was acidified again with 1M hydrochloric acid and extracted with toluene. After the extract was concentrated and crystallized, 350 mg of GFT-505 was obtained, with a yield of 45.5%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With caesium carbonate In N,N-dimethyl-formamide at 120℃; Sealed tube; | General procedure for the preparation of 2,4-diphenoxyquinoline (4a-4d). General procedure: A mixtureof 1 (10 mmol) and hydroxyl benzene (21 mmol) in DMF (30 mL) with anhydrous Cs2CO3( 20 mmol) was heated in a sealed tube, stirred at 120 °C for 8- 16 h, and cooled.Afterward, the mixture was poured into ice-water and extracted thrice with ethylacetate. The combined organic layers were washed with saturated NaCl and driedover Na2SO4. The crude product was purified on a silica gel column ( eluent:hexane/ethyl acetate) to obtain 4a-4d with 55%-65% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 69% 2: 14% | With caesium carbonate In N,N-dimethyl-formamide at 80℃; for 16h; Sealed tube; | General procedure for the preparation of 2-chloro-4-phenoxyquinoline (2a-2d). General procedure: Amixture of 2,4-dichloroquinoline (1, 10 mmol) and hydroxyl benzene (11 mmol) indimethylformamide (DMF, 30 mL) with anhydrous cesium carbonate ( Cs2CO3, 20mmol) was heated in a sealed tube, stirred at 80 °C for 16 h, and cooled. Then, themixture was poured into ice- water and extracted thrice with ethyl acetate. Thecombined organic layers were washed with saturated NaCl and dried over Na2SO4.The crude product was purified on a silica gel column (eluent: hexane/ethyl acetate) toobtain 2a-2d with 62%-69% yield. However, 4-chloro-2-phenoxyquinoline (3a-3d) wasalso found during the reaction progress as a side product with 5%-14% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | With phosphonic Acid; iodine In benzene at 100℃; for 12h; Sealed tube; Inert atmosphere; | 4.2. Typical procedure for preparation of targeted molecules General procedure: Under N2, a mixture of aromatic aldehyde 3 (0.6 mmol), H3PO3 (147.6 mg, 1.8 mmol), I2 (152.4 mg, 0.6 mmol) and benzene (1.2 mL) was stirred in a 25 mL closed sealed tube in oil bath at 100C for indicated time. After the mixture was cooled down to the room temperature, the mixture was quenched by Na2S2O3 aqueous solution and was extracted with EtOAc three times. Then the combined the organic layer was dried over MgSO4 and filtrated. The filtrate was concentrated and the residue was further purified by column chromatography on silica gel to give the product 4. |
[ 824-42-0 ]
2-Hydroxy-3-methylbenzaldehyde
Similarity: 0.97
[ 15174-69-3 ]
4-Hydroxy-3-methylbenzaldehyde
Similarity: 0.97
[ 6248-20-0 ]
2,4-Dihydroxy-3-methylbenzaldehyde
Similarity: 0.95
[ 7310-95-4 ]
2-Hydroxy-5-methylisophthalaldehyde
Similarity: 0.95
[ 824-42-0 ]
2-Hydroxy-3-methylbenzaldehyde
Similarity: 0.97
[ 15174-69-3 ]
4-Hydroxy-3-methylbenzaldehyde
Similarity: 0.97
[ 6248-20-0 ]
2,4-Dihydroxy-3-methylbenzaldehyde
Similarity: 0.95
[ 7310-95-4 ]
2-Hydroxy-5-methylisophthalaldehyde
Similarity: 0.95
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Code | Phrase |
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Code | Phrase |
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P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
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P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
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Code | Phrase |
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P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
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P321 | |
P322 | |
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P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
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P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
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P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
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P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
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P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
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P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
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P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
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P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
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P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
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P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
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P420 | Store away from other materials. |
P422 | |
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Disposal | |
Code | Phrase |
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Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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