Purity | Size | Price | VIP Price | USA Stock *0-1 Day | Global Stock *5-7 Days | Quantity | |||||
{[ item.p_purity ]} | {[ item.pr_size ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} | Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} {[ getRatePrice(item.pr_usd,1,item.mem_rate) ]} | {[ item.pr_usastock ]} | Inquiry - | {[ item.pr_chinastock ]} | Inquiry - |
* Storage: {[proInfo.prStorage]}
CAS No. : | 98556-31-1 | MDL No. : | MFCD01862193 |
Formula : | C8H4ClIN2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | BDAIUOPDSRAOKI-UHFFFAOYSA-N |
M.W : | 290.49 | Pubchem ID : | 11173809 |
Synonyms : |
|
Num. heavy atoms : | 12 |
Num. arom. heavy atoms : | 10 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 57.27 |
TPSA : | 25.78 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) : | -5.84 cm/s |
Log Po/w (iLOGP) : | 2.26 |
Log Po/w (XLOGP3) : | 3.15 |
Log Po/w (WLOGP) : | 2.89 |
Log Po/w (MLOGP) : | 2.72 |
Log Po/w (SILICOS-IT) : | 3.54 |
Consensus Log Po/w : | 2.91 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -4.24 |
Solubility : | 0.0166 mg/ml ; 0.0000573 mol/l |
Class : | Moderately soluble |
Log S (Ali) : | -3.36 |
Solubility : | 0.126 mg/ml ; 0.000435 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -4.89 |
Solubility : | 0.00377 mg/ml ; 0.000013 mol/l |
Class : | Moderately soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 0.0 |
Synthetic accessibility : | 1.8 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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 |
---|---|---|
99% | With Vilsmeier reagent In 1,2-dichloro-ethane for 4.5 h; Heating / reflux | Step B: 4-chloro-6-iodoquinazoline. To a stirred solution of anhydrous dimethyl foramide (DMF) (3.20 ml) in 1,2-dichloroethane (DCE) (10 ml), cooled in an ice-water bath, is added dropwise under nitrogen a solution of oxalyl chloride (5.2 ml, 60 mmol) in DCE (25 ml). A white precipitate forms during the addition. After the end of addition the cold bath is removed and the reaction mixture is stirred at room temperature for 5 minutes. 6-Iodo-quinazolin-4-ol (5.0 g, 18 mmol) is added in portions via scoopula under nitrogen flow and the mixture is heated immediately to reflux. Heating is continued for 4.5 hours, followed by cooling to room temperature. The reaction mixture is poured into excess ice-water mixture (approximately 300 ml) and extracted with DCM (approximately 500 ml). The aqueous layer is further extracted with DCM (2*50 ml). The combined organic extracts are dried (Na2SO4) and concentrated under reduced pressure to yield 5.2 g (99percent) of desired product as a tan solid. |
99% | for 4.5 h; Reflux | Step D: 4-chloro-6-iodoquinazoline (compound 1.4).[0105] To a solution of 6-Iodo-quinazolin-4-ol (5.0 g, 18 mmol) in thionyl chloride (10 mL) was added slowly DMF (0.5 mL) and the mixture is heated immediately to reflux. Heating is continued for 4.5 hours, followed by cooling to room temperature. The reaction mixture was then evaporated under reduced pressure to dryness. The residue was then redesolved ' in DCM (20 mL), and to it was added toluene (50 mL), and the mixture was then evaporated under reduced pressure to dryness. The procedure was repeated one more time to rid the product of thionyl chloride to yield 5.2 g (99percent) of desired product as a tan solid. |
99% | With oxalyl dichloride In tetrahydrofuran; N,N-dimethyl-formamide at 20℃; for 3 h; | Compound 1 (784 mg, 2.88 mmol) was dissolved in 10 ml of tetrahydrofuran (THF), and oxalyl chloride (731 mg, 5.76 mmol) was added. Two droplets of DMF were immediately added as a reaction catalyst. And the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was completely concentrated to obtain Compound 2 (828 mg, 2.85 mmol, 99percent). |
92.4% | With thionyl chloride In N,N-dimethyl-formamide for 4 h; Reflux | Compound 102 (14.4 g) was dissolved in thionyl chloride (50 ml)Adding 1 mL of the catalytic amount of anhydrous DMF,The reaction was refluxed for 4 hours.After completion of the reaction, excess thionyl chloride was distilled off under reduced pressure to give Compound 103. Yield 92.4percent. |
88% | With triethylamine; trichlorophosphate In toluene at 2 - 80℃; for 3.5 h; Inert atmosphere | Solution of 6-iodo-quinazolin-4-one (0.54g, 2mmol) was added phosphorus oxychloride (0.37g, 2.4mmol), under nitrogen in dry toluene (2ml), triethylamine (0.24 g, 2.4mmol), leopard after the dropping was raised to 80 stirred 2.5h. The reaction solution was cooled to 2 stirred for 1h, and filtered. The filter cake was washed with acetone, washed with 1mol / L aqueous sodium hydroxide solution (in 3 ml of), washed with water and then with acetone. Vacuum dried to give a beige powder (0.5g, 88percent) |
84% | Stage #1: With Chloro-oxo-acetic acid In 1,2-dichloro-ethane at 20 - 75℃; Heating / reflux Stage #2: With sodium carbonate In water; 1,2-dichloro-ethane at 20℃; |
Oxalyl chloride (11.8 g, 8.1 mL, 92.6 mmol, 2.0 equiv) was added to a suspension of 6-iodoquinazolin-4-ol (12.6 g, 46.2 mmol, 1.0 equiv), DMF (0.5 ml) and 1,2-dichloroethane (300 mL) resulting in the reaction temperature increasing from 21 to 25° C. The mixture was heated at about 75° C. overnight. TLC (50percent EtOAc/heptane) of an aliquot quenched with NaHCO3 showed the reaction to be incomplete. The mixture was cooled to room temperature, oxalyl chloride (2.0 mL, 0.5 equiv) added and the mixture refluxed for 7 hr. The clear dark brown solution was cooled to room temperature and poured very slowly into 10percent aqueous Na2CO3 solution (500 mL). The aqueous mixture was extracted with EtOAc (500 mL). Most of the aqueous phase was separated and the remaining mixture filtered to remove some insolubles at the interface. The phases of filtrate were separated, the organic phase washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The resulting solid was triturated with cold heptane (about 200 mL), filtered and dried to give 11.2 g (84percent) of 14 as a light brown solid that was used without further purification. |
77% | With thionyl chloride In N,N-dimethyl-formamide for 6 h; Reflux | 4-chloro-6-iodoquinazoline 6-iodo-4(1H)-quinazolinone (10 g, 37 mmol) was weighed into a 250 mL flask. Thionyl chloride (100 mL, 1.4 mmol) and DMF (0.5 mL, 6.5 mmol) were added to give a grey suspension. The mixture was heated to reflux. Heating was continued for 6 h and then the mixture was cooled on ice bath for 1 h. A yellow solid precipitated and was collected by filtration to afford 8.6 g (77percent) of the title compound. |
71% | at 0 - 90℃; | Step B: Preparation of 4-chloro-6-iodoquinazoline: To a cooled (0 °C) suspension of 6-iodoquinazolin-4-ol (107.6 g, 396 mmol) and DIEA (138 mL, 791 mmol) in dichloroethane (600 mL) was added POCl3 (44.25 mL, 475 mmol). After heating to 90 °C for 16 hours, the reaction mixture was cooled to room temperature and the crystals (73.8 g) collected by filtration. The filtrate was concentrated under reduced pressure and azeotroped twice with toluene. The solids (8.3 g) were triturated with isopropanol (450 mL) and cooled in an ice bath before collecting by filtration and drying under high vacuum. The two solids were combined to provide the product (82.1 g, 71percent) as white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With oxalyl dichloride; N,N-dimethyl-formamide In 1,2-dichloro-ethane for 4.5 h; Heating / reflux | To a stirred solution of anhydrous dimethyl foramide (DMF) (3.20 ml) in 1,2- dichloroethane (DCE) (10 ml), cooled in an ice-water bath, is added dropwise under nitrogen a solution of oxalyl chloride (5.2 ml, 60 mmol) in DCE (25 ml). A white precipitate forms during the addition. After the end of addition the cold bath is removed and the reaction mixture is stirred at room temperature for 5 minutes. 6-IODO-QUINAZOLIN-4-OL (5.0 g, 18 mmol) is added in portions via scoopula under nitrogen flow and the mixture is heated immediately to reflux. Heating is continued for 4.5 hours, followed by cooling to room temperature. The reaction mixture is poured into excess ice-water mixture (approximately 300 ml) and extracted with DCM (approximately 500 ml). The aqueous layer is further extracted with DCM (2X50 ml). The combined organic extracts are dried (NA2SO4) and concentrated under reduced pressure to yield 5.2 g (99percent) of desired product as a tan solid. |
92.7% | With oxalyl dichloride; N,N-dimethyl-formamide In 1,2-dichloro-ethane for 1 h; Inert atmosphere; Reflux | 3.2 ml of dry anhydrous DMF was added to 10 ml of dry DCE.At the same time, the reaction system was placed in a low-temperature cooling bath and stirred at 0°.Then 5.3 ml (60 mmol) of oxalyl chloride was added to 25 ml of dry anhydrous DCE to prepare a solution.The solution was slowly dropped into the appeal reaction system dropwise, kept stirring, and protected with nitrogen throughout.During the addition, a white solid precipitated in the reaction system and the reaction was removed after the dripping.Stir at room temperature for 5 minutes. Then compound 1 (5.0 g 18 mmol) was added to the reaction system.After the addition was complete, the reaction was transferred to an oil bath and the reaction was heated to reflux for 1 hour. Nitrogen protection was maintained throughout the reaction.After 1 hour, the reaction was removed from the oil bath and kept stirring to cool to room temperature.About 100 ml of ice water was added and the mixture was extracted with DCM (100 mL×3). The aqueous layer was separated and extracted with DCM. The combined organic phases were dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure to obtain 4.36 g of a light gray solid (yield: 92.7). percent). |
88% | With triethylamine; trichlorophosphate In toluene at 80℃; for 2.5 h; Inert atmosphere | To 6-iodo-quinazolin-4-one (0.54g, 2mmol) in dry toluene (2ml), was added a solution of phosphorus oxychloride (0.37g, 2.4mmol) under nitrogen, triethylamine (0.24 g, 2.4mmol) was added dropwise and the mixture was raised to 80 °C stirred for 2.5h. The reaction solution was cooled to 2 °C stirred for 1h and filtered. The filter cake was washed with acetone, washed with 1mol/L aqueous sodium hydroxide solution (in 3 ml) then washed with water and acetone and dried in vacuo to give a beige powder (0.5g, 88percent). |
77% | With thionyl chloride In N,N-dimethyl-formamideReflux | 6-iodo-4(1H)-quinazolinone (10 g, 37 mmol)was weighed into a 250 mL flask. Thionyl chloride (100 mL, 1.4 mmol) and DMF (0.5mL, 6.5 mmol) were added to give a grey suspension. The mixture was heated to reflux.Heating was continued for 6 h and then the mixture was cooled on ice bath for 1 h. A yellow solid precipitated and was collected by filtration to afford 8.6 g (77percent) of the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | Stage #1: With triethylamine; trichlorophosphate In toluene at 20 - 75℃; for 2 h; Stage #2: at 20℃; for 0.25 h; |
In a 20 mL-volume glass vessel equipped with a stirrer, a thermometer and a reflux condenser were placed2.00 g (7.35 mmol) of 6-iodoquinazolin-4-one, 1.24 g (8.09 mmol) of phosphorus oxychloride, and 10 mL of toluene ina nitrogen atmosphere. While the mixture was stirred at room temperature, 0.82 g (8.09 mmol) of triethylamine wasslowly added. The resulting mixture was heated to 75C, and the reaction was carried out for 2 hours. After the reactionwas complete, the reaction mixture was cooled to room temperature, and 100 mL of methanol was added. The mixturewas stirred for 15 minutes at the same temperature, to give 6-iodo-4-methoxyquinazoline. Analysis of the reactionmixture by high performance liquid chromatography indicated that 2.11 g (reaction yield: 99percent) of 6-iodo-4-chloroquinazolinewas produced. |
91% | Stage #1: With triethylamine; trichlorophosphate In toluene at 60 - 75℃; for 2.5 h; Stage #2: at 0 - 20℃; for 0.5 h; |
The procedures of Example IV-9 were repeated except for replacing acetone with methyl isopropyl ketone. There was produced 48.6 g (isolated yield: 91percent) of 6-iodo-4-chloroquinazoline. |
90% | Stage #1: With triethylamine; trichlorophosphate In toluene at 20 - 75℃; for 2 h; Stage #2: at 0℃; for 1 h; |
In a 100 mL-volume glass vessel equipped with a stirrer, a thermometer and a reflux condenser were placed20.0 g (73.5 mmol) of 6-iodoquinazolin-4-one, 13.5 g (88.2 mmol) of phosphorus oxychloride, and 60 mL of toluene ina nitrogen atmosphere. While the mixture was stirred at room temperature, 8.92 g (88.2 mmol) of triethylamine wasslowly added. The resulting mixture was heated to 75C, and the reaction was carried out for 2 hours. After the reactionwas complete, the reaction mixture was cooled to 0C and stirred for one hour. Thus precipitated pale yellow crystallineproduct of 6-iodo-4-chloroquinazoline was collected by filtration. Subsequently, the crystalline product was placed in100 mL of aqueous sodium hydroxide (1 mol/L), and the aqueous mixture was stirred for 30 minutes at room temperature.The crystalline product was collected by filtration, washed with 120 mL of water, and dried under reduced pressure,to give 19.3 g (isolated yield: 90percent, purity 99.3percent in terms of area percentage determined by high performanceliquid chromatography) of 6-iodo-4-chloroquinazoline as a yellowish crystalline product.The analysis of 6-halogeno-4-chloroquinazoline in the reaction mixture was performed by the following procedures: After the reaction was complete, 6-halogeno-4-chloroquinazoline was reacted with methanol to give 6-halogeno-4-methoxyquinazoline quantitatively, which was then analyzed by high performance liquid chromatography. 6-Iodo-4-chloroquinazoline had the following physical properties.1H-NMR (CDCl3, d (ppm)): 7.80 (1H, d, J=7.8Hz), 8.20 (1H, dd, J=2.1, 9.0Hz), 8.65 (1H, d, J=2.1Hz), 9.06 (1H, s)CI-MS (m/e): 291 (M+1) |
90% | Stage #1: With triethylamine; trichlorophosphate In toluene at 60 - 75℃; for 2.5 h; Stage #2: at 0 - 20℃; for 0.5 h; |
The procedures of Example IV-9 were repeated except for replacing acetone with chloroform. There was produced 48.1 g (isolated yield: 90percent) of 6-iodo-4-chloroquinazoline. |
90% | Stage #1: With triethylamine; trichlorophosphate In toluene at 60 - 75℃; for 2.5 h; Stage #2: at 0 - 20℃; for 0.5 h; |
The procedures of Example IV-9 were repeated except for replacing acetone with acetonitrile. There was produced 48.1 g (isolated yield: 90percent) of 6-iodo-4-chloroquinazoline. |
90% | Stage #1: With triethylamine; trichlorophosphate In chlorobenzene at 60 - 75℃; for 2.5 h; Stage #2: at 0 - 20℃; for 0.5 h; |
The procedures of Example IV-1 were repeated except for replacing toluene with chlorobenzene. There was produced 48.1 g (isolated yield: 90percent) of 6-iodo-4-chloroquinazoline. |
89% | Stage #1: With triethylamine; trichlorophosphate In toluene at 20 - 75℃; for 2.5 h; Stage #2: at 0 - 20℃; for 0.5 h; |
In a 500 mL-volume glass vessel equipped with a stirrer, a thermometer and a reflux condenser were placed50.0 g (184 mmol) of 6-iodoquinazolin-4-one, 33.8 g (221 mmol) of phosphorus oxychloride, and 300 mL of toluene ina nitrogen atmosphere. While the mixture was stirred at room temperature, 22.3 g (221 mmol) of triethylamine wasslowly added. The resulting mixture was heated at 60C for 30 minutes and then heated at 75C for 2 hours, for carryingout reaction. After the reaction was complete, the reaction mixture was cooled to room temperature, and 50 mL ofacetone was added. The mixture was then cooled to 0C and stirred for 30 minutes. Thus precipitated pale yellowcrystalline product of 6-iodo-4-chloroquinazoline was collected by filtration. Subsequently, the crystalline product wasplaced in 200 mL of water, and 9 mL of aqueous sodium hydroxide (1 mol/L) was added. The aqueous mixture (pH 10- 11) was stirred for 30 minutes at room temperature. The crystalline product was collected by filtration, washed successivelywith 100 mL of acetone, 200 mL of water and 100 mL of acetone, and dried at 60C under reduced pressure,to give 47.4 g (isolated yield: 89percent, purity 99percent in terms of area percentage determined by high performance liquidchromatography) of 6-iodo-4-chloroquinazoline as a yellowish crystalline product. |
89% | Stage #1: With triethylamine; trichlorophosphate In toluene at 60 - 75℃; for 2.5 h; Stage #2: at 0 - 20℃; for 0.5 h; |
The procedures of Example IV-9 were repeated except for replacing acetone with tetrahydrofuran. There was produced 47.6 g (isolated yield: 89percent) of 6-iodo-4-chloroquinazoline. |
84% | Stage #1: With triethylamine; trichlorophosphate In toluene at 60 - 75℃; for 2.5 h; Stage #2: at 0 - 20℃; for 0.5 h; |
The procedures of Example IV-9 were repeated except for replacing acetone with methyl ethyl ketone. There was produced 44.9 g (isolated yield: 84percent) of 6-iodo-4-chloroquinazoline |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With oxalyl dichloride; N,N-dimethyl-formamide; In 1,2-dichloro-ethane; for 4.5h;Heating / reflux; | To a stirred solution of anhydrous dimethyl foramide (DMF) (3.20 ml) in 1,2- dichloroethane (DCE) (10 ml), cooled in an ice-water bath, is added dropwise under nitrogen a solution of oxalyl chloride (5.2 ml, 60 mmol) in DCE (25 ml). A white precipitate forms during the addition. After the end of addition the cold bath is removed and the reaction mixture is stirred at room temperature for 5 minutes. 6-IODO-QUINAZOLIN-4-OL (5.0 g, 18 mmol) is added in portions via scoopula under nitrogen flow and the mixture is heated immediately to reflux. Heating is continued for 4.5 hours, followed by cooling to room temperature. The reaction mixture is poured into excess ice-water mixture (approximately 300 ml) and extracted with DCM (approximately 500 ml). The aqueous layer is further extracted with DCM (2X50 ml). The combined organic extracts are dried (NA2SO4) and concentrated under reduced pressure to yield 5.2 g (99%) of desired product as a tan solid. |
92.7% | With oxalyl dichloride; N,N-dimethyl-formamide; In 1,2-dichloro-ethane; for 1h;Inert atmosphere; Reflux; | 3.2 ml of dry anhydrous DMF was added to 10 ml of dry DCE.At the same time, the reaction system was placed in a low-temperature cooling bath and stirred at 0.Then 5.3 ml (60 mmol) of oxalyl chloride was added to 25 ml of dry anhydrous DCE to prepare a solution.The solution was slowly dropped into the appeal reaction system dropwise, kept stirring, and protected with nitrogen throughout.During the addition, a white solid precipitated in the reaction system and the reaction was removed after the dripping.Stir at room temperature for 5 minutes. Then compound 1 (5.0 g 18 mmol) was added to the reaction system.After the addition was complete, the reaction was transferred to an oil bath and the reaction was heated to reflux for 1 hour. Nitrogen protection was maintained throughout the reaction.After 1 hour, the reaction was removed from the oil bath and kept stirring to cool to room temperature.About 100 ml of ice water was added and the mixture was extracted with DCM (100 mL×3). The aqueous layer was separated and extracted with DCM. The combined organic phases were dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure to obtain 4.36 g of a light gray solid (yield: 92.7). %). |
88% | With triethylamine; trichlorophosphate; In toluene; at 80℃; for 2.5h;Inert atmosphere; | To 6-iodo-quinazolin-4-one (0.54g, 2mmol) in dry toluene (2ml), was added a solution of phosphorus oxychloride (0.37g, 2.4mmol) under nitrogen, triethylamine (0.24 g, 2.4mmol) was added dropwise and the mixture was raised to 80 C stirred for 2.5h. The reaction solution was cooled to 2 C stirred for 1h and filtered. The filter cake was washed with acetone, washed with 1mol/L aqueous sodium hydroxide solution (in 3 ml) then washed with water and acetone and dried in vacuo to give a beige powder (0.5g, 88%). |
77% | With thionyl chloride; In N,N-dimethyl-formamide;Reflux; | <strong>[16064-08-7]6-iodo-4(1H)-quinazolinone</strong> (10 g, 37 mmol)was weighed into a 250 mL flask. Thionyl chloride (100 mL, 1.4 mmol) and DMF (0.5mL, 6.5 mmol) were added to give a grey suspension. The mixture was heated to reflux.Heating was continued for 6 h and then the mixture was cooled on ice bath for 1 h. A yellow solid precipitated and was collected by filtration to afford 8.6 g (77%) of the title compound. |
53% | With trichlorophosphate; | 6-Iodoquinazolin-4(3H)-one (1Og, 37 mmol) was refluxed in POCI3 (100 mL) overnight. Then POCI3 was removed in vacuo. The residue was dissolved in CH2Cl2 (500 mL ). The organic phase was washed with water (100 mL) and dried (MgSO4). Then CH2Cl2 was removed in vacuo and 1404-174 was obtained (5.7 g, 53%): LC- MS: 291 [M+l]+, 1H NMR (CDCl3): delta 7.81 (d, J= 9.0 Hz, 1 H), 8.21 (dd, Ji = 9.0 Hz, J2 = 1.8 Hz, I H), 8.65 (d, J= 1.8 Hz, 1 H), 9.06 (s, 1 H). |
With tributyl-amine; trichlorophosphate; In toluene; at 20 - 90℃;Heating / reflux; | Example 1; Preparation of GW572016F; STAGE 1; A stirred suspension of 3H-<strong>[16064-08-7]6-iodoquinazolin-4-one</strong> (compound A) in toluene (5 vols) was treated with tri-n-butylamine (1.2 eq.) at 20 to 25C, then heated to 900C. Phosphorous oxychloride (1.1 eq) was added, the reaction mixture was then heated to reflux. The reaction mixture was cooled to 500C and toluene (5vols) added. Compound C (1.03 eq.) was added as a solid, the slurry was warmed back to 900C and stirred for 1 hour. The slurry was transferred to a second vessel; the first vessel was rinsed with toluene (2vol) and combined with the reaction mixture. The reaction mixture was cooled to 700C and 1.0 M aqueous sodium hydroxide solution (16 vols) added dropwise over 1 hour to the stirred slurry maintaining the contents temperature between 68-72C. The mixture was stirred at 65-700C for 1 hour and then cooled to 200C over 1 hour. The suspension was stirred at 200C for 2 hours, the product collected by filtration, and washed successively with water (3 x 5 vols) and ethanol (IMS, 2 x 5 vols), then dried in vacuo at 50-600C. <n="25"/>Volumes are quoted with respect of the quantity of Compound A used. Percent yield range observed: 90 to 95% as white or yellow crystals. | |
With tributyl-amine; trichlorophosphate; In toluene; at 20 - 90℃;Heating / reflux; | A stirred suspension of 3H-<strong>[16064-08-7]6-iodoquinazolin-4-one</strong> (compound A) in toluene (5 vols) was treated with tri-n-butylamine (1.2 eq.) at 20 to 25C, then heated to 900C. Phosphorous oxychloride (1.1eq) was added, the reaction mixture was then heated to reflux. The reaction mixture was cooled to 500C and toluene (5vols) added. Compound C (1.03 eq.) was added as a solid, the slurry was warmed back to 900C and stirred for 1 hour. The slurry was transferred to a second vessel; the first vessel was rinsed with toluene (2vol) and combined with the reaction mixture. The reaction mixture was cooled to 7O0C and 1.0 M aqueous sodium hydroxide solution (16 vols) added dropwise over 1 hour to the stirred slurry maintaining the contents temperature between 68-72C. The mixture was stirred at 65-700C for 1 hour and then cooled to 200C over 1 hour. The suspension was stirred at 200C for 2 hours, the product collected by filtration, and washed successively with water (3 x 5 vols) and ethanol (IMS, 2 x 5 vols), then dried in vacuo at 50-600C. Volumes are quoted with respect of the quantity of Compound A used. Percent yield range observed: 90 to 95% as white or yellow crystals. | |
With tributyl-amine; trichlorophosphate; In toluene; at 70 - 80℃; for 2h;Heating / reflux; | A stirred suspension of 3W-<strong>[16064-08-7]6-iodoquinazolin-4-one</strong> in toluene (5 vols) is treated with tri-n-butylamine (1.2 equiv.), and then heated to 70-800C. Phosphorous oxychloride (1.1 equiv.) is added and the reaction mixture is then heated to reflux and stirred at this temperature for at least 2 hours. The reaction mixture is then cooled to 55C and toluene (5vol) added followed by 3-chloro-4-[(3-fluorophenyl)rnethyl]oxy}aniline (1.03 equiv.). The reaction mixture is then warmed to 70-900C and stirred for at least 2 hours. The resultant slurry is transferred to a second vessel. The temperature is adjusted to 70-750C and 8 molar aqueous sodium hydroxide solution (2 vols) added over 1 hour, followed by water (6vol.) maintaining the contents at 70-850C. The mixture is stirred at 70-850C for ca. 1 hour and then cooled to 20-250C. The suspension is stirred for ca. 2 hours and the product collected by filtration, and washed successively with water, 0.1 molar aqueous sodium hydroxide, water, and IMS, then dried in vacuo. EPO <DP n="48"/> | |
With thionyl chloride; In N,N-dimethyl-formamide;Reflux; | Example 1 Preparation of N-(4-(3-fluorobenzyloxy)-3-chlorophenyl)-6-iodine-quinazolin-4-amine 6-Iodine-3H-quinazolin-4-ketone (100 g) was added into a 2000 mL flask, dissolved in a mixed solvent of thionyl chloride (1000 mL) and N,N-dimethylformamide (20 mL), heated to reflux until the reaction solution is clear and transparent. After thionyl chloride was removed, anhydrous toluene was added to the residues and removed under reduced pressure, and the process of the adding and removing of toluene was repeated again to removed the remained thionyl chloride residues. The intermediate was dissolved in isopropyl alcohol (2000 mL), 3-chloro-4-(3-fluoro-benzyloxy)-aniline hydrochloride was added, and anhydrous K2CO3 (150 g) was added with mechanical stirring before the mixture was heated to reflux over night. The reaction solution was cooled to room temperature overnight, the precipitation was filtered and washed with water for multi-times until the pH of washing solution reached neutral. After drying under vacuum, 95 g of the title product was collected in a pale white solid. m/z M+1+: 506 | |
With thionyl chloride; for 2h;Reflux; | Example 1 Synthesis of CD 8/CD 19 inhibitors SNX-2-1-165 was synthesized according to the scheme shown in Figure 2. All other compounds were synthesized using similar procedures. | |
With tributyl-amine; trichlorophosphate; In toluene; at 20℃;Heating / reflux; | A stirred suspension of 3H-<strong>[16064-08-7]6-iodoquinazolin-4-one</strong> (compound A) in toluene (5 vols) was treated with tri-n-butylamine (1.2 eq. ) at 20 to 25C, then heated to 90C. Phosphorous oxychloride (1.1eq) was added, the reaction mixture was then heated to reflux. The reaction mixture was cooled to 50C and toluene (5vols) added. Compound C (1.03 eq. ) was added as a solid, the slurry was warmed back to 90C and stirred for 1 hour. The slurry was transferred to a second vessel; the first vessel was rinsed with toluene (2vol) and combined with the reaction mixture. The reaction mixture was cooled to 70C and 1.0 M aqueous sodium hydroxide solution (16 vols) added dropwise over 1 hour to the stirred slurry maintaining the contents temperature between 68-72C. The mixture was stirred at 65-70C for 1 hour and then cooled to 20C over 1 hour. The suspension was stirred at 20C for 2 hours, the product collected by filtration, and washed successively with water (3 x 5 vols) and ethanol (IMS, 2 x 5 vols), then dried in vacuo at 50-60C. Volumes are quoted with respect of the quantity of Compound A used. Percent yield range observed: 90 to 95% as white or yellow crystals. | |
With tributyl-amine; trichlorophosphate; In toluene; at 20℃;Heating / reflux; | A stirred suspension of 3H-<strong>[16064-08-7]6-iodoquinazolin-4-one</strong> (compound A) in toluene (5 vols) was treated with tri-n-butylamine (1.2 eq. ) at 20 to 25C, then heated to 90C. Phosphorous oxychloride (1.1 eq) was added, the reaction mixture was then heated to reflux. | |
With P,P-dichlorophenylphosphine oxide; at 150℃; for 1h; | A mixture of 6-iodoquinazolin-4 (3H)-one (Intermediate 11,100 mg, 0.37 mmol) and phenylphosphonic dichloride (1.5 ML) was heated at 150 C for one h. After cooling the reaction mixture in an ice bath, isopropyl ether was added. The resultant crystalline precipitate was collected by filtration, and was then stirred with saturated aqueous sodium bicarbonate solution. The solution was extracted with three portions of ethyl acetate, and the combined extracts were dried (magnesium sulfate) and concentrated under reduced pressure to give the crude product. Purification by preparative thin layer chromatography (silica gel, 5% and 10% ethyl acetate/hexanes) afforded the desired product. LC/MS 291 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | In isopropyl alcohol; for 3.5h;Reflux; | 6-Iodo-(4-benzyloxy-3-trifluoromethyl-phenyl)-quinazolin-4-yl)amine (0648) The mixture of 4-chloro-6-iodo-quinazoline (366 mg, 1.26 mmol) and 4-O-benzyl-3-trifluoroaniline (405 mg, 1.26 mmol) in isopropanol (12 ml) was heated to reflux for 3.5 hours. Filtered, washed with isopropanol and dried. 535 mg yellow solid was afforded. (yield: 76%). ESI-MS m/z 522 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage 1: Preparation of N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6- iodo-4-quinazolinamine 4-Chloro-6-iodoquinazoline (1wt) was added to a solution of fluorobenzyloxyaniline (0.894wt, 1.03equiv) in N-methylpyrrolidinone (8.26wt, 8vol) at ca 20C, and after the initial exotherm had subsided, the resulting solution was stirred at 20-25C for at least 30 minutes. The dark solution was treated with triethylamine (0.58vol, 1.2equiv) and the mixture was stirred for 20-30 minutes. Isopropanol (2.5vol) was added and the mixture was heated to ca 50C. Water (up to 3vol) was added slowly to the vessel over 10-15 minutes, while keeping the temperature at ca 50C. Once crystallisation had commenced the addition was stopped and the resulting slurry was aged for 30-45 minutes at ca 50C. Any residual water (from the 3vol) was added, then further water (5vol) was added to the vessel over ca 30 minutes while maintaining the temperature at ca 50C. The resulting slurry was cooled to ca 20C over ca 30 minutes and aged at ca 20C for at least 30 minutes. The solid was collected by filtration and washed sequentially with water (2 x 5vol), then isopropanol (5vol). The product was dried in vacuo at ca 60C to give the title compound as a cream crystalline solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | In isopropyl alcohol; at 20℃;Heating / reflux; | [3-Chloro-4-(3-fluoro-α,α-d2-benzyloxy)phenyl](6-iodoquinazolin-4-yl)amine hydrochloride (41). To a suspension of 14 (ca. 400 mmol) in 2-propanol (2.2 L) was added 40 (104.5 g, 412.0 mmol). The reaction mixture was stirred under reflux conditions for 4 h, cooled to room temperature, and stirred overnight. The resulting precipitate was removed by filtration, washed with acetone (1.2 L), and dried at 60 C. for 2 h to give 41 (191 g, 88%) as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; johnphos; In 1,4-dioxane; at 120℃; for 0.416667h;Microwave irradiation; | Combine 3-boronic acid-2-[6-methyl-(pyridin-2-yl)]-5, 6-dihydro-4H-pyrrolo [1, 2- b] pyrazole (Preparation 2 ; 70 mg, 0.3 mmol) with 4-chloro-6-iodo-quinazoline (Davos Chemicals ; 130 mg, 0.45 mmol) in the presence of Pd (dppf) 2Cl2 (7 mg, 3% mol), biphenyl-2-yl-di-tert-butyl-phosphane (3 mg, 6% mol), 2M sodium carbonate (1 mL), and 2: 1 dioxane/ethylene glycol (6 mL) in a 10 mL glass tube. Seal the tube with a septum and place in a microwave reactor. Use microwave irradiation to raise the temperature to 120 C over 25 min. Dilute the reaction mixture with 1: 1 chlorofornllisopropyl alcohol and wash the resulting solution with brine. Dry the mixture (sodium sulfate), filter, and evaporate the solvents to give a viscous mixture. Purify the crude product with flash chromatography using dichloromethane to 1: 1 dichloromethane/methanol as gradient eluting solvents to give 80 mg (72%) of the desired compound. MS ES+ m/e 388.2 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | In 1,2-dichloro-ethane; tert-butyl alcohol; for 6h;Heating / reflux; | A mixture OF 3-METHYL-4-(6-METHYL-PYRIDIN-3-YLOXY)-PHENYLAMINE (4.96 g, 23.18 MMOL), 4-Chloro-6-iodo-quinazoline 604 g, 22.06 mmol) in tBuOH (60 mL) and DCE (60 mL) was refluxed for 6 hours. The reaction was cooled to 0C and the solid product (8. 44 g, 76%) was isolated by filtration and washed with cold CHACLA (50 mL) |
76% | In 1,2-dichloro-ethane; tert-butyl alcohol; for 6h;Heating / reflux; | Step C: (6-iodo-quinazolin-4-yl)-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenyl]-amine hydrochloride A mixture of 3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamine (4.96 g, 23.18 mmol), 4-Chloro-6-iodo-quinazoline 604 g, 22.06 mmol) in tBuOH (60 mL) and DCE (60 mL) was refluxed for 6 hours. The reaction was cooled to 0 C. and the solid product (8.44 g, 76%) was isolated by filtration and washed with cold CH2Cl2 (50 mL). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | In isopropanol; for 4h;Heating / reflux; | [3-Chloro-4-(3-fluorobenzyloxy)phenyl](6-iodoquinazolin-4-yl)amine hydrochloride (15). To a suspension of 14 (12.5 g, 43.0 mmol) in 2-propanol (300 mL) was added 13 (11.2 g, 44.3 mmol). The resulting suspension was refluxed 4 hours and then the volatiles were removed under reduced pressure and the crude solid was triturated with hot acetone (400 mL) and dried at 60 C. for 2 hours to give 15 (16.4 g, 70%) as a pale yellow solid. |
58% | In 1,2-dichloro-ethane; tert-butyl alcohol; for 19h;Heating / reflux; | 3-CHLORO-4- (3-FLUORO-BENZYLOXY)-PHENYLAMINE (3.1 g, 12 mmol) and 4-chloro-6-iodo- quinazoline (3.28 g, 11. 3 mmol) are dissolved in a 1 : 1 mixture of DCE : reaction mixture is REFLUXED for 19 hours. The product is isolated by suction filtration through sintered glass, washed with excess DCM, and air dried to afford 3.8 g (7. Ommol, 58%) of the clean desired material. <P>STEPF : (3- {4- [3-CHLORO-4- (3-FLUORO-BENZYLOXY)-PHENYLAMINO]-QUINAZOLIN-6-YL}-PROP-2-YNYL)- carbamic acid tert-butyl ester. |
58% | In 1,2-dichloro-ethane; tert-butyl alcohol; for 19h;Heating / reflux; | Step E: [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-iodo-quinazolin-4-yl)-amine hydrochloride salt. 3-Chloro-4-(3-fluoro-benzyloxy)-phenylamine (3.1 g, 12 mmol) and 4-chloro-6-iodo-quinazoline (3.28 g, 11.3 mmol) are dissolved in a 1:1 mixture of DCE:t-BuOH (56 ml). The reaction mixture is refluxed for 19 hours. The product is isolated by suction filtration through sintered glass, washed with excess DCM, and air dried to afford 3.8 g (7.0 mmol, 58%) of the clean desired material. |
In water monomer; at 25 - 60℃; for 6h; | KSM-01 l. lmol and KSM-02 Imole charge to the reactor followed by 15Vol water and allow to stir for 30min at 25-30C. Allow to heat for 5.5hrs at 55-60C and cool the reaction mass at 25-30C. Filter the reaction mass and suck dry well to get stage-01 of formula (P) as wet cake 2.5times (w/w). Yield: 2.15 (on dry basis w/w) HPLC purity: 99.187%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With ammonia; In methanol; at 70℃; for 1.5h; | A suspension of 0. 5 g (1. 7 mmol) <strong>[98556-31-1]4-chloro-6-iodoquinazoline</strong> (Davos Chemical Corp., Englewood Cliffs, NJ) in 10 mL of 7 M ammonia in methanol was heated to 70 C in a sealed tube with stirring for 90 minutes, then cooled to initiate crystal formation. The mixture was cooled to 0 C, filtered, washed with cold methanol and then petroleum ether, and air-dried to produce 0. 39 g (1. 4 mmol, 82%) of the title compound as a white SOLID. LH-NMR (300 MHz, DMSO-d6, 8) : 8. 64 (d, J= 2 Hz, 1H), 8. 39 (s, 1H), 8. 07 (dd, J= 2 Hz, 9 Hz, 1H), 7. 85 (br s, 2H), 7. 43 (D, J= 9 Hz, 1H) ; m/z : 272 [M+H] +. |
With ammonia; In ethanol; at 20℃; for 1h; | To the product (73.8 mg) from Step A was added a solution of 2M ammonia in ethanol (7 mL) and the resultant solution was stirred at room temperature for 2 h. The volatiles were removed under reduced pressure and the residue was triturated with diethyl ether to give the desired product as a white powder. LC/MS 271.8 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | In methanol; at 70℃; for 2h; | A suspension of 0. 5 g (1. 7 mmol) <strong>[98556-31-1]4-chloro-6-iodoquinazoline</strong> (Davos Chemical Corp., Englewood Cliffs, NJ) in 5 mL of 0. 5 M sodium METHOXIDE in methanol was heated to 70 C in a sealed tube with stirring for 2 hours, then cooled to initiate crystal formation. The mixture was concentrated in vacuo. The residue was suspended in water, filtered, washed with additional water, and air-dried to produce 0. 4 g (1. 4 mmol, 82%) of the title compound as fine, white NEEDLES. 1H-NMR (300 MHz, CDC13, 8) : 8. 82 (d, J= 2 Hz, 1H), 8. 55 (d, J= 2 Hz, 1H), 8. 07 (dt, J= 2 Hz, 9 Hz, 1H), 7. 67 (dd, J = 3 Hz, 9 Hz, 1H), 4. 18 (s, 3H) ; m/z : 287 [M+H] +. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | In tetrahydrofuran; at 56℃; for 2.66667h; | A 3 neck round bottom flask was fitted with a mechanical stirrer and kept under N2. The flask was charged with the 6-IODO-4-CHLOROQUINAZOLINE (10.0 g, 34.43 mol) and dry THF (35 ML). Thereafter, 3-METHYL-4- (6-METHYL-PYRIDINE-3-YLOXY)-PHENYLAMINE (7.38 g, 34.43 MMOL) and dry THF (45 ml) were added and the yellow suspension was heated to reflux. After 15 minutes most of the reactants went into solution and a fine yellow suspension was obtained. After 25 min, the internal temperature of the reaction mixture was 56C, and precipitation of the desired product started. Heating was continued for a further 2 hours and the reaction mixture was allowed to cool to room temperature while remaining in the oil bath. Yellow crystals were collected by filtration, washed with cold (0C) THF (1 x 10 ml) and dried at 50C, p < 200 mbar. The title compound was obtained as light yellow crystals (15.75g, 98%). Rf = 0.45 (EtOAc/MeOH = 9/1).'H NMR (CDCI3, 300 MHz): 8 = 11.40 (br, s, 1H, NH), 9.29 (d, J = Hz, 1H, H-2), 8.91 (S, 1H, H-2"), 8.36-8. 32 (m, 2H, H-7, H-8), 7.74-7. 73 (m, 2H, H-4", H-5), 7.62 (dd, J, = 8.7Hz, J2 = 2.6Hz, 1 H, H-5") 7.49-7. 46 (m, 2H, H-6', H-5), 7.06 (d, J = 8.7Hz, 1 H, H-2'), 2.54 (s, 3H, CH3), 2.26 (s, 3H, CH3). 13C NMR (CDCI3 + D6-DMSO, 75 MHz): 8 = 159.51, 153.63, 153.17, 152.82, 152.70, 145.26, 141.37, 138.01, 134.75, 134.65, 131.05, 129.10, 128.74, 126.77, 124.86, 124.43, 120.41, 116. 98, 94.89, 23.54, 17.67. The title compound had a tR (min) of 12.13 under the following RP-HPLC conditions: Symmetry Shield RP18, 75 x 4.6 mm; Flow 1.0 mL/min ; 205/210/220/245 nm; Temp. 25C ; Injection Volume: 10 uL OF A CA. 0.5% solution in ACN/H20 9/1; Eluent : B: ACN, C: 0.01 mmol NH40Ac in H20 pH = 6.0 ; and Gradient: 0 min: B = 30%, C = 70 %; and 20 min: B = 85%, C =15%. |
98% | In tetrahydrofuran; at 56℃; for 2.5h;Heating / reflux; | Synthesis of 6-Iodo-[3-methyl-4-(6-methyl-pyridine-3-yloxy)-phenylamino]-quinazoline A 3 neck round bottom flask was fitted with a mechanical stirrer and kept under N2. The flask was charged with the 6-iodo-4-chloroquinazoline (10.0 g, 34.43 mol) and dry THF (35 ml). Thereafter, 3-methyl-4-(6-methyl-pyridine-3-yloxy)-phenylamine (7.38 g, 34.43 mmol) and dry THF (45 ml) were added and the yellow suspension was heated to reflux. After 15 minutes most of the reactants went into solution and a fine yellow suspension was obtained. After 25 minutes, the internal temperature of the reaction mixture was 56 C., and precipitation of the desired product started. Heating was continued for a further 2 hours and the reaction mixture was allowed to cool to room temperature while remaining in the oil bath. Yellow crystals were collected by filtration, washed with cold (0 C.) THF (1*10 ml) and dried at 50 C., p<200 mbar. The title compound was obtained as light yellow crystals (15.75 g, 98%). Rf=0.45 (EtOAc/MeOH=9/1). 1H NMR (CDCl3, 300 MHz): δ=11.40 (br, s, 1H, N), 9.29 (d, J=Hz, 1H, -2), 8.91 (s, 1H, -2"), 8.36-8.32 (m, 2H, -7, -8), 7.74-7.73 (m, 2H, -4", -5), 7.62 (dd, J1=8.7 Hz, J2=2.6 Hz, 1H, H-5") 7.49-7.46 (m, 2H, H-6', H-5), 7.06 (d, J=8.7 Hz, 1H, -2'), 2.54 (s, 3H, C3), 2.26 (s, 3H, C3). 13C NMR (CDCl3+D6-DMSO, 75 MHz): δ=159.51, 153.63, 153.17, 152.82, 152.70, 145.26, 141.37, 138.01, 134.75, 134.65, 131.05, 129.10, 128.74, 126.77, 124.86, 124.43, 120.41, 116.98, 94.89, 23.54, 17.67. |
93% | In isopropyl alcohol; at 80℃; for 2h; | General procedure: To a solution of compound 12 (5.8 g, 20 mmol) in i-PrOH was added anilines (22 mmol) at room temperature (RT). Then the reaction mixture was heated to 80 C for 2 h. After the start material was completed, the mixture was filtered through celite, and the cake was washed by i-PrOH, then dried to obtain the desired compound 13a-f. |
In isopropyl alcohol; for 12h;Reflux; | Step C: N-(4-(6-methylpyridin-3-yloxy)-3-methylphenyl)-6-iodoquinazolin-4-amine(compound 12.3)[0141] 4-(6-methylpyridin-3-yloxy)-3-methylbenzenamine (812 mg, 3.79 mmol) and 4- chloro-6-iodo-quinazoline (I g, 3.4mmol) were dissolved in isopropanol (50 ml). The reaction mixture was refluxed for 12 hours. The solid product was collected by filtration, washed with cold isopropanol (10 mL) and ether (20 mL), and air dried to afford 1.1 g of the clean desired material. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | In a 20 mL-volume glass vessel equipped with a stirrer, a thermometer and a reflux condenser were placed2.00 g (7.35 mmol) of 6-iodoquinazolin-4-one, 1.24 g (8.09 mmol) of phosphorus oxychloride, and 10 mL of toluene ina nitrogen atmosphere. While the mixture was stirred at room temperature, 0.82 g (8.09 mmol) of triethylamine wasslowly added. The resulting mixture was heated to 75C, and the reaction was carried out for 2 hours. After the reactionwas complete, the reaction mixture was cooled to room temperature, and 100 mL of methanol was added. The mixturewas stirred for 15 minutes at the same temperature, to give 6-iodo-4-methoxyquinazoline. Analysis of the reactionmixture by high performance liquid chromatography indicated that 2.11 g (reaction yield: 99%) of 6-iodo-4-chloroquinazolinewas produced. | |
91% | The procedures of Example IV-9 were repeated except for replacing acetone with methyl isopropyl ketone. There was produced 48.6 g (isolated yield: 91%) of 6-iodo-4-chloroquinazoline. | |
90% | In a 100 mL-volume glass vessel equipped with a stirrer, a thermometer and a reflux condenser were placed20.0 g (73.5 mmol) of 6-iodoquinazolin-4-one, 13.5 g (88.2 mmol) of phosphorus oxychloride, and 60 mL of toluene ina nitrogen atmosphere. While the mixture was stirred at room temperature, 8.92 g (88.2 mmol) of triethylamine wasslowly added. The resulting mixture was heated to 75C, and the reaction was carried out for 2 hours. After the reactionwas complete, the reaction mixture was cooled to 0C and stirred for one hour. Thus precipitated pale yellow crystallineproduct of 6-iodo-4-chloroquinazoline was collected by filtration. Subsequently, the crystalline product was placed in100 mL of aqueous sodium hydroxide (1 mol/L), and the aqueous mixture was stirred for 30 minutes at room temperature.The crystalline product was collected by filtration, washed with 120 mL of water, and dried under reduced pressure,to give 19.3 g (isolated yield: 90%, purity 99.3% in terms of area percentage determined by high performanceliquid chromatography) of 6-iodo-4-chloroquinazoline as a yellowish crystalline product.The analysis of 6-halogeno-4-chloroquinazoline in the reaction mixture was performed by the following procedures: After the reaction was complete, 6-halogeno-4-chloroquinazoline was reacted with methanol to give 6-halogeno-4-methoxyquinazoline quantitatively, which was then analyzed by high performance liquid chromatography. 6-Iodo-4-chloroquinazoline had the following physical properties.1H-NMR (CDCl3, d (ppm)): 7.80 (1H, d, J=7.8Hz), 8.20 (1H, dd, J=2.1, 9.0Hz), 8.65 (1H, d, J=2.1Hz), 9.06 (1H, s)CI-MS (m/e): 291 (M+1) |
90% | The procedures of Example IV-9 were repeated except for replacing acetone with chloroform. There was produced 48.1 g (isolated yield: 90%) of 6-iodo-4-chloroquinazoline. | |
90% | The procedures of Example IV-9 were repeated except for replacing acetone with acetonitrile. There was produced 48.1 g (isolated yield: 90%) of 6-iodo-4-chloroquinazoline. | |
90% | The procedures of Example IV-1 were repeated except for replacing toluene with chlorobenzene. There was produced 48.1 g (isolated yield: 90%) of 6-iodo-4-chloroquinazoline. | |
89% | In a 500 mL-volume glass vessel equipped with a stirrer, a thermometer and a reflux condenser were placed50.0 g (184 mmol) of 6-iodoquinazolin-4-one, 33.8 g (221 mmol) of phosphorus oxychloride, and 300 mL of toluene ina nitrogen atmosphere. While the mixture was stirred at room temperature, 22.3 g (221 mmol) of triethylamine wasslowly added. The resulting mixture was heated at 60C for 30 minutes and then heated at 75C for 2 hours, for carryingout reaction. After the reaction was complete, the reaction mixture was cooled to room temperature, and 50 mL ofacetone was added. The mixture was then cooled to 0C and stirred for 30 minutes. Thus precipitated pale yellowcrystalline product of 6-iodo-4-chloroquinazoline was collected by filtration. Subsequently, the crystalline product wasplaced in 200 mL of water, and 9 mL of aqueous sodium hydroxide (1 mol/L) was added. The aqueous mixture (pH 10- 11) was stirred for 30 minutes at room temperature. The crystalline product was collected by filtration, washed successivelywith 100 mL of acetone, 200 mL of water and 100 mL of acetone, and dried at 60C under reduced pressure,to give 47.4 g (isolated yield: 89%, purity 99% in terms of area percentage determined by high performance liquidchromatography) of 6-iodo-4-chloroquinazoline as a yellowish crystalline product. | |
89% | The procedures of Example IV-9 were repeated except for replacing acetone with tetrahydrofuran. There was produced 47.6 g (isolated yield: 89%) of 6-iodo-4-chloroquinazoline. | |
84% | The procedures of Example IV-9 were repeated except for replacing acetone with methyl ethyl ketone. There was produced 44.9 g (isolated yield: 84%) of 6-iodo-4-chloroquinazoline | |
With triethylamine; trichlorophosphate; In toluene; at 80℃; for 2h; | Roschangar et al. ,Use of lithium N,O-dimethylhydroxylamide as an efficient in situ protecting agent for aromatic aldehydes. Tertrahedron 2002, 58, 1657-1666). Preparation analogous (Nishino et al.; Process for producing 4-aminoquinazoline compound by chlorination of quinazolin-4-one or its derivative and animation. 2003) as follows: To a mixture of 6-iodo-lH-quinazolin-4-one (10) (6.8Og; 25.0 mmol), toluene (5.0 mL) and POCl3 (27.5 mmol; 2.60 mL) carefully triethylamine (27.5 mmol; 3.81 mL) was added. The mixture was heated to 80 0C for 2 h, cooled to room temperature, a solution of 3-chloro~4-(3- fluorobenzyloxy)phenylamine (15) (27.50 mmol; 6.92 g) in 2~butanone (20.0 mL) added and the mixture stirred at 80 0C for another hour. The mixture was cooled to 00C, the yellow precipitate was filtered off and added to a NaOH solution (IN; 150 mL) by stirring. After 30 min the yellow solid was filtered off, washed with water and a small amount of acetone and dried in vacuo. Yield (8.38 g; 66%) analytical pure sample. 1H-NMR (DMSO-[D6]): δ (ppm) = 5.26 (s, 2H), 7.15-7.22 (m, IH), 7.27 (d, IH, J = 9.1 Hz), 7.29-7.35 (m, 2H), 7.43-7.51 (m, IH), 7.56 (d, IH, J = 8.8 Hz), 7.74 (dd, IH, J = 9.1 Hz, 4J = 2.5 Hz), 8.02 (d, IH5 4J = 2.5 Hz), 8.12 (dd; IH, J = 8.8 Hz, 4J = 1.7 Hz)5 8.62 (s, IH), 8.96 (d, 4J = 1.7 Hz), 9.90 (s, IH, exchangeable). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | In 1,2-dichloro-ethane; tert-butyl alcohol; at 90℃; for 8h; | Step C: [1-(3-Fluoro-benzyl)-1 H-indazol-5-yl]-(6-iodo-quinazolin-4-yl)-amine hydrochloride Follow general procedure from Example 1, step E. <strong>[98556-31-1]4-chloro-6-iodoquinazoline</strong> (1.18 g, 4.06 mmol) is mixed with 1-(3-Fluoro-benzyl)-1H-indazol-5-ylamine (1.09 g, 4.52 mmol), and a mixture of DCE (10 ml) and t-BuOH (10 ml) is added. The mixture is heated at 90 C. (oil bath temperature) for 8 hours. At 5 hours of heating LC/MS reveals substantial amount of product. Yield is 1.35 g (56%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With Vilsmeier reagent; In 1,2-dichloro-ethane; for 4.5h;Heating / reflux; | Step B: 4-chloro-6-iodoquinazoline. To a stirred solution of anhydrous dimethyl foramide (DMF) (3.20 ml) in 1,2-dichloroethane (DCE) (10 ml), cooled in an ice-water bath, is added dropwise under nitrogen a solution of oxalyl chloride (5.2 ml, 60 mmol) in DCE (25 ml). A white precipitate forms during the addition. After the end of addition the cold bath is removed and the reaction mixture is stirred at room temperature for 5 minutes. 6-Iodo-quinazolin-4-ol (5.0 g, 18 mmol) is added in portions via scoopula under nitrogen flow and the mixture is heated immediately to reflux. Heating is continued for 4.5 hours, followed by cooling to room temperature. The reaction mixture is poured into excess ice-water mixture (approximately 300 ml) and extracted with DCM (approximately 500 ml). The aqueous layer is further extracted with DCM (2*50 ml). The combined organic extracts are dried (Na2SO4) and concentrated under reduced pressure to yield 5.2 g (99%) of desired product as a tan solid. |
99% | With thionyl chloride; N,N-dimethyl-formamide; for 4.5h;Reflux; | Step D: 4-chloro-6-iodoquinazoline (compound 1.4).[0105] To a solution of 6-Iodo-quinazolin-4-ol (5.0 g, 18 mmol) in thionyl chloride (10 mL) was added slowly DMF (0.5 mL) and the mixture is heated immediately to reflux. Heating is continued for 4.5 hours, followed by cooling to room temperature. The reaction mixture was then evaporated under reduced pressure to dryness. The residue was then redesolved ' in DCM (20 mL), and to it was added toluene (50 mL), and the mixture was then evaporated under reduced pressure to dryness. The procedure was repeated one more time to rid the product of thionyl chloride to yield 5.2 g (99%) of desired product as a tan solid. |
99% | With oxalyl dichloride; In tetrahydrofuran; N,N-dimethyl-formamide; at 20℃; for 3h; | Compound 1 (784 mg, 2.88 mmol) was dissolved in 10 ml of tetrahydrofuran (THF), and oxalyl chloride (731 mg, 5.76 mmol) was added. Two droplets of DMF were immediately added as a reaction catalyst. And the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was completely concentrated to obtain Compound 2 (828 mg, 2.85 mmol, 99%). |
92.4% | With thionyl chloride; In N,N-dimethyl-formamide; for 4h;Reflux; | Compound 102 (14.4 g) was dissolved in thionyl chloride (50 ml)Adding 1 mL of the catalytic amount of anhydrous DMF,The reaction was refluxed for 4 hours.After completion of the reaction, excess thionyl chloride was distilled off under reduced pressure to give Compound 103. Yield 92.4%. |
88% | With triethylamine; trichlorophosphate; In toluene; at 2 - 80℃; for 3.5h;Inert atmosphere; | Solution of 6-iodo-quinazolin-4-one (0.54g, 2mmol) was added phosphorus oxychloride (0.37g, 2.4mmol), under nitrogen in dry toluene (2ml), triethylamine (0.24 g, 2.4mmol), leopard after the dropping was raised to 80 stirred 2.5h. The reaction solution was cooled to 2 stirred for 1h, and filtered. The filter cake was washed with acetone, washed with 1mol / L aqueous sodium hydroxide solution (in 3 ml of), washed with water and then with acetone. Vacuum dried to give a beige powder (0.5g, 88%) |
84% | Oxalyl chloride (11.8 g, 8.1 mL, 92.6 mmol, 2.0 equiv) was added to a suspension of 6-iodoquinazolin-4-ol (12.6 g, 46.2 mmol, 1.0 equiv), DMF (0.5 ml) and 1,2-dichloroethane (300 mL) resulting in the reaction temperature increasing from 21 to 25 C. The mixture was heated at about 75 C. overnight. TLC (50% EtOAc/heptane) of an aliquot quenched with NaHCO3 showed the reaction to be incomplete. The mixture was cooled to room temperature, oxalyl chloride (2.0 mL, 0.5 equiv) added and the mixture refluxed for 7 hr. The clear dark brown solution was cooled to room temperature and poured very slowly into 10% aqueous Na2CO3 solution (500 mL). The aqueous mixture was extracted with EtOAc (500 mL). Most of the aqueous phase was separated and the remaining mixture filtered to remove some insolubles at the interface. The phases of filtrate were separated, the organic phase washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The resulting solid was triturated with cold heptane (about 200 mL), filtered and dried to give 11.2 g (84%) of 14 as a light brown solid that was used without further purification. | |
77% | With thionyl chloride; In N,N-dimethyl-formamide; for 6h;Reflux; | 4-chloro-6-iodoquinazoline 6-iodo-4(1H)-quinazolinone (10 g, 37 mmol) was weighed into a 250 mL flask. Thionyl chloride (100 mL, 1.4 mmol) and DMF (0.5 mL, 6.5 mmol) were added to give a grey suspension. The mixture was heated to reflux. Heating was continued for 6 h and then the mixture was cooled on ice bath for 1 h. A yellow solid precipitated and was collected by filtration to afford 8.6 g (77%) of the title compound. |
71% | With N-ethyl-N,N-diisopropylamine; trichlorophosphate; at 0 - 90℃; | Step B: Preparation of 4-chloro-6-iodoquinazoline: To a cooled (0 C) suspension of 6-iodoquinazolin-4-ol (107.6 g, 396 mmol) and DIEA (138 mL, 791 mmol) in dichloroethane (600 mL) was added POCl3 (44.25 mL, 475 mmol). After heating to 90 C for 16 hours, the reaction mixture was cooled to room temperature and the crystals (73.8 g) collected by filtration. The filtrate was concentrated under reduced pressure and azeotroped twice with toluene. The solids (8.3 g) were triturated with isopropanol (450 mL) and cooled in an ice bath before collecting by filtration and drying under high vacuum. The two solids were combined to provide the product (82.1 g, 71%) as white solid. |
With oxalyl dichloride; N,N-dimethyl-formamide; In 1,2-dichloro-ethane; at 0 - 110℃; for 1.5h;Heating / reflux; | EXAMPLE 11; 4-(6-Iodo-quinazolin-4-yl)-piperidine-1-carboxylic acid (4-isopropoxy-phenyl)-amide; a. 4-Chloro-6-iodo-quinazoline; A mixture of 5-iodoanthranilic acid (9.96 g, 37.9 mmol) and formamidine acetate (4.20 g, 40.3 mmol) (adapted from J. Org. Chem. 51:616, 1986) in absolute EtOH (80 mL) was refluxed under air for 2 h. The smoky amber solution with heavy white precipitate was then concentrated under reduced pressure at 90 C., and residual protic solvent was removed with toluene rotary evaporation (2×100 mL) at 90 C. The resulting sticky tan solid was treated with a thick white slurry of Vilsmeier-Haack reagent in one portion under air at rt. [The Vilsmeier-Haack reagent was prepared by the addition of a solution of oxalyl chloride (10.9 mL, 125 mmol) in DCE (44 mL) to a solution of DMF (6.7 mL, 87 mmol) in DCE (21 mL) dropwise over 10 min at 0 C. with vigorous stirring. The ice bath was removed immediately following completion of oxalyl chloride addition, and the white slurry was stirred at “rt” for 5 min before transfer to the crude 4-hydroxy-6-iodo-quinazoline intermediate.] The reaction was then refluxed under air (oil bath 110 C.) for 1 h 15 min, and the resulting homogeneous brown solution was allowed to cool to rt, at which point a heavy precipitate formed. The reaction was poured into ice water (300 mL) and extracted with DCM (3×250 mL). The opaque organic layers were combined, dried (Na2SO4), and filtered to provide a clear red amber filtrate. Concentration under reduced pressure, followed by toluene rotary evaporation at 90 C. to remove potentially reactive volatiles, afforded the title compound as a tan powder (8.41 g, 94% from iodoanthranilic acid) suitable for treatment with LiHMDS in the next step. 1H-NMR (300 MHz, CDCl3) δ 9.07 (s, 1H), 8.67 (dd, 1H), 8.22 (dd, 1H), 7.81 (d, 1H). | |
With thionyl chloride; In N,N-dimethyl-formamide; at 80℃; for 5h;Reflux; | 6-chloro-4-hydroxyquinazoline (2.72 g, 10 mmol) and DMF (0.2 mL) were added to 24 mL of dichlorosulfoxide and refluxed5h. The thionyl chloride was distilled off under reduced pressure, and the remaining thionyl chloride was removed by steaming with ethyl acetate (100 mL x 3) to give a yellow solid 4-chloro-6-iodoquinazoline. 20 mL of isopropanol, 3-bromoaniline (2.06 g, 12 mmol) and triethylamine (1.00 g, 10 mmol) and refluxed at 80 C for 6 h. Cooled, filtered, the filtrate added ether to continue to precipitate the solid, the resulting solid with a large number of water and then Followed by suction filtration, drying, pale yellow solid 3.61g, yield 84.6%, Mp: 197-199 . | |
With triethylamine; trichlorophosphate; at 90℃; for 6h;Inert atmosphere; | At 0 C,The compound 6-iodo-4-quinazolinone (10 g, 30 mmol) was added to toluene (150 mL) under N2.Add triethylamine (9.09 g, 90 mmol),Phosphorus oxychloride (6.12 g, 40 mmol) was slowly added to the above solution, and a large amount of white smoke appeared, and the temperature was slowly raised to 90 C to stir the reaction for 6.0 h.Toluene (200 mL) was added to the above solution.The organic phase was washed once with saturated brine (100 mL).Anhydrous sodium sulfate (20 g) was dried and concentrated to give a red brown oil.This crude product was used in the next reaction without purification. | |
With thionyl chloride; In N,N-dimethyl-formamide; at 25 - 90℃; for 3h;Inert atmosphere; | To a stirred solution of 6-iodoquinazolin-4-ol (500 mg, 1.84 mmol) in thionyl chloride (7 mL)at 25C under nitrogen was added DMF (0.2 mL) and the reaction mixture was heated to 90Cfor 3 hours. The resulting mixture was evaporated to dryness and the residue was azeotropedwith excess toluene to afford 4-chloro-6-iodoquinazoline which was used without furtherpurification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetonitrile; for 18h;Heating / reflux; | (4-Benzyloxyphenyl)-(6-iodoquinazolin-4-yl)-amine hydrochloride 4-Chloro-6-iodoquinazoline (8 g) was treated with 4-benzyloxyaniline (5.5 g) in acetonitrile (500 ml) at reflux under N2 for 18 hours. Subsequent cooling and filtration gave the title compound (13.13 g); δH [2H6]-DMSO 11.45 (1H, b, NH), 9.22 (1H, s, 5-H), 8.89 (1H, s, 2-H), 8.36 (1H, d, 7-H), 7.69 (1H, d, 8-H), 7.63 (2H, d, 2'-H, 6'-H), 7.52-7.29 (5H, m, Ph-H), 7.14 (2H, d, 3'-H, 5'-H), 5.18 (2H, s, CH2); m/z (M+1)+ 454. | |
In acetonitrile; for 18h;Heating / reflux; | 4-Chloro-6-iodoquinazoline (8 g) was treated with 4-benzyloxyaniline (5.5 g) in acetonitrile (500 ml) at reflux under N2 for 18 hours. Subsequent cooling and filtration gave the title compound (13.13 g); δH [2H6]-DMSO 11.45 (1H, b, NH), 9.22 (1H, s, 5-H), 8.89 (1H, s, 2-H), 8.36 (1H, d, 7-H), 7.69 (1H, d, 8-H), 7.63 (2H, d, 2'-H, 6'-H), 7.52-7.29 (5H, m, Ph-H), 7.14 (2H, d, 3'-H, 5'-H), 5.18 (2H, s, CH2); m/z (M+1)+454. | |
13.13 g | In acetonitrile; for 18h;Reflux; Inert atmosphere; | (4-Benzyloxyphenyl)-(6-iodoquinazolin-4-yl)-amine hydrochloride (0637) 4-Chloro-6-iodoquinazoline (8 g) was treated with 4-benzyloxyaniline (5.5 g) in acetonitrile (500 ml) at reflux under N2 for 18 hours. Subsequent cooling and filtration gave the title compound (13.13 g); δH [2H6]-DMSO 11.45 (1H, b, NH), 9.22 (1H, s, 5-H), 8.89 (1H, s, 2-H), 8.36 (1H, d, 7-H), 7.69 (1H, d, 8-H), 7.63 (2H, d, 2′-H, 6′-H), 7.52-7.29 (5H, m, Ph-H), 7.14 (2H, d, 3′-H, 5′-H), 5.18 (2H, s, CH2); m/z (M+1)+ 454. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | In acetonitrile;Heating / reflux; | Step 3: Heating of 3-methoxy-4-morpholin-4-yl-phenylamine (136mg ) and 4- chloro-6-iodoquinazoline (186mg) in acetonitrile (10ml) at reflux overnight gave, on cooling, a precipitate that was isolated by filtration, washed with water then slurried with IN NaOH and washed with further water and dried. This gave the title compound (263mg, 88%) 6 (DMSO) 11.01 (1H, br s); 9.20 (lH, s); 8.83 (lH, s); 8.29 (1H, d, J8.85Hz); 7.67 (1H, d, J8.85Hz) ; 7.40 (2H, m) ; 6.98 (lH, d, J8.85Hz) ; 8.83 (3H, s) ; 3.76 (4H, m); 3.01 (4H, m). , LC-MS rt 2.74, m/z E+463 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | In acetonitrile;Heating / reflux; | Step3: A suspension of 4-chloro-6-iodo-quinazoline (500mg, 1.8mMol) and 2- methyl-4-morpholin-4-yl-phenylamine (360mg, 1.9mMol) in acetonitrile (3ml) was heated at reflux overnight, during which a precipitate developed. The reaction was cooled and the precipitate filtered off. This was washed with 1M sodium hydroxide solution and water before being air dried to give (6-iodo-quinazolin-4-yl)-(2-methyl-4- morpholin-4-yl-phenyl)-amine(738mg , 95%). LC/MS: RT- 3.55, MH+ 447 5 (DMSO) 10.35 (1H, br s); 9.04 (1H, d, 1.3Hz); 8.55 (lH, s); 8.20 (1H, dd, J 8.8Hz, 1.3Hz); 7.60 (1H, d, J 8.8Hz); 7.14 (1H, d, J 8.8Hz) ; 6.92 (1H, d, J 2.5); 6.87 (IH, dd, J 8.2Hz, 1.9Hz); 3.77 (4H, t, 4.4Hz); 3.15 (4H, t, 4.4Hz) ; 2.15 (3H, s) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetonitrile;Heating / reflux; | Step 3 : Treatment of the product from step 2 ( 280mg) with 4-chloro-6-iodo- quinazoline (300mg, 1.1mMol) in acetonitrile (4ml) at reflux overnight, gave a precipitate. The reaction was cooled and the precipitate filtered off. This was washed with 1M sodium hydroxide solution and water before being air dried to the title compound 8 (DMSO) 9.79 (1H, s) ; 8.85 (1H, s) ; 8.27 (1H, d, J 12.0Hz); 8.03 (1H, d, J 7.0Hz); 7.17-7.43 (4H, m) ; 3.72-3.78 (4H, m) ; 3.16-3.23 (4H, m), LC/MS: RT - 2.80, MH+ 501, |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetonitrile;Heating / reflux; | Step 3: A suspension of 4-chloro-6-iodo-quinazoline (300mg) and 3-methyl-4- morpholin-4-yl-phenylamine (240mg) in acetonitrile (4ml) was heated at reflux overnight, during which a precipitate developed. The reaction was cooled and the precipitate filtered off. This was washed with 1M sodium hydroxide solution and water before being air dried to give (6-iodo-quinazolin-4-yl)-(3-methyl-4-morpholin-4-yl- phenyl)-amine. LC/MS: RT - 2.81, MHl (at) 447; 8 (DMSO) 9.82 (lH, s); 9.03 (lH, d, J 1.9Hz); 8.59 (1H, s) ; 8.12 (1H, dd, J 8.8Hz, 1.9Hz); 7.60-7.70 (2H, m) ; 7.58 (lH, d, J 8.8Hz) ; 7.09 (1H, d, J 8.8Hz); 3.78 (4H, t, J 4.lHz); 2.87 (4H, t, J 4.lHz); 2.32 (3H, s) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | In acetonitrile;Heating / reflux; | Step 3: Heating of methyl-(4-morpholin-4-yl-phenyl)-amine (37mg ) and 4- chloro-6-iodoquinazoline (52mg) in acetonitrile (6ml) at reflux overnight gave, on cooling, a precipitate that was isolated by filtration, washed with water then slurried with IN NaOH and washed with further water and dried. This gave the title compound (22mg, 28%) 8(DMSO) 8.72 (1H, s), 7.90 (1H, d, J8.85Hz) ; 7.51 (1H, d, J8.85Hz); 7.15 (5H, m) ; 3.81 (4H, m) ; 3.56 (3H, s) ; 3.21 (4H, m), LC-MS rt 2.62, m/z E+447 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | To a cooled (0C) stirred suspension of NaH (4.8 g, 60%, 0.12 mol) in anhydrous DMF (60 ml) was added dropwise a solution of PHOH (11.3 G, 0.12 mol) in dry DMF (50 mL). After the addition, <strong>[98556-31-1]4-chloro-6-iodoquinazoline</strong> (29 g, 0.1 mol) was added portionwise. Thereafter the cooling bath was removed and the resulting solution was stitrred at room temperature for 1.5 h, quenched with water (300 mL). The product precipitated and was extracted with EtOAc (400 mL). The separated organic layer was washed with aq. NAOH, water, brine, dried over NA2SO4 and concentrated to give 6-IODO-4-PHENOXYQUINAZOLINE as off- white solid (32.9 g, 94%). Crystallization from EtOAc gave white soft and short needle crystals. | |
With NaH; In N,N-dimethyl-formamide; | 6-iodo-4-phenoxyquinazoline (14) A suspension of NaH (washed free of mineral oil) in DMF (40 mL) was cooled to 0 C. and a solution of phenol (5.65 g, 60 mmol) in DMF (20 mL) was added dropwise. Upon completion of addition, 6-iodo-4-chloroquinazoline 13 (14.6 g, 50.3 mmol) was added as a solid in small portions. The cooling bath was moved and the reaction mixture was stirred at room temperature for 2 hours. The mixture was then quenched with water (200 mL), diluted with EtOAc (300 mL) and transferred to a separatory funnel. The organic layer was washed with dilute aqueous NaOH, water and brine and dried over Na2SO4. Filtration of the solids and removal of the solvent provided 6-iodo4-phenoxyquinazoline 14 (17.2 g, 98%) as a yellow solid. 1H NMR (400 MHz; CDCl3): δ: 8.74 (d, 1H), 8.14 (s, 1H), 8.12 (dd, 1H), 7.71 (d, 1H). 7.49 (dd, 2H), 7.32 (t, 1H), 7.22 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tert-butyl alcohol; | (1-Benzenesulfonyl-1H-indol-5-yl)-(6-iodo-quinazolin4-yl)-amine (20) 6-iodo-4-chloroquinazoline 13 (2.38 g, 8.20 mmol) and 5-amino-1-benzenesulfonylindole 21 (2.46 g, 9.00 mmol) were combined in DCE (20 mL) and t-butanol (20 mL). The resulting mixture was heated at reflux under nitrogen for 18 hours to form a bright yellow suspension. Upon cooling the solids were filtered and rinsed with CH2Cl2 and placed under high vacuum to remove any excess solvent. The title compound (3.23 g, 75%) was obtained as a yellow solid. For compound 20: 1H NMR (DMSO-d6; 400 MHz): δ: 10.05 (s, 2H,), 8.93 (s, 1H), 8.53 (s, 1H), 8.25 (m, 1H,), 8.10 (m, 5H), 7.97 (m, 3H), 7.82 (m, 2H), 7.70 (m, 2H), 7.65 (m, 2H), 6.88 (d, 1H, J=3.57 Hz). | |
In tert-butyl alcohol; | (1-Benzenesulfonyl-1H-indol-5-yl)-(6-iodo-quinazolin-4-yl)-amine (14): 6-iodo-4-chloroquinazoline (2.38 g, 8.20 mmol) and 5-amino-1-benzenesulfonylindole (2.46 g, 9.00 mmol) were combined in DCE (20 mL) and t-butanol (20 mL). The resulting mixture was heated at reflux under nitrogen for 18 hours to form a bright yellow suspension. Upon cooling the solids were filtered and rinsed with CH2Cl2 and placed under high vacuum to remove any excess solvent. Quinazoline 14 (3.23 g, 75%) was obtained as a yellow solid. 1H NMR (DMSO d6; 400 MHz): δ: 9.24 (s, 1H, NH), 8.84 (s, 1H), 8.33 (dd, 1H, 8.9 Hz, 1.7 Hz), 8.01 (m, 4H), 7.90 (m, 2H), 7.70 (m, 2H), 7.60 (m, 3H), 6.92 (dd, 1H, J=3.7 Hz, 0.6 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium; In methanol; cyclohexane; ethyl acetate; | a 6-Iodo-4-ethyl-quinazoline 154 mg of sodium are dissolved in 20 ml of dry methanol and treated with 1.2 g of 4-chloro-6-iodo-quinazoline. The mixture is heated to reflux for 1 hour, and then the solvent is distilled off. The residue is partitioned between aqueous pH7 buffer solution and ethyl acetate. The aqueous layer is extracted with ethyl acetate, and the combined organic extracts are dried over magnesium sulfate and evaporated in vacuo. The residue is dissolved in cyclohexane/ethyl acetate (1/1) and filtered over silica gel. The title compound is obtained as slightly yellowish crystals after evaporation of the solvent. mp: 110-113. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dichloromethane; N,N-dimethyl-formamide; | 6-iodo4-chloroquinazoline (12): To a stirred solution of DMF (6.3 mL) in DCE (20 mL) cooled to 0 C. was added dropwise a solution of oxalyl chloride (60 mL of a 2M solution in DCE). After addition was complete, the cooling bath was removed and 6-iodo-3H-quinazolinone (10 g, 36.8 mmol) was added as a solid. The resulting mixture was heated to reflux under nitrogen for 3 hours. Upon cooling to room temperature, the reaction was quenched cautiously with H2O. CH2Cl2 was added and the bilayer transferred to a separatory funnel. The aqueous layer was extracted with CH2Cl2 (2*50 mL) and the combined organic layers dried (Na2SO4). The solvent was removed in vacuo to provide a yellow solid which was triturated with diethyl ether to remove any remaining impurities. The resulting yellow solid obtained by filtration was shown to be pure by NMR. 1H-NMR (CDCl3, 400 MHz): δ: 9.05 (s, 1H), 8.65 (d, 1H), 8.21 (dd, 1H), 7.78 (d, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With diisopropylamine;Pd(PPh3)2Cl2; In tetrahydrofuran; dichloromethane; | Method M: N-{3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-2-morpholin-4-yl-acetam 2-Chloro-N-[3-(4chloro-quinazolin-6-yl)-prop-2-ynyl]-acetamide: 2-Chloro-N-prop-2-ynyl-acetamide (385 mg; 2.93 mmol) and <strong>[98556-31-1]4-chloro-6-iodoquinazoline</strong> (850 mg; 1 equiv.) were dissolved in dry THF and diisopropylamine (296 mg; 0.41 ml; 1 equiv.). To this mixture was added 0.04 equivalents of copper iodide (22 mg) and Pd(PPh3)2Cl2 (82 mg). The reaction was stirred at room temperature under a nitrogen atmosphere overnight (-20 hrs). The solvent was then removed in vacuo and the residue dissolved in CH2Cl2. This solution was transferred to a separatory funnel and washed with 1* saturated NH4Cl, brine, dried over Na2SO4 and the solvent removed in vacuo. The product was purified by silica gel chromatography eluding with 1:1 hexlEtOAc and collecting fractions with an Rf=0.25. This yielded the 2-Chloro-N-[3-(4-chloro-quinazolin-6-yl)-prop-2-ynyl]-acetamide as an off white solid (454 mg; 53%). 1H NMR (400 MHz; CDCl3) δ 4.12 (2H, s), 4.40 (2H, d, J=5.2 Hz), 7.91-7.93 (1H, dd, J=2, 6.8 Hz), 8.00 (1H, d, J=8.4 Hz), 8.34 (1H, d, J=1.8 Hz), 9.03 (1H, s). Irms (M+): 294.0, 296.0, 298.1. 2-Chloro-N-{3-[4-(3-methyl-4-phenoxy-phenylamino)-quinazolin-yl]-prop-2-ynyl}-acetamide: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.22 g (72%) | With diisopropylamine;dichlorobis(triphenylphosphine)palladium[II]; In tetrahydrofuran; hexane; dichloromethane; ethyl acetate; | Method O: 4-Aminomethyl-1-[4-(3-methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-pent-1-yn-3-ol 5-(4-Chloro-quinazolin-ylethynyl)-4,4-dimethyl-oxazolidin-2-one: A mixture of 4,4-Dimethyl-5-ethynyl-2-oxazolidinone (1.10 g, 7.90 mmol), 4chloro-6-iodoquinazoline (1.63 g, 5.60 mmol), dichlorobis(triphenylphosphine)palladium(II) (200 mg, 0.28 mmol), copper iodide (53 mg, 0.28 mmol), and diisopropylamine (0.57 g, 5.60 mmol) in anhydrous THF (30 mL) was stirred at room temperature under nitrogen for 4 hours. After concentration, the residue was dissolved in CH2Cl2 (80 mL), washed with aqueous NH4Cl and brine, dried over sodium sulfate, and concentrated to give the crude product as brown oil. Purification by silica gel column using 50-70% EtOAc in hexane afforded 1.22 g (72%) of yellow solid: 1H NMR (CDCl3) δ 1.49 (s, 3H), 1.53 (s, 3H), 5.14 (s, 1H), 5.57 (brs, 1H), 7.95 (dd, 1H), 8.04 (d, 1H, J=8.8 Hz), 8.38 (d, 1H, J=2.0 Hz), 9.05 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N,N-dimethyl-formamide; at 0 - 20℃; for 1.5h; | Preparation of £-3-{4-[3-Methyl-4-(6-methyI-pyridin-3-yloxy)-phenylamino]- quinazolin-6-yl}-acrylic acid To a cooled (00C) stirred suspension of sodium hydride (NaH) ( 4.8 g, 60%, 0.12 mol) in anhydrous DMF (60 ml) was added dropwise a solution of phenol (PhOH) (11.3 g, 0.12 mol) in dry DMF (50 ml_). After the addition, <strong>[98556-31-1]4-chloro-6-iodoquinazoline</strong> (29 g, 0.1 mol) was added portionwise. Thereafter the cooling bath was removed and the resulting solution was stitrred at room temperature for 1.5 h, quenched with water (300 mL). The product precipitated and was extracted with ethyl acetate (EtOAc) (400 mL). The separated organic layer was washed with aq. sodium hydroxide NaOH, water, brine, dried over Na2SO4 and concentrated to give 6-iodo-4-phenoxyquinazoline as off-white solid (32.9 g, 94%). Crystallization from EtOAc gave white soft and short needle crystals.A mixture of 6-iodo-4-phenoxyquinazoline (3.5 g, 10 mmol), as prepared in the preceding paragraph, methyl acrylate (6g, 70 mmol) , Pd(OAc)2 (140 mg, 0.62 mmol) and Ph3P (320 mg, 1.22 mmol) in triethylamine (Et3N)/DMF was purged with N2 and the pressure reaction vessel was tightly capped. The reaction was then heated on an oil-bath at 1100C with stirring. Thin layer chromatography indicated that the reaction was complete after 3 hours. The product mixture was then transferred to a round bottomed flask and purged with a stream of N2 to remove the methyl acrylate. The residue was then dissolved in ethyl acetate, washed with water, brine, dried over sodium sulfate and concentrated to give crude E-3-(4-Phenoxy- quinazolin-6-yl)- acrylic acid methyl ester as yellow solid which was recrystallized from ethyl acetate to yield 2.3 g (70%) of pale yellow crystalline solid in two crops.A mixture of the product (E-3-(4-Phenoxy-quinazolin-6-yl)-acrylic acid methyl ester) from the preceding paragraph ( 307 mg, 1 mmol) and the desired aniline (215 mg, 1 mmol) was taken up in phenol (2 g) and the resultant mixture heated at 1000C on an oil-bath and a clear solution was obtained. After heating 2Oh, the brown solution was distilled under reduced EPO <DP n="37"/>pressure to remove phenol. The residue was partitioned between dilute NaOH and methylene chloride. The separated organic layer was washed with brine, dried over sodium sulfate and concentrated to give the crude product, which was purified by chromatography to give pure E- 3-{4-[3-Methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-acrylic acid methyl ester (480 mg).A mixture of the methyl ester (450 mg, 1 mmol) and LiOH1H2O (0.63 g, 15 mmol) in methanol/water (10/1 ml) was refluxed for 3 h. After cooling the reaction was neutralized with acetic acid (0.9 g, 15 mmol) in 2 mL of H2O to pH 6.0. A clear solution was obtained initially and the acid product precipitated later as a yellow solid, which was collected by vacuum filtration and dried to give the final product £-3-{4-[3-Methyl-4-(6-methyl-pyridin-3-yloxy)- phenylamino]-quinazolin-6-yl}-acrylic acid as a yellow solid (280 mg, 68%).1H (CD3OD): δ 2.24 (s, 3H), 2.48 (s, 3H), 6.70 (d, J=16 Hz, 1H), 6.98 (d, 1H), 7.28 (m, 2H), 7.6 (m, 1 H), 7.69 (m, 1H), 7.76 (m, 1H), 7.78 (d, J=16 Hz, 1H), 8.1 (m, 2H), 8.5 (s, 1 H), 8.6 (d, 1 H). m/z (ES+) (M+1) 413.4. HPLC Rt=4.831 mins |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With copper(l) iodide; diisopropylamine;bis-triphenylphosphine-palladium(II) chloride; In tetrahydrofuran; at 20℃; for 2h; | 4-(4-Chloro-quinazolin-6-ylethynyl)-piperidine-1-carboxylic acid tert-butyl ester: A mixture of 4-ethynyl-piperidine-1-carboxylic acid tert-butyl ester (1.12 g, 5.35 mmol), <strong>[98556-31-1]4-chloro-6-iodoquinazoline</strong> (1.35 g, 4.65 mmol), dichlorobis(triphenylphosphine) palladium(II) (0.16 g, 0.23 mmol), copper(I) iodide (0.044 g, 0.23 mmol), and diisopropylamine (0.47 g, 4.65 mmol) in anhydrous THF (20 mL) was stirred at room temperature under nitrogen for 2 hours. After concentration, the residue was dissolved in CH2Cl2 (100 mL), washed with aqueous NH4Cl and brine, dried over sodium sulfate, and concentrated to give the crude product as brown oil. Purification by silica gel column using 20% EtOAc in hexane afforded 1.63 g (94%) of the title compound as a sticky, yellow oil |
94% | With copper(l) iodide; diisopropylamine;bis-triphenylphosphine-palladium(II) chloride; In tetrahydrofuran; at 20℃; for 2h; | A mixture of 4-ethynyl-piperidine-1-carboxylic acid tert-butyl ester (1.12 g, 5.35 mmol), 4- chloro-6-iodoquinazoline (1.35 g, 4.65 mmol), dichlorobis(triphenylphosphine) palladium(ll) (0.16 g, 0.23 mmol), copper(l) iodide (0.044 g, 0.23 mmol), and diisopropylamine (0.47 g, 4.65 mmol) in anhydrous THF (20 mL) was stirred at room temperature under nitrogen for 2 hours. After concentration, the residue was dissolved in CH2CI2 (100 mL), washed with aqueous NH4CI and brine, dried over sodium sulfate, and concentrated to give the crude product as brown oil. Purification by silica gel column using 20% EtOAc in hexane afforded 1.63 g (94%) of the title compound as a sticky, yellow oil: 1 H NMR (CDCI3) δ 1.45 (s, 9H), 1.67 - 1.75 (m, 2H), 1.87 - 1.92 (m, 2H), 2.84 (m, 1 H), 3.20 - 3.26 (m, 2H), 3.78 (br d, 2H), 7.88 (dd, 1 H), 7.97 (d, 1 H), 8.26 (d, 1 H), 9.00 (s, 1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | 4-Chloro-6-iodo-quinazoline (1.00 g; 3.44 mmol) and 0.70 g (4.64 mmol) of thiazolo[5,4-b]pyridin-2-yl-amine were heated at 135C for 4 hours with stirring in 10 ml of phenol. Chloroform was added to the reaction solution followed by washing with a 1N aqueous solution of sodium hydroxide. The organic layer was dried and concentrated and the resulting residue was purified by a silica gel column chromatography (chloroform : methanol = 50:1) to give 486 mg (yield: 35%) of (6-iodo-qunazolin-4-yl)-thiazolo[5,4-b]pyridin-2-yl-amine as a yellow solid. To a solution of 80 mg (0.197 mmol) of the resulting iodine compound in 2 ml of N,N-dimethylacetamide were added 38 mg (0.197 mmol) of copper iodide, 128 mg (0.394 mmol) of cesium carbonate and 30 mg (0.295 mmol) of 3-mercapto-1,2,4-triazole followed by stirring at 140C for 5 hours. Water was added to the reaction solution followed by extracting with chloroform. The organic layer was dried and concentrated and the resulting residue was purified by a thin layer silica gel chromatography (chloroform : methanol = 8:1) to give 15 mg (yield: 20%) of the title compound as a yellow solid. 1 HNMR(CDCl3) δ: 7.43-7.46(1H,m),7.82(1H,d,J = 8.8Hz),7.90(1H,d,J = 8.8Hz),8.05(1H,d,J = 8.0Hz),8.18(1H,s),8.31(1H,s),8.43(1H,d,J = 3.6Hz),8.69(1H,s) ESI-MS(m/e):379[M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With copper(l) iodide; diisopropylamine;bis-triphenylphosphine-palladium(II) chloride; In tetrahydrofuran; at 20℃; for 20h; | 2-Chloro-N-[3-(4-chloro-quinazolin-6-yl)-prop-2-ynyl]-acetamide: 2-Chloro-N-prop-2-ynyl-acetamide (385 mg; 2.93 mmol) and <strong>[98556-31-1]4-chloro-6-iodoquinazoline</strong> (850 mg; 1 equiv.) were dissolved in dry THF and diisopropylamine (296 mg; 0.41 mL; 1 equiv.). To this mixture was added 0.04 equivalents of copper iodide (22 mg) and Pd(PPh3)2Cl2 (82 mg). The reaction was stirred at room temperature under a nitrogen atmosphere overnight (20 hrs). The solvent was then removed in vacuo and the residue dissolved in CH2Cl2. This solution was transferred to a separatory funnel and washed with 1×saturated NH4Cl, brine, dried over Na2SO4 and the solvent removed in vacuo. The product was purified by silica gel chromatography eluting with 1:1 Hexanes/EtOAc and collecting fractions with an Rf=0.25. 2-Chloro-N-[3-(4-chloro-quinazolin-6-yl)-prop-2-ynyl]-acetamide was obtained as an off white solid (454 mg; 53%) |
53% | With copper(l) iodide; diisopropylamine;bis-triphenylphosphine-palladium(II) chloride; In tetrahydrofuran; at 20℃; for 20h; | 2-ChIoro-N- prop-2-ynyl-acetamide (385mg; 2.93 mmol) and 4-chloro-6-iodoquinazone (850 mg; 1 equiv.) were dissolved in dry THF and diisopropylamine (296 mg; 0.41 mL; 1 equiv.). To this mixture was added 0.04 equivalents of copper iodide (22 mg) and Pd(PPh3)2CI2 (82 mg). The reaction was stirred at room temperature under a nitrogen atmosphere overnight (-20 hrs). The solvent was then removed in vacuo and the residue dissolved in CH2CI2. This solution was transferred to a separatory funnel and washed with 1 x saturated NH4CI, brine, dried over Na2SO4 and the solvent removed in vacuo. The product was purified by silica gel chromatography eluting with 1 :1 Hexanes/EtOAc and collecting fractions with an Rf = 0.25. 2-Chloro-N-[3-(4-chloro-quinazolin-6-yl)-prop-2-ynyl]-acetamide was obtained as an off white solid (454 mg; 53%). 1H NMR (400 MHz; CDCI3) δ 4.12 (2H, s), 4.40 (2H, d, J = 5.2 Hz), 7.91-7.93 (1 H1 dd, J = 2, 6.8 Hz), 8.00 (1H, d, J = 8.4 Hz), 8.34 (1 H, d, J = 1.6 Hz), 9.03 (1 H, s). lrms (M+): 294.0, 296.0, 298.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 1,2-dichloro-ethane; tert-butyl alcohol; at 90℃; for 0.5h; | Preparation of (5-{4-[(6-iodoquinazolie-4-yl)amino]-2-methylphenoxy}-1- oxidopyridin-2-yl)methanolA mixture of <strong>[98556-31-1]4-chloro-6-iodoquinazoline</strong> (374mg, 1.3mmol), 5-(4-amino-2methylphenoxy)-1-oxidopyridin-2-yl]methanol (160mg, 1.3mmol), 1 ,2- Dichloroethane (2mL) and t-BuOH (2mL) was heated up to 9O0C in a sealed tube for Vz hour. To the mixture was added Et20 and filtered the precipitation to obtain the desired product (456mg). m/z (ES+)(M+1): 501.2, HPLC:Rt= 5.169 mins. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetonitrile; for 6h;Heating / reflux; | 4-Chloro-6-iodoquinazoline (WO9609294 Al , 150 mg) was treated with 4- triazolyl aniline (28 mg, 1 eq) in MeCN and refluxed for 6 h. Cooled overnight and filtered to give the title compound (70 mg).1R NMR delta 11.75 (IH, br s), 9.4 (2H, s), 9.04 (IH, s), 8.43 (IH, d, J 8.85Hz),8.34 (IH, s), 8.0(4H, m), 7.82 (IH, d, J 8.85Hz); LC-MS rt 2.32 m/z 415 ES+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
24% | In isopropyl alcohol; at 80℃; for 4h; | Step C: Preparation of N-(4-(H-imidazo[1,2-a]pyridin-7-yloxy)-3-methylphenyl)-6-iodoquinazolin-4-amine hydrochloride: To a solution of <strong>[98556-31-1]4-chloro-6-iodoquinazoline</strong> (6.07 g, 20.9 mmol) in isopropanol (83 mL) was added 4-(H-imidazo[1,2-a]pyridin-7-yloxy)-3-methylbenzenamine (5.00 g, 20.9 mmol). After heating to 80 C for 4 hours, the mixture was cooled to room temperature and filtered. The solid was washed with cold isopropanol and recrystallized from isopropanol to provide the product (2.66 g, 24%) as yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | 18a) 4-BENZVLOXV-6-IODO-QUINAZOLINE NaH (152 mg, 5.7 mmol, 1.5 eq) is added to a solution of benzyl alcohol (820 mg, 7. 6 mmol, 2 eq) in DMF (10 mL) an the resulting suspension is stirred for 30 min. Then 4- CHLORO-6-IODO-QUINAZOLINE- (1.1 g, 3.8 MMOL, 1 eq) is added to this solution and the reaction mixture is heated to 100 C for 4 h. CH2CI2 (50 mL) is added and the solution is washed with H20 and brine. Chromatography (SIO2, 10-60% EtOAc-hexanes gradient elution) provides 4-benzyloxy-6-iodo-quinazoline (1.21 g, 88 %). MS/ESI, M+1 = 362.88 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 6: N-r3-Chloro-4-(3-Fluorobenzyloxy)-Phenyll-6-Iodoquinazolin-4-amine preparation (one-pot process)[00088] 30.0 g of "Intermediate-A" (compound of Formula A), 17.8 g of iron powder (70 mesh), 51.3 g of ammonium chloride, 432 ml of ethanol and 108 ml of water were refluxed for 5 hours in IL reactor equipped with mechanical stirrer and condenser. The reaction mixture was then cooled to 20-250C and separated from insoluble iron oxide by vacuum filtration. The filtered solids were washed with ethanol (4 x 100 ml). The resulting filtrate was evaporated from reactor under reduced pressure to resulting in a wet orange residue. The residue was dissolved in 350 ml of dichloromethane and 300 ml water. The separated organic phase was washed with water (2 x 300 ml). The obtained organic solution was concentrated to about 150 ml followed by addition of 300 ml iso- propanol. The mixture was concentrated to 300 ml followed by addition 150 ml iso- propanol. The resulting mixture was concentrated to 300 ml. Then iso-propanol was added to obtain a final volume of about 570 ml (purity determined by HPLC: 98.5%).[00089] 23.8 g of <strong>[98556-31-1]4-chloro-6-iodoquinazoline</strong> were added to the organic solution, heated to reflux, stirred for 30 minutes and then cooled to 20-250C. The slurry was filtered and washed with 110 ml iso-propanol to obtain 53.5 g of wet crude product. Then it was triturated in 830 ml of boiling acetone for an hour, cooled and filtered. The product was triturated twice again each time in 655 ml of boiling acetone for an hour, cooled and filtered. Finally it was dried at 250C in vacuum oven to afford 32.2 g of "Intermediate-C" (Yield: 60%, Purity: 92.62%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In isopropyl alcohol; for 12h;Reflux; | Step C: [3-chloro-4-(2-pyridylmetoxyl)-phenyl]-(6-iodo-quinazolin- 4-yl)-aminehydrochloride salt (compound 8.3).[0126] 470mg of compound 8.3 (2 mmol) and 580mg of 4-chloro-6-iodo-quinazoline (2 mmol) were dissolved in isopropanol (10 ml). The reaction mixture was refluxed for 12 hours. The solid product was collected by filtration, washed with cold isopropanol (10 mL) and ether (20 mL), and air dried to afford 450 mg of the clean desired material. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In isopropyl alcohol; for 12h;Reflux; | Step C: N-(4-(3-fluorobenzyloxy)-3-bromophenyl)-6-iodoquinazolin-4-amine (compound 14.3)[0149] 4-(3-fluorobenzyloxy)-3-bromobenzenamine (1.48 g, 5 mmol) and 4-chloro-6-iodo- quinazoline (1.45 g, 5 mmol) were dissolved in isopropanol (50 ml). The reaction mixture was refluxed for 12 hours. The solid product was collected by filtration, washed with cold isopropanol (10 mL) and ether (20 mL), and air dried to afford 2.7 g of the clean desired material. | |
In acetonitrile;Reflux; | General procedure: (A) Reaction of an Amine with a Bicyclic Species Containing a 4-chloropyrimidine or 4-chloropyridine Ring; The optionally substituted bicyclic species and the specified amine were mixed in an appropriate solvent (typically acetonitrile unless otherwise specified, although ethanol, 2-propanol or DMSO may also be used), and heated to reflux. When the reaction was complete (as judged by tlc), the reaction mixture was allowed to cool. The resulting suspension was diluted, e.g. with acetone, and the solid collected by filtration, washing e.g. with excess acetone, and dried at 60 C. in vacuo, giving the product as the hydrochloride salt. If the free base was required (e.g. for further reaction), this was obtained by treatment with a base e.g. triethylamine; purification by chromatography was then performed if required.; The title compound was prepared according to Procedure A from 3-bromo-4-(3-fluorobenzyloxy)-aniline (0.79 g, 2.7 mmol) and <strong>[98556-31-1]4-chloro-6-iodoquinazoline</strong> (0.8 g, 2.7 mmol). 1H NMR (DMSO-d6) δ 11.1 (bs, 1H); 9.10 (s, 1H); 8.87 (s, 1H); 8.29 (d, 1H); 8.03 (s, 1H); 7.68 (m, 1H); 7.62 (d, 1H); 7.45 (m, 1H); 7.33-7.26 (m, 3H); 7.16 (m, 1H); 5.28 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | In isopropyl alcohol; for 3.5h;Inert atmosphere; Reflux; | Under nitrogen, 4-chloro-6-iodo-quinazoline (0.6g, 2mmol) and 3-chloro-4- (3-fluoro-benzyloxy) aniline (0.5g, 2mmol) in isopropanol (15ml ) was stirred at reflux for 3.5h. Cooled to room temperature and filtered to give a yellow crystalline solid (1g, 96%). |
96% | In isopropyl alcohol; for 3.5h;Inert atmosphere; Reflux; | Under nitrogen, 4-chloro-6-iodo-quinazoline (0.6g, 2mmol) and 3-chloro-4-(3-fluorobenzyloxy)aniline (0.5g, 2mmol) in isopropanol (15ml ) was stirred at reflux for 3.5h. Cooled to room temperature and filtered to give a yellow crystalline solid (1g, 96%). |
In isopropyl alcohol; for 12h;Reflux; | Step F: [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-iodo-quinazolin- 4-yl)-aminehydrochloride salt (compound 1.6).[0107] 3-Chloro-4-(3-fluoro-benzyloxy)-phenylamine (3.1 g, 12 mmol) and 4-chloro-6-iodo- quinazoline (3.28 g, 11.3 mmol) were dissolved in isopropanol (50 ml). The reaction mixture was refluxed for 12 hours. The solid product was collected by filtration, washed with cold isopropanol (10 mL) and ether (20 mL), and air dried to afford 3.8 g of the clean desired material. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10% | Method of svnthesising quinazoline D.4Aminoalcohol ED.6 (98 μΙ_, 0.76 mmol) is placed in DMF, combined with K2C03 (105 mg, 0.76 mmol) and stirred for 5 min at 20C. Then quinazoline D*.4 (200 mg, 0.69 mmol) is added and the mixture is stirred for 30 min at 150C. The solvent is removed and D.4 (24 mg, 10 %; HPLC-MS: MS(M+H)+ = 358; tRet = 1.78 min; method LCMSBAS1 ) is obtained. | |
10% | Method of Synthesising Quinazoline D.4Aminoalcohol ED.6 (98 μL, 0.76 mmol) is placed in DMF, combined with K2CO3 (105 mg, 0.76 mmol) and stirred for 5 min at 20 C. Then quinazoline D*.4 (200 mg, 0.69 mmol) is added and the mixture is stirred for 30 min at 150 C. The solvent is removed and D.4 (24 mg, 10%; HPLC-MS: MS (M+H)+=358; tRet.=1.78 min; method LCMSBAS1) is obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With copper(l) iodide; N-ethyl-N,N-diisopropylamine;tetrakis(triphenylphosphine) palladium(0); In dimethyl sulfoxide; at 40℃; for 3h; | E.1Iodide D*.4 (1 .60 g, 5.00 mmol), propargylamide C.1 (1 .71 g, 5.50 mmol), Pd(PPh3)4 (1 17 mg, 10 mol %) and Cul (20 mg, 10 mol %) are placed in DMSO (20 mL), combined with DIPEA (5 mL) and stirred for 3 h at 40C. The reaction mixture is combined with water and DCM, the organic phase is separated off and extracted another 2 x with water. Then the organic phase is dried, the solvent is eliminated in vacuo, the crude product is purified by chromatography and quinazoline E.1 (2.12 g, 46 %; HPLC-MS: MS(M-H)" = 464; tRet.= 1.93 min; method LCMSBAS1 ) is obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide;Reflux; | Example 1 Preparation of N-(4-(3-fluorobenzyloxy)-3-chlorophenyl)-6-iodine-quinazolin-4-amine 6-Iodine-3H-quinazolin-4-ketone (100 g) was added into a 2000 mL flask, dissolved in a mixed solvent of thionyl chloride (1000 mL) and N,N-dimethylformamide (20 mL), heated to reflux until the reaction solution is clear and transparent. After thionyl chloride was removed, anhydrous toluene was added to the residues and removed under reduced pressure, and the process of the adding and removing of toluene was repeated again to removed the remained thionyl chloride residues. The intermediate was dissolved in isopropyl alcohol (2000 mL), 3-chloro-4-(3-fluoro-benzyloxy)-aniline hydrochloride was added, and anhydrous K2CO3 (150 g) was added with mechanical stirring before the mixture was heated to reflux over night. The reaction solution was cooled to room temperature overnight, the precipitation was filtered and washed with water for multi-times until the pH of washing solution reached neutral. After drying under vacuum, 95 g of the title product was collected in a pale white solid. m/z M+1+: 506 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98.7% | In isopropyl alcohol; at 70℃; for 2h;Inert atmosphere; | In a glass flask provided with a condenser, thermometer, mechanical stirrer and nitrogen inlet, - under nitrogen flow - 15.0 g of 3-chloro-4-[(2-fluorobenzyl) oxy]aniline of formula (IV), 17.49 g of <strong>[98556-31-1]4-chloro-6-iodoquinazoline</strong> of formula (VIII)(available in the market), 300 mL of Isopropanol are introduced. The reaction mixture is stirred at 70 C for 2 hrs. Upon completing the reaction cooling is carried out at ambient temperature. The formed yellow solid is filtered washing the solid with 20 mL of cold Isopropanol. 31.9 g of product equivalent to a 98.7% molar yield are obtained. 1H-NMR spectrum according to figure 5. |
98.7% | In isopropyl alcohol; at 70℃; for 2h;Inert atmosphere; | In a glass flask provided with a condenser, thermometer, mechanical stirrer and nitrogen inlet, -under nitrogen flow-15.0 g of 3-chloro-4-[(2-fluorobenzyl)oxy]aniline of formula (IV), 17.49 g of <strong>[98556-31-1]4-chloro-6-iodoquinazoline</strong> of formula (VIII) (available in the market), 300 mL of Isopropanol were introduced. The reaction mixture was stirred at 70 C. for 2 hrs. Upon completing the reaction cooling was carried out at ambient temperature. The formed yellow solid was filtered washing the solid with 20 mL of cold Isopropanol. 31.9 g of product equivalent to a 98.7% molar yield were obtained. 1H-NMR spectrum according to FIG. 5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.5% | To a stirred mixture of 4-Chloro-6-iodoquinazoline ( 10.0 g) and 4-Amino-2- chlorophenol (4.94 g) in Acetonitrile (100 ml) was refluxed for 1 hour. Reaction was monitored by TLC. On completion of reaction the reaction mixture was cooled to 20- 25C and the solid was filtered. Crude 2-chloro-4-(6-iodoquinazolin-4-ylamino)phenol hydrochloride so obtained was dissolved in demineralized water and neutralized with Sodium carbonate (3.65 g). Solid was filtered and dried under vacuum at 60-65C till constant weight. Weight: 13 g Yield: 94.5 % MS (ES+) m/z: 398 [M+H]+ & 400 [M+H+2]+ 1H NMR (400 MHz; DMSO-d6): 7.06 (d, J=8.8 Hz, 1H), 7.47 (d, J=8.8 Hz, 1H), 7.64 (d, J=8.8 Hz, 1H), 7.77 (s, 1H), 8.28 (d, J=8.8 Hz, 1H), 8.84 (s, 1H), 9.13 (s, 1H), 10.39 (s, 1H, OH), 1 1.06 (s, 1Eta, NuEta). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In 1,4-dioxane; at 80℃; for 2h; | 10.1 Preparation of 6-iodo-4-(7-methoxy-3,4-dihydro-1H-isoquinolin-2-yl)-quinazoline 0.75 g of 4-chloro-6-iodoquinazoline, 0.58 g of <strong>[43207-78-9]7-methoxy-1,2,3,4-tetrahydro-isoquinoline</strong> and 0.64 ml of triethylamine in 5 ml of dioxane are heated at 80 C. in a flask until the quinazoline has reacted completely (HPLC check, about 2 hours). The cooled reaction solution is diluted with EA and washed 3 times with water. The organic phase is dried over sodium sulfate and purified by means of column chromatography (gradient heptane: EA 5-100% in 22 min.), giving 0.60 g of 6-iodo-4-(7-methoxy-3,4-dihydro-1H-isoquinolin-2-yl)quinazoline as yellowish solid (yield 57%, content 93%); MS-FAB (M+H+)=418.0; Rf (polar method): 1.87 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With triethylamine; In 1,4-dioxane; at 80℃; for 24h; | 11.1 Preparation of 4-(6-iodoquinazolin-4-yl)-3,4-dihydro-2H-benzo-1,4-oxazine 0.75 g of <strong>[98556-31-1]4-chloro-6-iodoquinazoline</strong>, 0.39 g of 3,4-dihydro-2H-benzo-1,4-oxazine and 0.50 ml of triethylamine in 5 ml of dioxane are heated at 80 C. in a flask until the quinazoline has reacted completely (HPLC check, about 24 hours). The cooled reaction solution is evaporated to dryness. The residue is washed by stirring with EA and filtered off with suction, giving 0.35 g of 4-(6-iodoquinazolin-4-yl)-3,4-dihydro-2H-benzo-1,4-oxazine as yellowish solid (yield 40%, content 96%); MS-FAB (M+H+)=390.0; Rf (polar method): 2.36 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In 1,4-dioxane; at 80℃; for 24h; | 12.1 Preparation of 1-(6-iodoquinazolin-4-yl)-2,3,4a,8a-tetrahydro-1H-quinolin-4-one 0.75 g of <strong>[98556-31-1]4-chloro-6-iodoquinazoline</strong>, 0.51 g of 2,3,4a,8a-tetrahydro-1H-quinolin-4-one and 0.96 ml of triethylamine in 5 ml of dioxane are heated at 80 C. in a flask until the quinazoline has reacted completely (HPLC check, about 24 hours). The cooled reaction solution is diluted with EA and washed 3 times with water. The organic phase is dried over sodium sulfate and purified by means of column chromatography (gradient heptane: EA 5-100% in 16 min.), giving 0.40 g of 1-(6-iodoquinazolin-4-yl)-2,3,4a,8a-tetrahydro-1H-quinolin-4-one as yellowish solid (yield 40%, content 91%); MS-FAB (M+H+)=402.0; Rf (polar method): 2.20 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With triethylamine; In 1,4-dioxane; at 80℃; for 24h; | 1.2 Preparation of 4-(2,3-dihydroindol-1-yl)-6-iodoquinazoline 0.60 g of <strong>[98556-31-1]4-chloro-6-iodoquinazoline</strong>, 0.31 ml of 2,3-dihydro-1H-indole and 0.50 ml of triethylamine in 5.00 ml of dioxane are heated at 80 C. in a flask until the quinazoline has reacted completely (HPLC check, about 24 hours). The cooled reaction solution is evaporated to dryness in a rotary evaporator. The residue is purified by means of column chromatography (gradient EA: methanol 0-20% in 16 min.), giving 0.60 g of 4-(2,3-dihydroindol-1-yl)-6-iodo-quinazoline as yellowish solid (yield 85%, content 97%); MS-FAB (M+H+)=373.8; Rf (polar method): 2.21 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In 1,4-dioxane; at 80℃; for 3h; | 2.1 Preparation of 4-(1,3-dihydroisoindol-2-yl)-6-iodoquinazoline 0.50 g of <strong>[98556-31-1]4-chloro-6-iodoquinazoline</strong>, 0.27 g of 2,3-dihydro-1H-isoindole, 0.42 ml of triethylamine in 4 ml of dioxane are heated at 80 C. in a flask until the quinazoline has reacted virtually completely (HPLC check, about 3 hours). The cooled reaction solution is evaporated to dryness in a rotary evaporator. The residue is suspended in EA. The undissolved solid is filtered off, rinsed with water and dried, giving 0.56 g of 4-(1,3-dihydroisoindol-2-yl)-6-iodoquinazoline as slightly yellowish solid (yield 93%, content 94%); MS-FAB (M+H+)=373.8; Rf (polar method): 1.73 min. This is employed for the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | In 1,4-dioxane; at 110℃; for 3h; | 7.1 Preparation of 4-(3,4-dihydro-2H-quinolin-1-yl)-6-iodoquinazoline 1.30 g of <strong>[98556-31-1]4-chloro-6-iodoquinazoline</strong>, 1.50 ml of 1,2,3,4-tetrahydroquinoline in 10 ml of dioxane are heated at 110 C. in a flask until the quinazoline has reacted completely (HPLC check, about 3 hours). The cooled reaction solution is diluted with EA and washed 3 times with 5% citric acid. The organic phase is dried over sodium sulfate and purified by means of column chromatography (gradient heptane: EA 0-100% in 18 min.), giving 1.27 g of 4-(3,4-dihydro-2H-quinolin-1-yl)-6-iodoquinazoline as yellowish solid (yield 81%, content 99%); MS-FAB (M+H+)=388.0; Rf (polar method): 2.89 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In 1,4-dioxane; at 80℃; for 3h; | 6.3 Preparation of 4-(3,4-dihydro-1H-isoquinolin-2-yl)-6-iodoquinazoline 0.75 g of <strong>[98556-31-1]4-chloro-6-iodoquinazoline</strong>, 0.45 g of 1,2,3,4-tetrahydroisoquinoline and 0.63 ml of triethylamine in 6.0 ml of dioxane are heated at 80 C. in a flask until the quinazoline has reacted completely (HPLC check, about 3 hours). The cooled reaction solution is evaporated to dryness in a rotary evaporator. The residue is purified by means of column chromatography (gradient heptane: EA 10-100% in 20 min.), giving 0.87 g of 4-(3,4-dihydro-1H-isoquinolin-2-yl)-6-iodoquinazoline as yellowish solid (yield 90%, content 92%); MS-FAB (M+H+)=388.0; Rf (polar method): 1.84 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In acetonitrile; for 1h;Reflux; | Example 1 Synthesis of CD 8/CD 19 inhibitors SNX-2-1-165 was synthesized according to the scheme shown in Figure 2. All other compounds were synthesized using similar procedures. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | In isopropyl alcohol; at 20℃; for 0.5h; | To a solution of 4-chloro-6-iodoquinazoline (2.60 g, 8.95 mmol) in isopropanol (60 mL) was added <strong>[1123-93-9]1,3-benzothiazol-5-amine</strong> (1.479 g, 9.85 mmol). The mixture was then placed in oil bath10 preheated to 90°C. The reaction was complete in 30 min., and the solution was allowed tocool to room temperature. A yellow solid precipitated and was filtered and dried toprovide 3.6 g (91 percent) of the title compound. |
91% | In isopropyl alcohol; at 90℃; for 0.5h; | N-1,3-benzothiazol-5-yl-6-iodo-4-quinazolinamine To a solution of 4-chloro-6-iodoquinazoline (2.60 g, 8.95 mmol) in isopropanol (60 mL) was added <strong>[1123-93-9]1,3-benzothiazol-5-amine</strong> (1.479 g, 9.85 mmol). The mixture was then placed in oil bath preheated to 90°C. The reaction was complete in 30 min., and the solution was allowed to cool to room temperature. A yellow solid precipitated and was filtered and dried to provide 3.6 g (91 percent) of the title compound. The following intermediate, N-(5-fluoro-1H-indazol-3-yl)-6-iodo-4-quinazolinamine, was made in the same manner: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In 1,4-dioxane; | To a vial was added 4-chloro-6-iodo-quinazoline (100 mg; 0.34 mmol, commercially available), pyridin-4-amine (3 equiv., 1.03 mmol, 97.19 mg, commercially available), and 2 drops of 4M HCl/dioxane. The reaction vial was heated until solids melted. LCMS of resultant solution showed clean product formation. Upon cooling the product re-solidified. The solid was suspended in dichloromethane:water, and collected by filtration. 95 mg of 6-iodo-N-(4-pyridyl)quinazolin-4-amine was recovered as an orange solid, which was carried on directly to the Suzuki step. LCMS M/Z (M+H)=350. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N,N-dimethyl-formamide; at 60℃; for 3h; | To 8 mL screw-cap vials was added 4-chloro-6-iodo-quinazoline (0.25 mmol, 73 mg), cyclopropyl amine 3 equiv., 0.75 mmol, 43 mg), and dimethylformamide (0.5 mL). The reaction was capped and shaken at 60 C. for 3 h. The crude N-cyclopropyl-6-iodo-quinazolin-4-amine was then cooled to room temperature, concentrated via GeneVac, and then carried on to the Suzuki step. LCMS M/Z (M+H)=312. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With triethylamine; In isopropyl alcohol; at 60℃; for 20h;Inert atmosphere; | To a solution of <strong>[98556-31-1]4-chloro-6-iodoquinazoline</strong> (500 mg, 1.7 mmol) and 1,2,3,4- tetrahydronaphthalen-1-amine (252 mg, 1.7 mmol) in isopropyl alcohol (30 mL) was added triethylamine (0.7 mL, 5.0 mmol). The resulting solution was heated to 60 C under nitrogen for 20 h. LC-MS analysis showed completed consumption of starting material. The mixture was cooled down and excess isopropyl alcohol was removed by rotary evaporation. The residue was purified by Prep-HPLC to give A28-001 as a yellow solid (400 mg, yield:60%). LC-MS 402 (M+H), purity 100% (UV 214 nm); ‘H NMR (400 MHz, DMSO-d6) ö8.82 (d, J = 2.0 Hz, 1H), 8.62 (d, J = 8.0 Hz, 1 H), 8.53 (s, 1 H), 8.02 (d, J = 8.8 Hz, 1 H),7.48 (d, J = 8.8 Hz, 1 H), 5.73-5.70 (m, 1 H), 2.84-2.8 1 (m, 2 H), 2.03-1.90 (m, 4 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | With triethylamine; In isopropyl alcohol; at 65℃; for 18h;Inert atmosphere; | To a solution of <strong>[98556-31-1]4-chloro-6-iodoquinazoline</strong> (124 mg, 0.42 mmol) and 6-fluoro- 1,2,3,4-tetrahydronaphthalen-2-amine (70 mg, 0.42 mmol) in isopropyl alcohol (10 mL) was added triethylamine (127 mg, 1.3 mmol). The resulting solution was heated to 65 C under nitrogen for 18 h. LC-MS analysis showed completed consumption of starting material. The reaction mixture was cooled down and excess isopropyl alcohol was removed by rotary evaporation. The residue was purified by Prep-HPLC to give A28-002 as a white solid (60 mg, yield: 34%). LC-MS 420 (M+H), purity 100% (UV 214 nm); ‘H NMR (400 MHz, DMSO-d6) ö 8.80 (d, J = 2.0 Hz, 1 H), 8.50 (s, 1 H), 8.23 (d, J = 7.2 Hz, 1 H), 8.04 (dd, J = 9.2 Hz, 2.0 Hz, 1 H), 7.47 (d, J = 8.8 Hz, 1 H), 7.16 (t, J = 6.8 Hz, 1 H), 6.98-6.94 (m, 2 H), 4.62-4.58 (m, 1 H), 3.16 (dd, J = 16.0 Hz, 5.2 Hz, 1 H), 2.94-2.85 (m, 3 H), 2.14- 2.16 (m, 1 H), 1.88-1.80 (m, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 16h;Inert atmosphere; | To a solution of <strong>[98556-31-1]4-chloro-6-iodoquinazoline</strong> (144 mg, 0.49 mmol) and 1, 2, 3, 4 - tetrahydronaphthalene-1,6-diamine 9b (80 mg, 0.49 mmol) in DMF (10 mL) was added potassium carbonate (205 mg, 1.48 mmol). The resulting solution was heated to 90 C under nitrogen for 16 h. LC-MS analysis showed completed consumption of starting material. The reaction mixture was cooled down and poured into water (20 mL), extracted with ethyl acetate (2 x 50 mL). The organic phase was dried over sodium sulfate, filtered, and the filtrate was evaporated in vacuo to give the crude product A23-025-1 (85 mg, yield:4 1%). LC-MS 417 (M+H), purity 90% (UV 214 nm). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 90℃;Inert atmosphere; | To a solution of <strong>[98556-31-1]4-chloro-6-iodoquinazoline</strong> (144 mg, 0.49 mmol) and 1, 2, 3, 4 - tetrahydronaphthalene-2,6-diamine (80 mg, 0.49 mmol) in DMF (10 mL) was added potassium carbonate (205 mg, 1.48 mmol). The resulting solution was heated to 90 C under nitrogen for overnight. LC-MS analysis showed completed consumption of starting material. The reaction mixture was cooled down and poured into water (20 mL), extracted with ethyl acetate (2 x 30 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo to give the crude product compound A23-016-1 (62 mg yield:30%). LC-MS 417 (M+H), purity 70% (UV 214 nm). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 16h;Inert atmosphere; | To a solution of <strong>[98556-31-1]4-chloro-6-iodoquinazoline</strong> (144 mg, 0.49 mmol) and 1, 2, 3, 4 - tetrahydronaphthalene-2,7-diamine 9d (80 mg, 0.49 mmol) in DMF (10 mL) was added potassium carbonate (205 mg, 1.48 mmol). The resulting solution was heated to 90 C under nitrogen for 16 h. LC-MS analysis showed completed consumption of starting material. The reaction mixture was cooled down and poured into water (20 mL), extracted with ethyl acetate (2 x 100 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo to give the crude product A23-026-1(85 mg yield: 4 1%). LC-MS 417 (M+H), purity 90% (UV 214 nm). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With triethylamine; In isopropyl alcohol; at 60℃; for 16h;Inert atmosphere; | To a solution of 2-amino-1,2,3,4-tetrahydronaphthalen-1-ol hydrochlorid 12 (580 mg, 2.0 mmol) and <strong>[98556-31-1]4-chloro-6-iodoquinazoline</strong> (580 mg, 2.0 mmol) in isopropyl alcohol (20 mL) was added triethylamine (1.5 mL, 10.8 mmol). The resulting solution was heated to 60 C under nitrogen for 16 h. The reaction mixture was cooled down and excess isopropyl alcohol was removed by rotary evaporation. The residue was purified by PrepHPLC to give A30-002 as a yellow solid (400 mg, yield: 48%). LC-MS 418 (M+H), purity 96% (UV 214 nm); ‘H NMR (400 MHz, DMSO-d6) ö 8.81 (s, 1 H), 8.48 (s, 1 H), 8.22-8.20 (m, 1 H), 8.04-8.01 (m, 1 H), 7.54-7.45 (m, 2 H), 7.22-7.10 (m, 3 H), 5.52-5.50 (m, 1 H), 4.85-4.81 (m, 1 H), 4.47-4.45 (m, 1 H), 2.93-2.83 (m, 2 H), 2.16-2.12 (m, 1 H), 1.84-1.79 (m, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With triethylamine; In isopropyl alcohol; at 85℃; for 3h; | To a solution of 5-fluoro-2,3-dihydro-1H-inden-2-amine hydrochloride (75 mg,0.4 mmol) in i-PrOH (10 mL) were added <strong>[98556-31-1]4-chloro-6-iodoquinazoline</strong> (116 mg, 0.4 mmol)and TEA (0.5 mL). The mixture was stirred at 85 C for 3 h. All of the volatiles wereevaporated and the residue was purified by silica gel column chromatography (usingpetroleum ether : EtOAc = 10:1 - 3:1) to give the desired compound A29-028 as a whitesolid (50 mg, yield: 30%). LC-MS 406 (M+H), purity 100% (UV 214 nm); ‘H NMR(DMSO-d6, 400 MHz) ö 8.78 (d, J = 6.0, 1 H), 8.53 (s, 1 H), 8.45 (d, J = 6.8 Hz, 1 H), 8.03-8.00 (m, J, = 2.0 Hz, J2 = 8.8 Hz, 1 H), 7.47 (d, J = 8.8 Hz, 1 H), 7.29-7.26 (m, 1 H), 7.12-7.09 (dd, J, = 2.4 Hz, J2 = 9.2 Hz, 1 H), 6.99 (t, J = 9.6 Hz, 1 H), 5.03-5.00 (m, 1 H), 3.41-3.33 (m, 2 H), 3.09-3.02 (m, 2 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With triethylamine; In isopropyl alcohol; at 85℃; for 3h; | To a solution of 5-methoxy-2,3-dihydro-1H-inden-1-amine (526 mg, 2.0 mmol) in iPrOH (20 mL) were added <strong>[98556-31-1]4-chloro-6-iodoquinazoline</strong> (580 mg, 2.0 mmol) and TEA (1.0mL). The mixture was stirred at 85 C for 3 h. All of the volatiles were evaporated and theresidue was purified by silica gel column chromatography (using petroleum ether : EtOAc= 10:1 - 2:1) to give the desired compound A29-029 as a pale yellow solid (400 mg, yield:48%). LC-MS 418 (M+H), purity 97% (UV 214 nm); ‘H NMR (DMSO-d6, 400 MHz) ö8.80 (s, 1 H), 8.55-8.52 (m, 2 H), 8.03-8.00 (dd, J, = 2.0 Hz, J2 = 8.4 Hz, 1 H), 7.47 (d, J =8.8 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1 H), 6.88 (s, 1 H), 6.75-6.72 (dd, J, = 2.4 Hz, J2= 8.4 Hz,1 H), 5.93-5.90 (m, 1 H), 3.73 (s, 3 H), 3.03-3.00 (m, 1 H), 2.88-2.83 (m, 1 H), 2.56-2.51(m, 1 H), 2.07-2.03 (m, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With triethylamine; In isopropyl alcohol; at 70℃; for 8h; | In another approach, to a solution of <strong>[98556-31-1]4-chloro-6-iodoquinazoline</strong> (1.23 mg, 4.2 mmoL) in isopropanol (30 mL was added compound 1 (631 mg, 3.5 mmol) and triethylamine (0.5 g, 5.0 mmol). The mixture was stirred at 70 for 8 h. The mixture is cooled down and isopropanol is removed by rotary evaporation. The residue was purified by silica gel to give desired product A29-003 (923 mg, yield: 50 %) as a yellow solid. LCMS (mlz): 433.0 (M+H). ‘HNMR (400 MHz, DMSO-d6): ö 8.75 (s, 1H), 7.56 (s, 1H), 8.46 (d, J = 6.4 Hz, 1H), 8.15 (s, 1H), 8.09 (d, J = 6.4 Hz, 1H), 8.03 (d, J = 7.2 Hz, 1H),7.55 (d, J = 8.4 Hz, 1H), 7.48 (d, J = 8.8 Hz, 1H), 5.08-5.06 (m, 2H), 3.53-3.47 (m, 2H),3.19-3.14 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With triethylamine; In isopropyl alcohol; at 80℃; for 3h; | To a solution of 5 -methoxy-2,3 -dihydro- 1H-inden-2-amine hydrochloride (290 mg, 1.0 mmol) in i-PrOH (15 mL) were added <strong>[98556-31-1]4-chloro-6-iodoquinazoline</strong> (160 mg, 0.8 mmol) and TEA (1.0 mL). The mixture was stirred at 80 C for 3 h. All of the volatiles were evaporated and the residue was purified by silica gel column chromatography (using petroleum ether : EtOAc = 10:1 - 2:1) to give the desired compound A29-048 as a pale yellow solid (170 mg, yield: 50%). LC-MS 417 (M+H), purity 97% (UV 214 nm); ‘H NMR (DMSO-d6, 400 MHz) ö 8.78 (s, 1 H), 8.52 (s, 1 H), 8.43 (d, J = 6.4 Hz, 1 H), 8.42- 8.00 (dd, J, = 1.6 Hz, J2 = 8.4 Hz, 1 H), 7.46 (d, J = 8.0 Hz, 1 H), 6.85 (s, 1 H), 6.75-6.73 (dd, J, = 2.4 Hz, J2 = 8.4 Hz, 1 H), 5.0 1-4.97 (m, 1 H), 3.73 (s, 3 H), 3.36-3.26 (m, 2 H), 3.04-2.92 (m, 2 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In isopropyl alcohol; at 70℃; for 9h; | To a solution of compound SP-0011507-023 (330 mg, 1.33 mmol) in isopropanol (30 mL) were added <strong>[98556-31-1]4-chloro-6-iodoquinazoline</strong> (464 mg, 1.60 mmol) and triethylamine (057 mL, 3.99 mmol). The mixture was stirred at 70 C for 9 h. The mixture was cooled down and isopropanol was removed by rotary evaporation. The residue was purified by silica gel column chromatography (using petroleum ether/EtOAc = 6:1-1:2) to give compound SP-0011507-027 as a yellow solid (310 mg, yield: 46%). LC-MS 503 (M+H), purity 60% (UV 214 nm). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26% | With triethylamine; In isopropyl alcohol; at 80℃; for 3h; | To a solution of <strong>[98556-31-1]4-chloro-6-iodoquinazoline</strong> (870 mg, 3.0 mmol) in isopropanol (10 mL) was added compound 3 (453 mg, 3.0 mmol) and triethylamine (0.7 mL, 5.0 mmol). The reaction mixture was stirred at 80 C for 3 h. After thereaction mixture was cooled down, isopropanol was removed by rotary evaporation. The residue was purified by PrepHPLC to give the title compound A28-007 (320 mg, yield: 26%). LC-MS 406 (M+H), purity 100% (UV 214 nm); ‘H NMR (400 MHz, MeOH-d4): ö 8.68 (s, 1 H), 8.53 (s, 1 H), 8.09-8.06 (m, 1 H), 7.50 (d, J= 8.8, 1 H), 7.3 1-7.21 (m, 1 H), 7.03-7.01 (m, 1 H), 6.95-6.91 (m, 1 H), 6.02 (t, J= 7.2, 1 H), 3.12-3.10 (m, 1 H), 2.98-2.96 (m, 1 H), 2.72-2.67 (m, 1 H), 2.17-2.13 (m, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With triethylamine; In isopropyl alcohol; at 70℃;Inert atmosphere; | To a solution of compound <strong>[98556-31-1]4-chloro-6-iodoquinazoline</strong> (1.10 g, 3.8 mmol) and 4,5,6,7-tetrahydrobenzothiazole-2,6-diamine (1.26 g, 3.8 mmol) in isopropyl alcohol (20 mL) was added triethylamine (5.0 mL, 36 mmol). The resulting solution was heated to 70C under nitrogen overnight. LC-MS analysis showed completed consumption of starting material. The mixture was cooled down and excess isopropyl alcohol was removed by rotary evaporation. The residue was purified by Prep-HPLC to give A28-008 as a yellow solid (1.5 g, yield: 93%). LC-MS 424 (M+H), purity 100% (UV 214 nm); ‘H NMR (400 MHz, DMSO-d6) ö 8.78 (d, J = 1.2 Hz, 1 H), 8.50 (s, 1 H), 8.22 (d, J = 7.2 Hz, 1 H), 8.01- 8.04 (m, 1 H), 7.45 (d, J = 8.4 Hz, 1 H), 6.69 (s, 2 H), 4.54 (d, J = 3.2 Hz, 1 H), 2.92-2.97 (m, 1 H), 2.60-2.63 (m, 3 H), 1.99-2.09 (m, 1 H), 1.88-1.99 (m, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | With triethylamine; In isopropyl alcohol; at 90℃;Inert atmosphere; | To a solution of <strong>[98556-31-1]4-chloro-6-iodoquinazoline</strong> (986 mg, 3.4 mmol) and 1,2,3,4- tetrahydronaphthalen-2-amine (500 mg, 3.4 mmol) in isopropyl alcohol (30 mL) was added triethylamine (2.0 mL, 14 mmol). The resulting solution was heated to 90 C under nitrogen for overnight. LC-MS analysis showed completed consumption of starting material. The reaction mixture was cooled down and excess isopropyl alcohol was removed by rotary evaporation. The residue was purified by Prep-HPLC to give A22-060 as a white solid (450 mg, yield: 33%). LC-MS 402 (M+H), purity 100% (UV 214 nm); ‘H NMR (400 MHz, CDC13) ö 8.67 (s, 1 H), 8.02-7.94 (m, 2 H), 7.58-7.55 (m, 1 H), 7.17-7.11 (m, 4 H), 5.73- 5.70 (m, 1 H), 4.75 (m, 1 H), 3.38-3.32 (m, 1 H), 3.02-2.96 (m, 2 H), 2.89-2.82 (m, 1 H),2.00-1.96 (m, 2 H), 2.35-2.29 (m, 2 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | In isopropyl alcohol; for 5h;Reflux; | The raw material I-1 (14.52g, 50.0mmol) dissolved in the isopropanol 400mL,stirring to add 3- chloro-4-(pyridin-2-methoxy ) benzeneamine, (11.73g,50.0mmol)heating reflux 5hours, cooling to room temperature, static for 6hours, there are a large number of solid separate out filtration, filter cake with a small amount of Isopropanol washing, drying, getintermediate I-2a (yellow solid (23.4g, yield96%). |
91% | In isopropyl alcohol; at 20 - 80℃; for 2h; | General procedure: To a solution of compound 9 (5.8 g, 20 mmol) in 2-propanol was added anilines (22 mmol) at room temperature (r.t.). Then the reaction mixture was heated to 80 C for 2 hours. After the start material was completed, the mixture was filtered through celite, and the cake was washed by 2-propanol, then dried to obtain the desired compounds 10a-10d. |
Tags: 98556-31-1 synthesis path| 98556-31-1 SDS| 98556-31-1 COA| 98556-31-1 purity| 98556-31-1 application| 98556-31-1 NMR| 98556-31-1 COA| 98556-31-1 structure
[ 39576-82-4 ]
2,4-Dichloro-6-methylquinazoline
Similarity: 0.77
[ 625080-60-6 ]
4-Chloro-6,7-difluoroquinazoline
Similarity: 0.74
[ 39576-82-4 ]
2,4-Dichloro-6-methylquinazoline
Similarity: 0.77
Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
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. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
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 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
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 |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
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. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
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. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
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.
Home
* Country/Region
* Quantity Required :
* Cat. No.:
* CAS No :
* Product Name :
* Additional Information :