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CAS No. : | 13790-39-1 |
Formula : | C10H9ClN2O2 |
M.W : | 224.64 |
SMILES Code : | ClC1=NC=NC2=CC(=C(C=C12)OC)OC |
MDL No. : | MFCD01570172 |
InChI Key : | LLLHRNQLGUOJHP-UHFFFAOYSA-N |
Pubchem ID : | 2769364 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302+H312+H332-H315-H319-H335 |
Precautionary Statements: | P261-P280-P305+P351+P338 |
* 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 |
---|---|---|
91% | With trichlorophosphate; In toluene; | Production Example 36: 4-Chloro-6,7-dimethoxyquinazoline Toluene (100 ml) and phosphorus oxychloride (7.4 g, 48.6 mmol) were added to 6,7-dimethoxy-4-quinazolone (10.0 g, 48.5 mmol), and the mixture was stirred at 120C for 6.5 hr. The reaction solution was cooled to room temperature, was then filtered, was washed with toluene (100 ml, 50 ml), and was dried to give 11.5 g (yield 91%) of the target product. |
82.15% | With thionyl chloride; In N,N-dimethyl-formamide;Reflux; | 6,7-dimethoxyquinazoline-4(1H)-one (compound 28) (6 g, 29 mmol) was dissolved in 100 mL of thionyl chloride and 10 mL of DMF, and the reaction was refluxed overnight. The solution was cooled to room temperature, the majority of the solvent was spun to dryness, then slowly poured into ice water to precipitate the solid, filtered, washed with water and ether, and drained to obtain 5.34 g (82.15%) of the solid. 1HNMR (500 MHz, d6-DMSO), δ 8.88 (s, 1H), 7.46 (s, 1H), 7.40 (s, 1H), 4.02 (s, 3H), 4.00 (s, 3H). MS (ESI), m/z: 226[M+H]+. |
79% | With thionyl chloride; N,N-dimethyl-formamide; for 3h;Heating / reflux; | Obtainment of 6, 7- Dimethoxy-4-quinazolinone (3a) A 6, 7- dimethoxy-4-quinazolinone suspension (2a) (0.79 g, 3.83 mmol) in thionyl chloride (7.0 mL) containing 10 drops of N, N-dimethylformamide (DME) was agitated and heated under reflux for 3 h, until a solution was obtained. The reaction mixture was left cooling at room temperature. The reaction environment was diluted in dichloromethane and water (160 mL) and left in ice bath. The material was treated under agitation with 30 mL of saturated Na2C03 solution. Na2CO3 was carefully added until pH was adjusted to 7-8 range. Then, the aqueous phase was extracted with CH2C12 (2 x 30 mL), and the organic phase compound was washed with salt solution (2 x 10 mL), dried over magnesium sulfate, filtered, and the solvent was evaporated in a rotatory evaporator in order to provide 6, 7-dimethoxy-4-chloroquinazoline (3a) with a yellow solid (0.68 g, 3.03 mmol, 79%), which was used without purification in the next stage: melting point 185-187C. RMN of 1H [500 MHz, (CD3) 2SO, ppm] so 8.90 (1H, s, H-2), 7. 39 (1H, s, H-5), 7.34 (1H, s, H-8), 4.08 (6H, s, H-6a and H-7a). IV (KBr/ cm-1) v: 2975 (C-H), 1619 (C-N of an aromatic), 1511 (C-C of an aromatic), 1233 (C-O-C), 789 (C-H), 872 (C-Cl). |
71.4% | With sodium hydroxide; trichlorophosphate; In tetrahydrofuran; sulfolane; | Production Example 35: 4-Chloro-6,7-dimethoxyquinazoline Sulfolane (250 ml) and phosphorus oxychloride (250 ml = 412.5 g, 2.69 mol) were added to 6,7-dimethoxy-4-quinazolone (50.1 g, 0.24 mol), and the mixture was stirred at 120C for one hr. The reaction mixture was cooled to room temperature, and the excess phosphorus oxychloride was then removed by distillation under the reduced pressure. The residue was poured into ice water (1000 ml), and chloroform (1000 ml) was added thereto. The aqueous layer was adjusted to pH 6.5 by the addition of a 20% sodium hydroxide solution, followed by the separation of the organic layer from the aqueous layer.The separated organic layer was washed with water (1000 ml * six times), was dried over sodium sulfate, and was then concentrated under the reduced pressure. Tetrahydrofuran (470 ml) was added to the residue, and the mixture was refluxed. The reaction solution was cooled to -5C to -10C and was filtered and dried to give 38.5 g (yield 71.4%) of the target product. 1H-NMR (DMSO-d6, 400 MHz): δ 4.09 (s, 3H), 4.09 (s, 3H), 7.14 (s, 1H), 7.34 (s, 1H), 7.61 (s, 1H), 7.97 (s, 1H) |
With trichlorophosphate; at 115℃; for 8h; | General procedure: General procedures for the preparation of substituted 4-chloroquinazolines (3a and 3b) In a dry flask, quinazolin-4(1H)-one (4.38 g, 30 mmol) and POCl3 (19.2 mL, 210 mmol) were added sequentially, and then the mixture was stirred at 115 C for 8 h. The reaction mixture was concentrated under reduced pressure, cooled to room temperature, and then poured into ice water. Excess saturated sodium hydrogen carbonate solution was added to neutralize the generated acid, and then the mixed solution was extracted with CH2Cl2 (3 * 60 mL).;The product 4-chloroquinazoline (3a) was obtained after the organic phase was combined, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. Compound 3a was directly used in the next step without further purification [18] ;4-Chloro-6,7-dimethoxyquinazoline (3b) was synthesized following the same procedures. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 20 - 110℃; for 2h; | A solution of <strong>[13790-39-1]4-chloro-6,7-dimethoxyquinazoline</strong> (224 mg, 1.00 mmol), potassium carbonate (152 mg, 1.10 mmol) and 4-iodophenol (244 mg, 1.10 mmol) in dimethylformamide (4 ml) was heated at 110 C for 2 hours before the reaction was allowed to cool to ambient temperature. The reaction was poured into water and the solid which had precipitated was collected by suction filtration and washed with a mixture of diethyl ether (10 ml), ethyl acetate (10 ml) and isohexane (10 ml). Drying of this material yielded, yielded 4-(4-iodophenoxy)-6,7-dimethoxyquinazoline (340 mg, 83 % yield) as a white solid:1H-NMR (DMSO d6) : 8.55 (s, 1H), 7.80 (d, 2H, J = 8 Hz), 7.50 (s, 1H), 7.35 (s, 1H), 7.15 (d, 2H, J = 8 Hz), 3.95 (s, 3H), 3.90 (s, 3H): MS (+ve ESI) : 409 (M-H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With hydrogenchloride; In acetonitrile;Heating / reflux; | A mixture of 4- chloro-6,7-dimethoxy-quinazoline (548mg, 2. 4mmol), 2-fluoro-4-nitro-phenylamine (392mg, 2. 5mmol), AcCN (10ML), and conc'd HC1 (O. 050ml) was heated to reflux for several hrs. After the reaction mixture was allowed to cool to room temperature, the resulting solids were filtered, washed with AcCN and air-dried to give (6,7-dimethoxy- QUINAZOLIN-4-YL)- (2-FLUORO-4-NITRO-PHENYL)-AMINE (673mgs, 80%). |
69% | With caesium carbonate; In N,N-dimethyl-formamide; at 90℃; | Step 1. N-(2-fluoro-4-nitrophenyl)-6,7-dimethoxyquinazolin-4-amine (41) A stirred suspension of <strong>[13790-39-1]4-chloro-6,7-dimethoxyquinazoline</strong> (40) (prepared according to A. J. Bridges et al., J. Med. Chem., 1996, 39, 267) (1.00 g, 4.45 mmol), 2-fluoro-4-nitroaniline (940 mg, 6.02 mmol) and cesium carbonate (3.20 g, 9.82 mmol) in anhydrous DMF (20 mL) was heated at 90 C. overnight under nitrogen. The reaction mixture was allowed to cool to room temperature. The reaction mixture was diluted with AcOEt, successively washed with water and a saturated solution of ammonium chloride, concentrated and triturated with AcOEt/hexanes. After filtration, the cake was adsorbed on silica gel and purified by flash column chromatography on (eluents MeOH/DCM: 2/98→10/90) to afford the title compound 41 (1.06 g, 69% yield) as a yellow-green solid. MS (m/z): 345.0 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 90℃; for 2h; | 6.7-dimethoxy-4-(3-phenylpiperidin-1-yQquinazoline: 4-chloro-6,7- dimethoxyquinazoline (15 g, 66.8 mmol) was mixed with 3-phenylpiperidine (11.8 g, 73.5 mmol) in isopropanol (300 ml_), then diisopropylethylamine (23 ml_, 133.6 mmol) was added and the mixture was heated at 900C for 2 h. After cooling to room temperature, the solvent was removed in vacuo, the residue was diluted with water and chloroform, and the mixture was made basic by adding sodium hydroxide (pH <12). The mixture was extracted with chloroform, the organic layer was washed with brine and was dried over MgSO4, was filtered, and was concentrated in vacuo. Purification by silica gel chromatography (100% chloroform to 100-1-1 chloroform/methanol/aqu. cone, ammonium hydroxide) afforded 17.5 g (75% yield) of the title compound; MS (AP/CI): 350.2 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | In ethanol; at 80℃; for 2h;Inert atmosphere; | A mixture of compound 7 (2.00 g, 8.90 mmol) and 1,3-phenylenediamine (1.06 g, 9.79 mmol) in EtOH (35 mL)was stirred at 80 C for 2 h. The reaction mixture wasallowed to cool to room temperature and the precipitate wasthen collected by filtration, washed with cold EtOH, coldEt2O, and dried to afford 8 (2.51 g, 95%) as a green solid.Analytical data for compound 8 are in agreement with theliterature (Garske et al. 2011). |
89.2% | In isopropyl alcohol; for 2h;Reflux; | To the reactor was added 4-chloro-6,7-dimethoxy-4 (3H) -quinazoline (2.25 g, 10 mmol)Add 50mL isopropanol dissolved, adding m-phenylenediamine (1.19g, 11mmol), stirring evenly,The temperature was raised to reflux for 2 hours. The reaction is completeAfter cooling to room temperature. The resulting solid was recrystallized from ethanol to give 4- (3-amino) phenyl-6,7-dimethoxyquinazoline2.64 g, yield 89.2%. |
41% | With hydrogenchloride; sodium hydroxide; In diethyl ether; isopropyl alcohol; | 3-Aminoaniline (4.79 g) was added to a suspension of <strong>[13790-39-1]4-chloro-6,7-dimethoxyquinazoline</strong> (1.99 g) in isopropanol (100 ml). A 1M solution of hydrogen chloride in diethyl ether (8.86 ml) was added and the reaction mixture was stirred and heated to 90 C. for 3 hours. The mixture was cooled to ambient temperature and the precipitated solid was isolated, washed with isohexane and diethyl ether and then dried under vacuum. The resulting solid was then stirred with 1M aqueous sodium hydroxide solution and the mixture was extracted with methylene chloride. The methylene chloride extract was evaporated to dryness. There was thus obtained the required starting material (1.07 g, 41%); NMR: 3.91 (s, 3H), 3.93 (s, 3H), 5.03 (s, 2H), 6.31 (d, 1H), 6.87 (d, 1H), 7.00 (m, 2H), 7.13 (s, 1H), 7.81 (s, 1H), 8.39 (s, 1H), 9.20 (s, 1H); m/s: M+H+297. |
26% | In ethanol; for 3.5h;Heating / reflux; | [[00149]] a) 720 mg, 2 mM, 4-chloro 6,7-dimethoxy quinazoline, AG [1477,] and [350] mg, 3.2 mM, 1, [3- PHENYLENE DIAMINE] in 20 ml ethanol were refluxed 3.5 hours. Workup (KOH) and chromatography gave 0.245 gr light-brown solid, 26% yield, mp-2400 NMR [CDC13] 8 8.67 [(LH,] s, [H2),] 7.36 [(LH,] s, H5), 7.26 [(LH,] m, [H2,),] 7.17 [(LH,] t, J=8. [0HZ,] [HS),] 7.0 [(LH,] s, [HS),] 6.90 (1H. dd), 6.50 [(LH,] dd), 4.04, 4.02 (6H, 2s, [OCH3).] |
Heating; | General procedure: 4-Chloro-6,7-dimethoxyquinazoline 3 and the required nucleophile were heated in solvent either thermally or using microwave heating until no further reaction was observed. On cooling, the hydrochloride salt was isolated by filtration. Alternative isolation procedures were employed if precipitation did not occur. Additional purification by preparative HPLC or flash column chromatography was employed in some cases. Spectroscopic data for compounds 4 [13], 6-9 [14-16], 20-21 [13], 25 [13], 28 [17] and 30 [18] are in agreement with those reported in the literature. | |
In isopropyl alcohol; at 60℃; | To a stirred solution of compound 2 (10 mmol) in isopropyl alcohol (25 mL) meta-phenylenediamine was added (10 mmol). The reaction mass was heated to 60 C and stirred for about 3-4 h. Reaction was monitored by TLC. After completion, the reaction mass was quenched in ice water and sodium bicarbobnate and extracted with ethyl acetate. Organic layer was concentrated under vacuum to obtain compound 3. The obtained crude product was purified by column chromatography to get pure compound 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With potassium hydroxide; In dimethyl sulfoxide; at 20℃; | [[00118]] 500 mg, 2.2 mM, 4-chloro 6,7-dimethoxy quinazoline, 400 mg, 2.8 mM, 3-formyl indole and 0.3 gr crushed KOH in 10 ml DMSO were stirred at ambient temperature. Workup and [RECRYSTALIZATION] from benzene gave 550 mg, 75% yield, white solid. NMR [CDC13] [6] 10.21 [(LH,] s, CHO), 9.15 [(LH,] s, [H2),] 8.45 [(LH,] d, J=8.0 Hz, [H7,),] 8. 30 [(LH,] s, [H2,),] 7.49 [(LH,] s, H8), 7. [40] [(3H, M),] 7. [04] [(LH, S,] [H5),] 4. [13, 3.] 80 (6H, [2 S,] OCH3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | 3-[4-(6,7-Dimethoxy-quinazolin-4-ylamino)-2-methyl-phenoxy]-benzoic acid hydrochloride: To a suspension of 4-chloro-6,7-dimethoxy-quinazoline (3.0 g, 13.35 mmol) in 1,2-dichloroethane (40 mL) and tert-butyl alcohol (40 mL) was added 3-(4-amino-2-methyl-phenoxy)-benzoic acid tert-butyl ester (3.99 g, 13.35 mmol). The reaction was heated at 90 C. for 90 minutes. The reaction was then cooled to room temperature and hydrogen chloride gas was bubbled through the solution for 40 minutes. A small amount of hot methanol was added to solublize the gummed solids. Solids then crashed out upon cooling. The solids were filtered and rinsed with cold ethyl acetate. The solids were further dried at 50 C. in a vacuum oven, yielding light yellow solids as the mono hydrochloride salt (5.79 g, 93%). 1H NMR (400 MHz, DMSO-d6) δ 11.39 (bs, 1H), 8.82 (s, 1H), 8.29 (s, 1H), 7.64 (d, J=7.06 Hz, 1H), 7.63 (s, 1H), 7.55 (d, J=8.72 Hz, 1H), 7.50 (t, J=15.78, 7.89 Hz, 1H), 7.33 (s, 1H), 7.30 (s, 1H), 7.08 (d, J=8.72 Hz, 1H), 3.98 (s, 3H), 3.96 (s, 3H), 2.17 (s, 3H), LRMS (M+): 732.3, (M-): 430.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | 4-[4-(6,7-Dimethoxy-quinazolin-4-ylamino)-2-methyl-phenoxy]-benzoic acid hydrochloride: To a suspension of 4-chloro-6,7-dimethoxy-quinazoline (3.0 g, 13.35 mmol) in 1,2-dichloroethane (40 mL) and tert-butyl alcohol (40 mL) was added 4-(4-amino-2-methyl-phenoxy)-benzoic acid tert-butyl ester (3.99 g, 13.35 mmol). The reaction was heated at 90 C. for 90 minutes. The reaction was then cooled to room temperature and hydrogen chloride gas was bubbled through the solution for 40 minutes. A small amount of hot methanol was added to solublize the gummed solids. Solids then crashed out upon cooling. The solids were filtered and rinsed with cold ethyl acetate. The solids were further dried at 50 C. in a vacuum oven, yielding light yellow solids (5.99 g, 96%) as the mono hydrochloride salt. 1H NMR (400 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.40 (s, 1H), 7.93 (d, J=9.14 Hz, 2H), 7.67 (d, J=2.07 Hz, 1H), 7.37 (s, 1H), 7.13 (d, J=8.72 Hz, 1H), 6.94 (d, J=8.72 Hz, 2H), 3.99 (s, 3H), 2.14 (s, 3H), LRMS (M+): 432.3, (M-): 430.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | Compound 161: {2-[(6,7-Dimethoxy-4-quinazolyl)oxy]-5-methylphenyl}-(phenyl)methanone; 4-Chloro-6,7-dimethoxyquinazoline (59 mg), 2-hydroxy-5-methylbenzophenone (279 mg), and 4-dimethylaminopyridine (168 mg) were suspended in o-dichlorobenzene (5 ml), and the suspension was stirred at 160C for 10 min. The reaction solution was cooled to room temperature, the solvent was then removed therefrom by distillation under the reduced pressure, and chloroform was added to the residue. The mixture was washed with a 1 N aqueous potassium hydroxide solution and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform and by thin layer chromatography using acetone-hexane to give the title compound (97 mg, yield 92%). 1H-NMR (CDCl3, 400 MHz): δ 2.46 (s, 3H), 3.90 (s, 3H), 4.01 (s, 3H), 7.03 (s, 1H), 7.19 (s, 1H), 7.22 - 7.27 (m, 2H), 7.31 (d, J = 8.6 Hz, 1H), 7.33 - 7.39 (m, 1H), 7.43 - 7.49 (m, 2H), 7.67 - 7.73 (m, 2H), 8.49 (s, 1H) Mass spectrometric value (ESI-MS, m/z): 401 (M+1)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With hydrazine; In tetrahydrofuran; at 20℃; for 16h; | To a suspension of 4-Chloro-6,7-dimethoxy-quinazoline (0.20 g, 0.89 mmol) in anhydrous THF (0.5 ml) was added hydrazine (1M in THF, 2.0 ml, 2.0 mmol). The mixture was stirred at room temperature for 16 hours whereupon a precipitate had formed which was removed by filtration and washed with cold THF to give the desired product (177 mg, 91%) as a sticky off white solid which was sufficiently pure to be used without any further purification. m/z (LC-MS, ESP): 221 [M+H]+, R/T=2.48 mins. |
70% | With hydrazine hydrate; In tetrahydrofuran; at 20℃; for 16h; | Compound 7 (10 mmol) and hydrazine hydrate 85% (30 mmol) in 50 mL of THF was stirred for 16 h at room temperature. The reaction mixture was concentrated and allowed to cool. The solid product obtained was filtered, washed with water and dried. Recrystallization with ethanol and water afforded the desired solid compound 8, mp. 199-202 C in 70% yield. 1H NMR (DMSO-d6, 600 MHz) δ 3.84 (s, 3H, CH3O), 3.88 (s, 3H, CH3O), 4.56 (s, 2H, NH2), 7.08 (s, 1H, Ar-H), 7.57 (s, 1H, Ar-H), 8.37 (s, 1H, CH), 9.19 (s, 1H, NH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | A mixture of 3,3- dimethoxy-pyrrolidine (2.97 g, 17.8 mmol)and 4-chloro-6,7-dimethoxyquinazoline (4.38 g, 19.5 mmol) in THF (30 ml_)and satd. NaHCO3 (50 ml_) was heated to reflux for 5 h. The mixture was cooled and partitioned between water and ethyl acetate. The extract was washed with brine, and then extracted twice with 1 N HCI. After 20 min the combined acidic extracts were poured carefully into an excess of potassium carbonate in water. The mixture was then extracted three times with methylene chloride and the combined extracts were concentrated to a slurry. The slurry was diluted with an equal volume of hexanes and stirred over night. The EPO <DP n="41"/>resultant solids were collected via filtration and rinsed with ether to provide 3.71 g (76%) of the title compound as a tan powder. MS = 274.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | In isopropyl alcohol; | Example 17 4-(5-Fluoro-2,3-dihydro-indol-1-yl)-6,7-dimethoxy-quinazoline Utilizing a procedure analogous to that described in Example 1, this product was prepared in 81% yield from 5-fluoro-indoline (1.1 eq.) and 4-chloro-6,7-dimethoxy-quinazoline (1.0 eq)in i-PrOH. (M.P. 190-191 C.; LC-MS: 326 (MH+); anal. RP18-HPLC RT: 4.40 min.). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11% | Example 103 4-(7-Bromo-3,4-dihydro-2H-quinolin-1-yl)-6,7-dimethoxy-quinazoline Utilizing a procedure analogous to that described in Example 1, this product was prepared in 11% yield from <strong>[114744-51-3]7-bromo-1,2,3,4-tetrahydroquinoline</strong> and 4-chloro-6,7-dimethoxy-quinazoline. (film; LC-MS: 399 (MH+)). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | In isopropyl alcohol; | Example 23 6,7-Dimethoxy-4-(5-methyl-2,3-dihydro-indol-1-yl)-quinazoline Utilizing a procedure analogous to that described in Example 1, this product was prepared in 94% yield from <strong>[65826-95-1]5-methyl-indoline</strong> (1.1 eq.) and 4-chloro-6,7-dimethoxy-quinazoline (1.0 eq) in i-PrOH. (M.P. 180-181 C.; GC/MS: 321 (M+); anal. RP18-HPLC RT: 4.37 min.). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With caesium carbonate; In dimethyl sulfoxide; at 120℃; | Dimethylsulfoxide (2.5 ml) was added to 5,6-dimethyl-[2,2']bipyridinyl-3-ol (50 mg), <strong>[13790-39-1]4-chloro-6,7-dimethoxyquinazoline</strong> (169 mg), and cesium carbonate (244 mg), and the mixture was stirred at 120C overnight. The reaction mixture was cooled to room temperature, water was added to the cooled mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography with an ethyl acetate system to give the title compound (79 mg, yield 81%). 1H-NMR (CDCl3, 400 MHz): δ 2.41 (s, 3H), 2.63 (s, 3H), 4.03 (s, 3H), 4.05 (s, 3H), 7.06 (ddd, 7.6, 4.9, 1.2 Hz, 1H), 7.28 (s, 1H), 7.50 (s, 1H), 7.55 (s, 1H), 7.62 (ddd, J = 7.6, 4.9, 1.7 Hz, 1H), 7.89 (d, J = 7.8 Hz, 1H), 8.26 (d, J = 4.1 Hz, 1H), 8.48 (s, 1H) Mass spectrometric value (ESI-MS, m/z): 411 (M+Na)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With dmap; In 1,2-dichloro-benzene; at 130℃; | 1,2-Dichlorobenzene (2.5 ml) was added to 5,6-dimethyl-[2,3']-bipyridinyl-3-ol (50 mg), <strong>[13790-39-1]4-chloro-6,7-dimethoxyquinazoline</strong> (169 mg), and 4-dimethylaminopyridine(92 mg), and the mixture was stirred at 130C overnight. The reaction mixture was cooled to room temperature, water was added to the cooled mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography with a hexane-acetone system to give the title compound (81 mg, yield 84%). 1H-NMR (CDCl3, 400 MHz): δ 2.40 (s, 3H), 2.62 (s, 3H), 4.04 (s, 3H), 4.05 (s, 3H), 7.23 (ddd, J = 8.0, 4.9, 1.0 Hz, 1H), 7.29 (s, 1H), 7.45 (s, 1H), 7.47 (s, 1H), 8.09 (ddd, J = 7.8, 2.2, 2.2 Hz, 1H), 8.47 (dd, J = 4.9, 1.7 Hz, 1H), 8.55 (s, 1H), 9.04 (dd, J = 2.2, 0.8 Hz, 1H) Mass spectrometric value (ESI-MS, m/z): 411 (M+Na)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With potassium carbonate; In acetonitrile; at 90℃; | The piperidine salt 21 (84?mg, 0.346?mmol) was dissolved in acetonitrile (13.5?mL), K2CO3 (59.8?mg, 0.432?mmol), 4-chloro-2,6-dimethoxyquinazoline (64.8?mg, 0.288?mmol) was added and stirred overnight at 90?C. The solvent was removed under vacuum and the product was purified by flash column chromatography using CH2Cl2/CH3OH (95:5) to afford 28 as a beige solid (112?mg, 98%). Mp: 161-163?C; IR (ATR, ZnSe): ν (cm-1) 2908, 2850, 1545, 1474, 1244, 1007, 984, 861, 792, 704; 1H NMR (500?MHz, DMSO-d6): δ (ppm) 8.51 (s, 1H), 7.19 (s, 1H), 7.09 (s, 1H), 6.97 (t, J?=?5.9?Hz, 1NH), 4.13 (d, J?=?13.2?Hz, 2H), 3.92 (s, 3H), 3.90 (s, 3H), 3.03-2.98 (m, 4H), 2.90 (s, 3H), 1.81 (d, J?=?10.8?Hz, 2H), 1.68 (br s, 1H), 1.48 (q, J?=?7.0?Hz, 2H), 1.36 (qd, J?=?13.2, 3.7?Hz, 2H); 13C NMR (126?MHz, DMSO-d6): δ (ppm) 163.2, 154.1, 152.5, 148.4, 147.9, 110.5, 107.1, 103.4, 55.8, 55.5, 49.6, 40.0, 39.1, 36.0, 32.9, 31.5; HRMS-ESI calcd for C18H27N4O4 [M+H]+ 395.1748 found 395.1759. |
With triethylamine; In ethanol; water; | EXAMPLE 1 Preparation of 6,7-Dimethoxy-4-[4-(2- methanesulphonamidoethyl) piperidino]quinazoline STR7 4-Chloro-6,7-dimethoxy quinazoline (1.1 g.), 4- (2-methanesulphonamidoethyl)piperidine hydrochloride (1.5 g.) and triethylamine (1.5 ml.) in ethanol (30 ml.) were heated together under reflux for 1.5 hours. The solution was then cooled to room temperature, concentrated in vacuo, suspended in water (70 ml.) and basified to pH 10 with 10% aqueous sodium carbonate solution. The mixture was extracted with chloroform (2*70 ml.), the extracts combined, dried (MgSO4), and taken to dryness in vacuo. The resultant pale yellow oil was triturated with ether (70 ml.) to give a white solid which was collected by filtration. Crystallization of this solid from ethanol yielded 6,7-dimethoxy-4-[4-(2-methanesulphonamidoethyl)-piperidino]quinazoline (1.7 g.), m.p. 162-164 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | 60% Sodium hydride dispersion (0.11 g, 2.7 mmol) was added portionwise to DMSO (3 mL)at 22"C under nitrogen. The resulting slurry was stirred at ambient temperature for 5 minutes.5 4-Amino-3-methoxyphenol (0.37 g, 2.7 mmol) was added to the mixture at 22 - 28C undernitrogen and the resulting grey slurry was stirred at ambient temperature for 5 minutes. 4-Chloro-6,7-dimethoxyquinazoline (0.5 g, 2.2 mmol) was added to the mixture at 22 - 28Cunder nitrogen. The resulting dark mixture was stirred at 60C for 30 minutes then at ambienttemperature for 3 hours. Water (40 mL) was added to the mixture. The resulting precipitate10 was collected by filtration and washed with water (2 x 10 mL). The solid was treated withmethanol (5 mL) and evaporated to afford the title compound as a grey solid (0.54 g, 75%),which was used without further purification. 1H NMR (500 MHz, DMSO, 27 oq 8 3.74 (3H,s), 3.96 (6H, d), 4.67 (2H, s), 6.59 (lH, dd), 6.67 (lH, d), 6.76 (lH, d), 7.35 (lH, s), 7.51 (lH,s), 8.51 (lH, s). m/z: ES+ [M+H]+ 328. | |
72% | With dimethyl sulfoxide; In methanol; water; | Production Example 5: 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-methoxyaniline Sodium hydride (60 wt%, 3.2 g) was added to dimethyl sulfoxide (50 ml), and the mixture was stirredat 50C for 20 min. 4-Amino-3-methoxyphenol (5.6 g) was added thereto, and the mixture was stirred at room temperature for 10 min. Next, <strong>[13790-39-1]4-chloro-6,7-dimethoxyquinazoline</strong> (7.0 g) was added thereto, and the mixture was stirred at 100C overnight. Water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was then washed with a saturated aqueous sodium hydrogencarbonate solution and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. Methanol was added to the residue, and the precipitated crystal was collected by suction filtration to give the title compound (7.3 g, yield 72%). Mass spectrometry value (ESI-MS, m/z): 328 (M++1) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With lithium hexamethyldisilazane; In tetrahydrofuran; at -78 - 20℃; for 72h; | c. 4-(6,7-Dimethoxy-quinazolin-4-yl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester; To a mixture of piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester (17.1 g, 70.5 mmol), as prepared in the previous step, and <strong>[13790-39-1]4-chloro-6,7-dimethoxyquinazoline</strong> (15.0 g, 67.0 mmol) (Oakwood Products, Inc.) immersed in a -78 C. bath was added 1.08 M LiHMDS/THF (71 mL, 77 mmol) in 20 mL portions under argon via syringe along the sides of the flask (to allow cooling of the hindered base before reaction with the ester). Following completion of LiHMDS/THF addition, the reaction was allowed to sit in the -78 C. bath for 2-3 min before removing the cold bath and allowing the mixture to stir with gradual warming to rt. After 18 h stirring at rt, and an additional 2 d sitting at rt, the mixture was quenched with 0.5 M NaH2PO4 (150 mL) and extracted with DCM (1×150 mL and 1×100 mL). The organic layers were combined, dried (Na2SO4), and concentrated under reduced pressure to provide the crude title compound as a translucent yellow oil that was used in the next step without further purification (33 g, “114%” crude yield). A small sample was purified by flash chromatography (1:1 hex/EtOAc) for characterization. 1H-NMR (400 MHz, CDCl3) δ 9.11 (s, 1H), 7.34 (s, 1H), 7.29 (s, 1H), 4.05 (s, 3H), 3.96 (s, 3H), 3.76-3.67 (m, 2H), 3.62-3.49 (m, 2H), 3.61 (s, 3H), 2.50-2.36 (br s, 4H), 1.46 (s, 9H). LC/MS (ESI): calcd mass 431.2, found 432.2 (MH)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃; for 16h; | To a stirred solution of <strong>[13790-39-1]4-chloro-6,7-dimethoxyquinazoline</strong> (1) (1 g, 4.64 mmol, 1 eq) in DMF (10 mL) was added K2CO3 (1 .92 g, 13.92 mmol, 3 eq) and tert-buty piperidin-4-yl carbamate (2) (1 g, 5.35 mmol, 1.2 eq) at 0C. The reaction mixture was stirred at room temperature for 16 h. After completion of reaction by TLC, the reaction mixture was diluted with water and extracted with Ethyl acetate (2 X 70 mL). The combined organic layers were washed with brine (50 mL) dried over sodium sulfate and concentrated under reduced pressure to afford crude. The crude purified by trituration with diethyl ether to afford tert-butyl (l -(6,7-dimethoxyquinazolin-4-yl) piperidin-4-yl) carbamate (01) (1.45 g, yield: 88%) as white solid. TLC system MeOH:DCM (5:95), Rf value:0.25; LCMS (m/z): 389.3 (M+H)+; 'HNMR (400 MHz, DMSO-d6) d 8.52 (s, 1H), 7.20 (s, 1H), 7.08 (s, 1H), 6.92 (d, ./= 7.6 Hz, 1H), 4.1 1-4.07 (m, 2H), 3.93 (s, 3H), 3.91 (s, 3H), 3.57-3.75 (m, 1 H), 3.15 (t, ./ = 1 1.6 Hz, 2H), 1.91-1.89 (m, 2H), 1 .64-1 .54 (m, 2H), 1.40 (s, 9H). |
78% | With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 100℃; for 1h; | To a solution of 4-chloro-6,7-dimethoxy-quinazoline (44.8 mg, 0.20 mmol) in i-PrOH (2 mL) was added 4-(N-Boc amino)-piperidine (43.9 mg, 0.22 mmol), followed by DIEA (51.4 mg, 0.4 mmol). The mixture was heated at 100 C. with stirring. After stirring for 1 h, the homogeneous solution was concentrated under reduced pressure and the residue was partitioned between EtOAc and water. The organic layers were combined, dried (over Na2SO4) and concentrated to give the title compound as a white solid (60 mg, 78%). 1H NMR (300 MHz, CD3OD) δ 8.58 (s, 1H), 7.34 (s, 1H), 7.18 (s, 1H), 4.72 (m, 2H), 4.04 (s, 3H), 4.00 (s, 3H), 3.80 (m, 1H), 3.68 (m, 2H), 2.12 (m, 2H), 1.65 (m, 2H), 1.45 (s, 9H). LC/MS (ESI): calcd mass 388.2, found 389.3 (MH+). |
78% | With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 100℃; for 1h; | EXAMPLE 21; N-[1-(6,7-Dimethoxy-quinazolin-4-yl)-piperidin-4-yl]-2-(4-isopropyl-phenyl)-acetamide (Compound No. 21); a. [1-(6,7-Dimethoxy-quinazolin-4-yl)-piperidin-4-yl]-carbamic acid tert-butyl ester; To a solution of 4-chloro-6,7-dimethoxy-quinazoline (44.8 mg, 0.20 mmol) in i-PrOH (2 mL) was added 4-(N-Boc amino)-piperidine (43.9 mg, 0.22 mmol), followed by DIEA (51.4 mg, 0.4 mmol). The mixture was heated at 100 C. with stirring. After stirring for 1 h, the homogeneous solution was concentrated under reduced pressure and the residue was partitioned between EtOAc and water. The organic layers were combined, dried (over Na2SO4) and concentrated to give the title compound as a white solid (60 mg, 78%). 1H NMR (300 MHz, CD3OD) δ 8.58 (s, 1H), 7.34 (s, 1H), 7.18 (s, 1H), 4.72 (m, 2H), 4.04 (s, 3H), 4.00 (s, 3H), 3.80 (m, 1H), 3.68 (m, 2H), 2.12 (m, 2H), 1.65 (m, 2H), 1.45 (s, 9H). LC/MS (ESI): calcd mass 388.2, found 389.3 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With potassium carbonate; In ISOPROPYLAMIDE; at 120℃; for 2h; | A mixture of <strong>[13790-39-1]4-chloro-6,7-dimethoxyquinazoline</strong> (0.50 g, 0.0022 mol),6-methoxycarbonyl-l,2,3,4-tetrahydroisoquinoline hydrochloride (0.660 g, 2.90 mmol), potassium carbonate (0.923 g, 6.68 mmol) and N,N-dimethylacetamide (15 mL) was heated at 120 0C for 2 hours. The solvent was then evaporated, and the residue was diluted with ethyl acetate (100 mL) and washed with sodium bicarbonate (2 x 50 mL). The organics were separated and concentrated and the residue was purified by column chromatography (using 3% methanol in ethyl acetate/hexane 1 :1, ammonia 0.03%) to afford 675 mg (80 %) of methyl 2-(6,7-dimethoxyquinazolin-4-y I)- 1,2,3,4 tetrahydroisoquinoline-6-carboxylate as a pale yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With potassium carbonate;tetra-(n-butyl)ammonium iodide; In ISOPROPYLAMIDE; at 140℃; for 2.5h; | 6-(2-Methoxyethoxy)-l,2,3,4-tetrahydroisoquinoline (29 mg, 0.14 mmol) was dissolved in 1.0 mL N,N-dimethylacetamide to give a clear, colorless solution. 4- Chloro-6,7-dimethoxyquinazoline (43.3 mg, 0.193 mmol) was added, resulting in the formation of a cloudy yellow suspension. Tetra-n-butylammonium iodide (16 mg, 0.043 mmol) and potassium carbonate (57.4 mg, 0.415 mmol) were subsequently added, and the reaction mixture was heated in a sealed tube at 140 0C for 2.5 hours. The reaction was concentrated to yield a brown solid. The brown solid was dissolved in ethyl acetate (30 mL) and the organic layer was washed with water (3 x 10 mL) and with brine (1 x 10 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to provide a yellow-orange oil. Purification on a C18 column preparative (30 x 100 mm) HPLC column using a gradient of 20-80% acetonitrile:water (with 0.1% formic acid) and a flow rate of 45 mL/min yielded a yellow oil. The yellow oil was then loaded onto an SCX column (0.25g), washed with methanol, eluted with 4 mL ammonia in methanol (7M)5 and concentrated. Dissolution in dichloromethane, followed by concentration in vacuo afforded 29.3 mg (53 %) of 6,7-dimethoxy-4-[6-(2-methoxyethoxy)-3,4-dihydroisoquinolin-2(lH)-yl]quinazoline as a light yellow foam. MS [M+H] = 396.2, LC/MS (EI) tR 3.81 min (Method B), 1HNMR (CDCl3) δ (ppm) 8.18 (s, IH), 7.19 (s, IH), 7.10 (d, J = 9.0 Hz, IH), 6.82 (m, 2H), 4.78 (s, 2H), 4.13 (t, J = 6Hz5 2H), 4.04 (s, 3H), 4.00 (s, 3H), 3.93 (t, J = 6Hz5 2H), 3.77 (t, J = 6Hz, 2H), 3.47 (s, 3H), 3.15 (t, J = 6Hz, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With caesium carbonate; In dimethyl sulfoxide; at 20 - 140℃; for 3h; | Example 1 Preparation of 6-(6,7-dimethoxyquinazolin-4-yloxy)-1-naphthoic acid 6-Hydroxy-1-naphthoic acid (1.43 g, 7.6 mmol) and 38 ml of DMSO were stirred at room temperature while cesium carbonate (7.5 g, 22.9 mmol) and 4-chloro-6,7-dimethoxy-quinazoline (2.05 g, 9.14 mmol) were added. The mixture was heated at 140 C. for 3 hours. The mixture was cooled to room temperature and diluted with 40 mL of H2O. The mixture was neutralized with 2 N HCl to 6.5. The deposited solids were collected by vacuum filtration, washed with H2O, dried under vacuum and recrystallized from methanol to give the title compound (1.68 g, 59% yield) as a brown solid. LC-MS (m/z) 377 (M+1). |
59% | Example 1 Preparation of 6-(6,7-dimethoxyquinazolin-4-yloxy)-1-naphthoic acid 6-Hydroxy-1-naphthoic acid (1.43 g, 7.6 mmol) was dissolved in 38 ml of DMSO, then cesium carbonate (7.5 g, 22.9 mmol) and 4-chloro-6,7-dimethoxy-quinazoline (2.05 g, 9.14 mmol) were added. The mixture was heated at 140 C for 3 hours. When the reaction was finished the mixture was cooled to room temperature and diluted with 40 mL of H2O. The mixture was neutralized with 2 N HCl to pH=6.5. The deposited solids were filtered, washed with H2O, dried and recrystallized from methanol to give the title compound (1.68 g, 59% yield) as a brown solid. LC-MS (m/z) 377 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | In isopropyl alcohol;Reflux; | General procedure: A mixture of compound 2 (1.82 g, 8.8 mmol) and DMF (30 drops) in SOCl2 (50 mL) was refluxed for 7 h. The excess SOCl2 was removed by vacuum distillation. The residue was stirred with diethyl ether, filtered, washed, and dried to give compound 3 as a beige solid (1.83 g, 92%). A mixture of compound 3 and various amines in 2-propanol or DMF was refluxed. Upon completion of the reaction, it was cooled in an ice bath. The residue was filtered, washed, and dried to isolate the product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 110℃; for 0.5h;Microwave irradiation; | General procedure: Preparation of compounds V: 241, V: 243-V: 245 A sample of 3H-spiro [isobenzofuran- 1 ,4?-piperidine] hydrochloride (1.2 equiv), corresponding 4-chloro quinazolines (1 equiv.) and DIEA (2 equiv.) was taken in a microwave vial and was added i-PrOH. The reaction mixture was heated to 110 °C for 30 mm in microwave. The solvents were concentrated in vacuo, the residue partitioned between EtOAc and H20, organic layer separated, washedwith sat. brine solution, dried over anhyd. Na2SO4, solvents removed in vacuo and the crude was purified by column chromatography to obtain desiredproducts in 3 5-70percent yields. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | In acetonitrile;Heating; | General procedure: 4-Chloro-6,7-dimethoxyquinazoline 3 and the required nucleophile were heated in solvent either thermally or using microwave heating until no further reaction was observed. On cooling, the hydrochloride salt was isolated by filtration. Alternative isolation procedures were employed if precipitation did not occur. Additional purification by preparative HPLC or flash column chromatography was employed in some cases. Spectroscopic data for compounds 4 [13], 6-9 [14-16], 20-21 [13], 25 [13], 28 [17] and 30 [18] are in agreement with those reported in the literature. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Heating; | General procedure: 4-Chloro-6,7-dimethoxyquinazoline 3 and the required nucleophile were heated in solvent either thermally or using microwave heating until no further reaction was observed. On cooling, the hydrochloride salt was isolated by filtration. Alternative isolation procedures were employed if precipitation did not occur. Additional purification by preparative HPLC or flash column chromatography was employed in some cases. Spectroscopic data for compounds 4 [13], 6-9 [14-16], 20-21 [13], 25 [13], 28 [17] and 30 [18] are in agreement with those reported in the literature. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 16h; | [0513] Procedure: To a stirred solution of 4-chloro-6,7-dimethoxyquinazoline (0.2 g, 0.89 mmol) in DMF (10 mL) was added K2CO3 (0.184 g, 1.33 mmol) followed by <strong>[929302-18-1]2-(tert-butoxycarbonyl)-2,7-diazaspiro[3.5]nonan-7-ium hydrochloride</strong> (0.221 g, 0.979 mmol). Reaction mixture was stirred for 16 h at 90 °C. Progress of the reaction was monitored by TLC. Reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (2 x 50mL). The combined organic layer was washed with brine (10mL), dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure. The crude residue was purified by combiflash using ethyl acetate in hexaneto afford tert-butyl 7-(6,7- dimethoxyquinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (0.3g, 81percent) as an off white solid. LC-MS (ES) m/z =415.2 [M+H]+. |
Tags: 4-Chloro-6,7-dimethoxyquinazoline | Quinazolines | Chlorides | Ethers | Organic Building Blocks | Heterocyclic Building Blocks | 13790-39-1
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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 |
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