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CAS No. : | 1237535-78-2 | MDL No. : | MFCD19703686 |
Formula : | C8H7FN2O | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | NOGFPJHXTCXVDA-UHFFFAOYSA-N |
M.W : | 166.15 | Pubchem ID : | 46853239 |
Synonyms : |
|
Num. heavy atoms : | 12 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.25 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 44.29 |
TPSA : | 41.99 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -7.01 cm/s |
Log Po/w (iLOGP) : | 1.42 |
Log Po/w (XLOGP3) : | 0.43 |
Log Po/w (WLOGP) : | 0.95 |
Log Po/w (MLOGP) : | 1.09 |
Log Po/w (SILICOS-IT) : | 2.0 |
Consensus Log Po/w : | 1.18 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.51 |
Solubility : | 5.12 mg/ml ; 0.0308 mol/l |
Class : | Very soluble |
Log S (Ali) : | -0.88 |
Solubility : | 21.9 mg/ml ; 0.132 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -3.07 |
Solubility : | 0.142 mg/ml ; 0.000857 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.99 |
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 |
---|---|---|
47% | With N-ethyl-N,N-diisopropylamine In water; N,N-dimethyl-formamide at 140℃; for 5 h; | Step 3 Preparation of 5-fluoro-3,4-dihydro-1,8-naphthyridin-2(1H)-one A round bottom flask was charged with tert-butyl (4-fluoro-3-iodopyridin-2-yl)carbamate (20.0 g, 59.2 mmol), 3,3-diethoxy-1-propene (13.5 mL, 88.7 mmol), DMF (150 mL), water (50 mL), DIPEA (15.4 mL, 88.7 mmol) and Pd catalyst 1 (Corma, A.; Garcia, H.; Leyva, A. Tetrahedron 61, 9848, 2005) (480 mg, 0.827 mmol) and the reaction mixture was stirred in an oil bath at 140° C. After 5 h, the reaction mixture was cooled in a refrigerator for 2 days. The precipitate was isolated by filtration, washed with diethyl ether, and dried to give 3.25 g of pink needles. The filtrate was concentrated to give a reddish semi-solid. This material was redissolved in DCM, and the solution was passed through 200 g of SiO2. Concentration of the resulting solution provided a red/orange residue which was recrystallized from 2-propanol (150 mL) to give 9.4 g of a pink solid. Purification of this pink solid by column chromatography (SiO2, elution with 0-75percent EtOAc/DCM) provided 1.41 g of a white powder. Overall, 4.66 g of final productproduct was isolated (47percent yield). LC/MS: (FA) ES+ 167. 1H NMR (300 MHz, d6 DMSO): δ 10.67 (s, 1H), 8.13-8.08 (m, 1H), 6.93-6.88 (m, 1H), 2.87 (t, 2H), and 2.51 (t, 2H). This reaction may also be carried out under the same conditions using Pd(OAc)2 as catalyst, both in the presence or absence of tri-o-tolylphosphine as ligand. In a method analogous to that described for 5-fluoro-3,4-dihydro-1,8-naphthyridin-2(1H)-one, 5-chloro-3,4-dihydro-1,8-naphthyridin-2(1H)-one was prepared from 2,4-dichloropyridine. LC/MS: (AA) ES+ 183. 1H NMR (400 MHz, d6 DMSO): δ 10.68 (s, 1H), 8.07-8.06 (m, 1H), 7.13-7.11 (m, 1H), 2.96 (t, 2H), and 2.55 (t, 2H). |
47% | With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 140℃; for 5 h; | Step 3: 5-fluoro-3,4-dihydro-l,8-naphthyridin-2(lH)-one Intermediate-28 [00201] A round bottom flask was charged with f erf-butyl (4-fluoro-3-iodopyridin-2-yl)carbamate (Int-27, 20 g, 59.2 mmol), 3,3-diethoxy-l-propene (13.5 mL, 88.7 mmol), NN-dimethylformamide (150 mL), water (50 mL), NN-diisopropylethylamine (15.4 mL, 88.7 mmol) and the Pd catalyst ("Palladacyle 1" from Corma et. al. Tetrahedron 2005, 61(41):9848; 480 mg, 0.827 mmol) and the reaction mixture was warmed to 140 °C. After 5 h, the reaction mixture was cooled in a refrigerator for 2 days. The resulting precipitate was isolated by suction filtration, washed with diethyl ether, and dried to give 3.25 g of pink needles. The filtrate was concentrated to give a reddish semi-solid. This material was redissolved in methylene chloride and the solution was passed through 200 g of silica. Concentration of the resulting solution provided a red/orange residue which was recrystallized from 2-propanol (150 mL) to give 9.4 g of a pink solid. Purification of this pink solid by column chromatography (Si02} elution with 0-75percent ethyl acetate in methylene chloride) provided 1.41 g of a white powder, Overall, 4.66 g of 5-fluoro-3,4- dihydro-l,8-naphthyridin-2(lH)-one was isolated (47percent yield). LC-MS: (FA) ES+ 167; NMR (400 MHz, <3/4-DMSO) 5 ppm 10.7 (s, 1 H), 8.1 1 (dd, J = 8.5, 5.7 Hz, 1 H), 6.91 (dd, J = 8.8, 5.7 Hz, H), 2.91- 2.85 (m, 2 H), 2.55-2.50 (m, 2 H). |
47% | With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 140℃; for 5 h; | Step 3: 5-fluoro-3,4-dihydro-1,8-naphthyridin-2(1H)-one Intermediate 31 A round bottom flask was charged with tert-butyl (4-fluoro-3-iodopyridin-2-yl)carbamate (Int-30, 20 g, 59.2 mmol), 3,3-diethoxy-1-propene (13.5 mL, 88.7 mmol), N,N-dimethylformamide (150 mL), water (50 mL), N,N-diisopropylethylamine (15.4 mL, 88.7 mmol) and the Pd catalyst ("Palladacyle 1” from Corma et. al., Tetrahedron 2005, 61(41):9848; 480 mg, 0.827 mmol) and the reaction mixture was warmed to 140° C. After 5 h, the reaction mixture was cooled in a refrigerator for 2 days. The resulting precipitate was isolated by suction filtration, washed with diethyl ether, and dried to give 3.25 g of pink needles. The filtrate was concentrated to give a reddish semi-solid. This material was redissolved in methylene chloride and the solution was passed through 200 g of silica. Concentration of the resulting solution provided a red/orange residue which was recrystallized from 2-propanol (150 mL) to give 9.4 g of a pink solid. Purification of this pink solid by column chromatography (SiO2, elution with 0-75percent ethyl acetate in methylene chloride) provided 1.41 g of a white powder. Overall, 4.66 g of 5-fluoro-3,4-dihydro-1,8-naphthyridin-2(1H)-one was isolated (47percent yield). LC-MS: (FA) ES+ 167; 1H NMR (400 MHz, d6-DMSO) δ ppm 10.7 (s, 1H), 8.11 (dd, J=8.5, 5.7 Hz, 1H), 6.91 (dd, J=8.8, 5.7 Hz, 1H), 2.91-2.85 (m, 2H), 2.55-2.50 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With caesium carbonate; In N,N-dimethyl-formamide; at 140℃; for 3h; | Method 1 A mixture of (7R)-7-amino-5,6,7,8-tetrahydronaphthalen-2-ol hydrobromide (16.7 g, 68.2 mmol), <strong>[1237535-78-2]5-fluoro-3,4-dihydro-1,8-naphthyridin-2(1H)-one</strong> (11.36 g, 64.95 mmol), and cesium carbonate (63.49 g, 194.9 mmol) in DMF (216 mL) was stirred at 140 C. for 2 h. The reaction was not complete, so additional (7R)-7-amino-5,6,7,8-tetrahydronaphthalen-2-ol hydrobromide (1.70 g, 6.82 mmol) was added. After an additional 1 h at 140 C., the reaction mixture was cooled to rt, and carefully treated with a solution of HCl (1 M). The reaction mixture was then diluted with DCM and filtered through Celite. The phases were separated and the aqueous phase was brought to pH 7 by the addition of a solution of NaOH (1.0 M). The brown precipitate was then removed by filtration through Celite, and the filtrate was washed with DCM. The aqueous phase was then brought to pH 14 by addition of a solution of NaOH (1.0 M) and an off-white precipitate formed. This suspension was treated with solid NaCl and stirred for 1 h. The solid was isolated by filtration and dried under vacuum to give a 17.7 g of an off-white solid (88% yield). LC/MS: (AA) ES+ 310. 1H NMR (400 MHz, d6 DMSO) delta: 10.47 (s, 1H), 7.94 (d, 1H), 7.12 (d, 1H), 6.85-6.81 (m, 2H), 6.26 (d, 1H), 3.03-2.96 (m, 1H), 2.89 (t, 2H), 2.85-2.79 (m, 1H), 2.76-2.66 (m, 1H), 2.51 (t, 2H), 2.44-2.38 (m, 1H), 1.90-1.84 (m, 1H), 1.65 (br s, 2H), and 1.50-1.40 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With N-ethyl-N,N-diisopropylamine;di-mu-chlorobis[5-hydroxy-2-[1-(hydroxyimino)ethyl]phenyl]palladium(II) dimer; In water; N,N-dimethyl-formamide; at 140℃; for 5h; | Step 3 Preparation of 5-fluoro-3,4-dihydro-1,8-naphthyridin-2(1H)-one A round bottom flask was charged with tert-butyl (4-fluoro-3-iodopyridin-2-yl)carbamate (20.0 g, 59.2 mmol), 3,3-diethoxy-1-propene (13.5 mL, 88.7 mmol), DMF (150 mL), water (50 mL), DIPEA (15.4 mL, 88.7 mmol) and Pd catalyst 1 (Corma, A.; Garcia, H.; Leyva, A. Tetrahedron 61, 9848, 2005) (480 mg, 0.827 mmol) and the reaction mixture was stirred in an oil bath at 140 C. After 5 h, the reaction mixture was cooled in a refrigerator for 2 days. The precipitate was isolated by filtration, washed with diethyl ether, and dried to give 3.25 g of pink needles. The filtrate was concentrated to give a reddish semi-solid. This material was redissolved in DCM, and the solution was passed through 200 g of SiO2. Concentration of the resulting solution provided a red/orange residue which was recrystallized from 2-propanol (150 mL) to give 9.4 g of a pink solid. Purification of this pink solid by column chromatography (SiO2, elution with 0-75% EtOAc/DCM) provided 1.41 g of a white powder. Overall, 4.66 g of final productproduct was isolated (47% yield). LC/MS: (FA) ES+ 167. 1H NMR (300 MHz, d6 DMSO): delta 10.67 (s, 1H), 8.13-8.08 (m, 1H), 6.93-6.88 (m, 1H), 2.87 (t, 2H), and 2.51 (t, 2H). This reaction may also be carried out under the same conditions using Pd(OAc)2 as catalyst, both in the presence or absence of tri-o-tolylphosphine as ligand. In a method analogous to that described for 5-fluoro-3,4-dihydro-1,8-naphthyridin-2(1H)-one, 5-chloro-3,4-dihydro-1,8-naphthyridin-2(1H)-one was prepared from 2,4-dichloropyridine. LC/MS: (AA) ES+ 183. 1H NMR (400 MHz, d6 DMSO): delta 10.68 (s, 1H), 8.07-8.06 (m, 1H), 7.13-7.11 (m, 1H), 2.96 (t, 2H), and 2.55 (t, 2H). |
47% | With N-ethyl-N,N-diisopropylamine;Pd catalyst; In N,N-dimethyl-formamide; at 140℃; for 5h; | Step 3: 5-fluoro-3,4-dihydro-l,8-naphthyridin-2(lH)-one Intermediate-28 [00201] A round bottom flask was charged with f erf-butyl (4-fluoro-3-iodopyridin-2-yl)carbamate (Int-27, 20 g, 59.2 mmol), 3,3-diethoxy-l-propene (13.5 mL, 88.7 mmol), NN-dimethylformamide (150 mL), water (50 mL), NN-diisopropylethylamine (15.4 mL, 88.7 mmol) and the Pd catalyst ("Palladacyle 1" from Corma et. al. Tetrahedron 2005, 61(41):9848; 480 mg, 0.827 mmol) and the reaction mixture was warmed to 140 C. After 5 h, the reaction mixture was cooled in a refrigerator for 2 days. The resulting precipitate was isolated by suction filtration, washed with diethyl ether, and dried to give 3.25 g of pink needles. The filtrate was concentrated to give a reddish semi-solid. This material was redissolved in methylene chloride and the solution was passed through 200 g of silica. Concentration of the resulting solution provided a red/orange residue which was recrystallized from 2-propanol (150 mL) to give 9.4 g of a pink solid. Purification of this pink solid by column chromatography (Si02} elution with 0-75% ethyl acetate in methylene chloride) provided 1.41 g of a white powder, Overall, 4.66 g of 5-fluoro-3,4- dihydro-l,8-naphthyridin-2(lH)-one was isolated (47% yield). LC-MS: (FA) ES+ 167; NMR (400 MHz, <¾-DMSO) 5 ppm 10.7 (s, 1 H), 8.1 1 (dd, J = 8.5, 5.7 Hz, 1 H), 6.91 (dd, J = 8.8, 5.7 Hz, H), 2.91- 2.85 (m, 2 H), 2.55-2.50 (m, 2 H). |
47% | With N-ethyl-N,N-diisopropylamine;Palladacyle 1; In N,N-dimethyl-formamide; at 140℃; for 5h; | Step 3: 5-fluoro-3,4-dihydro-1,8-naphthyridin-2(1H)-one Intermediate 31 A round bottom flask was charged with tert-butyl (4-fluoro-3-iodopyridin-2-yl)carbamate (Int-30, 20 g, 59.2 mmol), 3,3-diethoxy-1-propene (13.5 mL, 88.7 mmol), N,N-dimethylformamide (150 mL), water (50 mL), N,N-diisopropylethylamine (15.4 mL, 88.7 mmol) and the Pd catalyst ("Palladacyle 1? from Corma et. al., Tetrahedron 2005, 61(41):9848; 480 mg, 0.827 mmol) and the reaction mixture was warmed to 140 C. After 5 h, the reaction mixture was cooled in a refrigerator for 2 days. The resulting precipitate was isolated by suction filtration, washed with diethyl ether, and dried to give 3.25 g of pink needles. The filtrate was concentrated to give a reddish semi-solid. This material was redissolved in methylene chloride and the solution was passed through 200 g of silica. Concentration of the resulting solution provided a red/orange residue which was recrystallized from 2-propanol (150 mL) to give 9.4 g of a pink solid. Purification of this pink solid by column chromatography (SiO2, elution with 0-75% ethyl acetate in methylene chloride) provided 1.41 g of a white powder. Overall, 4.66 g of 5-fluoro-3,4-dihydro-1,8-naphthyridin-2(1H)-one was isolated (47% yield). LC-MS: (FA) ES+ 167; 1H NMR (400 MHz, d6-DMSO) delta ppm 10.7 (s, 1H), 8.11 (dd, J=8.5, 5.7 Hz, 1H), 6.91 (dd, J=8.8, 5.7 Hz, 1H), 2.91-2.85 (m, 2H), 2.55-2.50 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step 4: 6-(7-oxo-5,6,7,8-tetrahydro-l,8-naphthyridin-4-yloxy)quinoline-3-carboxylic acidIntermediate-29 [00202] 5-fluoro-3,4-dihydro-l,8-naphthyridin-2(lH)-one (Int-28, 120 mg, 0.72 mmol), 6- hydroxyquinoline-3-carboxylic acid (1.5 mg, 0.794 mmol), and cesium carbonate (706 mg, 2.17 mmol) were weighed into a microwave vial. N,N-Dimethylformamide (3.5 mL) was added and the vial was sealed and heated in a microwave at 150 C for 4 h. The vial was opened and water was added (5 mL). The resulting clear solution was neutralized by the addition of IN HC1 and washed with ethyl acetate. The washed aqueous phase was acidified to pH 3 and pure product was collected by suction filtration. LC-MS: (FA) ES+ 336; ]H NMR (400 MHz, i/6-DMSO) delta ppm 13.55 (s, 1 H), 10.60 (s, 1 H), 9.27 (d, J = 2.1 Hz, 1 H), 8.94 (d, J = 1.9 Hz, 1 H), 8.17 (d, J = 9.1 Hz, 1 H), 8.07-8.02 (m, 1 H), 7.85 (d, J = 2.7 Hz, I H), 7.74 (dd, J = 9.1, 2.8 Hz, 1 H), 6.52 (d, J = 5.7 Hz, 1 H), 2.92 (t, J = 7.7, 7.7 Hz, 2 H), 2.54 (dd, J = 8.3, 7.1 Hz, 2 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | With caesium carbonate; In ISOPROPYLAMIDE; at 150℃; for 1h;Microwave irradiation; Sealed vial; | Step 4: (S)-7-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yloxy)-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid Intermediate 325-Fluoro-3,4-dihydro-1,8-naphthyridin-2(1H)-one (Int-31, 50 mg, 0.301 mmol), (2S)-7-hydroxy-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (63.6 mg, 0.331 mmol), and cesium carbonate (294 mg, 0.903 mmol) were weighed into a microwave vial (2-5 mL) followed by N,N-dimethylacetamide (1.4 mL). The vial was sealed and the resulting mixture was stirred for 1 h at 150 C. under microwave irradiation. The contents of the vial were cooled to room temperature, water (5 mL) was added and the resulting mixture was stirred for a few minutes. The clear solution was neutralized by addition of 1N HCl and the resulting suspension was filtered through a Celite pad. The solid residue was washed with methanol then the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (2-10% methanol in methylene chloride gradient) to provide 52 mg of product as a colorless solid (41%). The enantiomeric purity of this product was assessed by chiral HPLC (85% ee). Column: IA 4.6×250 mm Elute: 100/0.1 EtOH/TFA; 0.5 mL/min 10 uL injection 50 min. LC-MS: (FA) ES+ 339; 1H NMR (400 MHz, d6-DMSO) delta ppm 12.33 (s, 1H), 10.49 (s, 1H), 8.00-7.90 (m, 1H), 7.15 (d, J=8.3 Hz, 1H), 6.90 (d, J=2.4 Hz, 1H), 6.87 (dd, J=8.2, 2.5 Hz, 1H), 6.28 (d, J=5.8 Hz, 1H), 2.98-2.74 (m, 5H), 2.71-2.61 (m, 1H), 2.57-2.51 (m, 3H), 2.14-2.06 (m, 1H), 1.73 (dddd, J=13.0, 10.0, 9.9, 6.7 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 2h;Inert atmosphere; | The mixture of the product from step H (90 mg, 0.38 mmol), 5-fluoro-3,4-dihydro-l,8- naphthyridin-2(lH)-one (64 mg, 0.38 mmol) and cesium carbonate (188 mg, 0.58mmol) in DMF (5 mL) was stirred at 120 C for 2 hrs. The reaction was diluted with water (10 mL) and extracted with ethyl acetate (2x20 mL). The combined organic phase was washed with brine (20 mL), dried over sodium sulfate anhydrous and concentrated under reduced pressure. The residue was used in next step without further purification. | |
With caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 2h; | The mixture of the product from step H (90 mg, 0.38 mmol), <strong>[1237535-78-2]5-fluoro-3,4-dihydro-1,8-naphthyridin-2(1H)-one</strong> (64 mg, 0.38 mmol) and cesium carbonate (188 mg, 0.58 mmol) in DMF (5 mL) was stirred at 120 C. for 2 hrs. The reaction was diluted with water (10 mL) and extracted with ethyl acetate (2*20 mL). The combined organic phase was washed with brine (20 mL), dried over sodium sulfate anhydrous and concentrated under reduced pressure. The residue was used in next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
320 mg | With caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 2h;Inert atmosphere; | The mixture of the product from step A (577 mg, 2.3 mmol), 5-fluoro-3,4-dihydro-l,8- naphthyridin-2(lH)-one (377 mg, 2.3 mmol) and cesium carbonate (1.1 g, 3.4 mmol) in DMF (20 mL) was stirred at 120 C for 2 hrs. The reaction was diluted with water (40 mL) and extracted with ethyl acetate (2x30 mL). The combined organic phase was washed with brine (40 mL), dried over sodium sulfate anhydrous and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluted with EtOAc:PE = 1 :5 ~ 1 : 1) to afford the title compound (320 mg, 80%) as a white solid |
320 mg | With caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 2h; | The mixture of the product from step A (577 mg, 2.3 mmol), <strong>[1237535-78-2]5-fluoro-3,4-dihydro-1,8-naphthyridin-2(1H)-one</strong> (377 mg, 2.3 mmol) and cesium carbonate (1.1 g, 3.4 mmol) in DMF (20 mL) was stirred at 120 C. for 2 hrs. The reaction was diluted with water (40 mL) and extracted with ethyl acetate (2*30 mL). The combined organic phase was washed with brine (40 mL), dried over sodium sulfate anhydrous and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluted with EtOAc:PE=1:5-1:1) to afford the title compound (320 mg, 80%) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 2h;Inert atmosphere; | The mixture of the product from step E (2.0 g, 9 mmol), 5-fluoro-3,4-dihydro-l,8- naphthyridin-2(lH)-one (1.5 g, 9 mmol) and cesium carbonate (6 g, 18mmol) in DMF (30 mL) was stirred at 120 C for 2hours. The reaction was diluted with water (30 mL) and extracted with ethyl acetate (2x40 mL). The combined organic phase was washed with brine (50 mL), dried over sodium sulfate anhydrous and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluted with EtOAc:PE = 1 :5 ~ 1 : 1) to obtain the title compound (1.4 g, 42%) as a white solid. |
42% | With caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 2h; | The mixture of the product from step E (2.0 g, 9 mmol), <strong>[1237535-78-2]5-fluoro-3,4-dihydro-1,8-naphthyridin-2(1H)-one</strong> (1.5 g, 9 mmol) and cesium carbonate (6 g, 18 mmol) in DMF (30 mL) was stirred at 120 C. for 2 hours. The reaction was diluted with water (30 mL) and extracted with ethyl acetate (2*40 mL). The combined organic phase was washed with brine (50 mL), dried over sodium sulfate anhydrous and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluted with EtOAc:PE=1:5-1:1) to obtain the title compound (1.4 g, 42%) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 2h; | The mixture of the product from step C (3.8 g, 0.017 mol), 5-fluoro-3,4-dihydro-l,8- naphthyridin-2(lH)-one (2.85 g, 0.017 mol) and cesium carbonate (11.2 g, 0.034 mol) in DMF (50 mL) was stirred at 120 C for 2hrs. The reaction was diluted with water (20 mL) and extracted with ethyl acetate (2^30 mL). The combined organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluted with EtOAc:PE = 1 :5 ~ 1 : 1) to obtain the title compound (2.8 g, 44%) as a white solid. -NMR (400 MHz, CDC13) delta 9.99 (s, 1H), 8.06 (d, J = 5.8 Hz, 1H), 7.10 (s, 1H), 6.90 - 6.82 (m, 2H), 6.23 (d, J = 5.8 Hz, 1H), 5.10 (d, J = 5.4 Hz, 1H), 4.22 - 4.07 (m, 2H), 3.24 (s, 1H), 3.03 (t, J = 7.8 Hz, 2H), 2.67 (t, J = 7.9 Hz, 2H), 1.36 - 1.30 (m, 1H), 1.29 - 1.17 (m, 3H) ppm. MS: M/e 367 (M+l)+. |
44% | With caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 2h; | The mixture of the product from step C (3.8 g, 0.017 mol), <strong>[1237535-78-2]5-fluoro-3,4-dihydro-1,8-naphthyridin-2(1H)-one</strong> (2.85 g, 0.017 mol) and cesium carbonate (11.2 g, 0.034 mol) in DMF (50 mL) was stirred at 120 C. for 2 hrs. The reaction was diluted with water (20 mL) and extracted with ethyl acetate (2*30 mL). The combined organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluted with EtOAc:PE=1:5-1:1) to obtain the title compound (2.8 g, 44%) as a white solid. 1H-NMR (400 MHz, CDCl3) delta 9.99 (s, 1H), 8.06 (d, J=5.8 Hz, 1H), 7.10 (s, 1H), 6.90-6.82 (m, 2H), 6.23 (d, J=5.8 Hz, 1H), 5.10 (d, J=5.4 Hz, 1H), 4.22-4.07 (m, 2H), 3.24 (s, 1H), 3.03 (t, J=7.8 Hz, 2H), 2.67 (t, J=7.9 Hz, 2H), 1.36-1.30 (m, 1H), 1.29-1.17 (m, 3H) ppm. MS: M/e 367 (M+1)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With potassium tert-butylate; In N,N-dimethyl-formamide; at 120℃; for 2h;Inert atmosphere; | The mixture of the product of Step G (66.3 g, 0.3 mol) and 5-fluoro-3,4-dihydro- 1,8-naphthyridin-2(1H)-one (50 g, 0.3 mol) in DMF (850 mL) was added Potassium tert-butoxide(35.4 g, 0.32 mol) and the mixture was stirred at 120 C under nitrogen for 2hrs. The reaction was cooled to room temperature and filtered through a celite pad and the filtrate was removed half of the solvent. The residue was added into stirred 2L water in drops. A solid was precipitated out of the solution. The solid was filtered, washed with water and dried in air. Thedried title compound (108.2 g, 98%) as a gray solid was used into next step directly. ?H NMR(400 IVIFIz, DMSO-d6) 10.43 (s, 1H), 7.92 (d, J= 5.8 Hz, 1H), 7.30 (d, J 2.4 Hz, 1H), 6.98 (d,J= 8.8 Hz, 1H), 6.94 (dd, J= 8.8, 2.4 Hz, 1H), 6.21 (d, J= 5.8 Hz, 1H), 5.26 (dd, J 5.4, 1.0 Hz,1H), 4.08 (q, J= 7.0 Hz, 2H), 3.34 (dd, J= 5.4, 3.2 Hz, 1H), 2.89 (t, J 7.8 Hz, 2H), 2.51 (t, J7.8 Hz, 2H), 1.34 (dd, J 3.2, 1.0 Hz, 1H), 1.18 (t, J= 7.0 Hz, 3H) ppm. MS: M/e 367 (M+1). |
98% | With potassium tert-butylate; In N,N-dimethyl-formamide; at 120℃; for 2h;Inert atmosphere; | To the mixture of the product of Step G (66.3 g, 0.3 mol) and 5-fluoro-3,4-dihydro- 1,8- naphthyridin-2(lH)-one (50 g, 0.3 mol) in DMF (850 mL) was added Potassium tert-butoxide (35.4 g, 0.32 mol) and the mixture was stirred at 120 C under nitrogen for 2hrs. The reaction was cooled to room temperature and filtered through a celite pad and the filtrate was removed half of the solvent. The residue was added into stirred 2L water in drops. A solid was precipitated out of the solution. The solid was filtered, washed with water and dried in air. The dried title compound (108.2 g, 98%) as a gray solid was used into next step directly. XH NMR (400 MHz, DMSO-^6) delta 10.43 (s, 1H), 7.92 (d, J= 5.8 Hz, 1H), 7.30 (d, J= 2.4 Hz, 1H), 6.98 (d, J= 8.8 Hz, 1H), 6.94 (dd, J= 8.8, 2.4 Hz, 1H), 6.21 (d, J= 5.8 Hz, 1H), 5.26 (dd, J= 5.4, 1.0 Hz, 1H), 4.08 (q, J= 7.0 Hz, 2H), 3.34 (dd, J= 5.4, 3.2 Hz, 1H), 2.89 (t, J= 7.8 Hz, 2H), 2.51 (t, J= 7.8 Hz, 2H), 1.34 (dd, J= 3.2, 1.0 Hz, 1H), 1.18 (t, J= 7.0 Hz, 3H) ppm. MS: M/e 367 (M+l)+. |
54.6% | With caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 2h; | The mixture of Intermediate III (400 mg, 1.8 mmol), 5-fluoro-3,4-dihydro-l,8- naphthyridin-2(lH)-one (250 mg, 1.5 mmol) and cesium carbonate (801 mg, 2.3 mol) in DMF (20 mL) was stirred at 120 C for 2hrs. The reaction was diluted with water (10 mL) and extracted with ethyl acetate (2x 10 mL). The combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluted with EtOAc:PE = 3: 1) to obtain the title compound (360 mg, 54.6%) as a white solid. |
54.6% | With caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 2h; | The mixture of Intermediate III (400 mg, 1.8 mmol), <strong>[1237535-78-2]5-fluoro-3,4-dihydro-1,8-naphthyridin-2(1H)-one</strong> (250 mg, 1.5 mmol) and cesium carbonate (801 mg, 2.3 mol) in DMF (20 mL) was stirred at 120 C. for 2 hrs. The reaction was diluted with water (10 mL) and extracted with ethyl acetate (2*10 mL). The combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluted with EtOAc:PE=3:1) to obtain the title compound (360 mg, 54.6%) as a white solid. |
54.6% | With caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 2h; | Example 2: Synthesis of compounds 2.1-2.37 Step A: (1S,1aS,6bR)-5-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)oxy)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-1-carboxylic acid ethyl ester Intermediate III (400mg, 1.8mmol), <strong>[1237535-78-2]5-fluoro-3,4-dihydro-1,8-naphthyridin-2(1H)-one</strong> (250mg, 1.5mmol), and cesium carbonate (801mg, 2.3mol) in DMF (20mL) was stirred at 120C for 2 hours. The reaction mixture was washed with water (10mL). The reaction was diluted and extracted with ethyl acetate (2 × 10mL). The combined organic extracts were washed with brine (20mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography (PE:EtOAc = 3:1 elution) to give the target compound as a white solid (360mg, 54.6%). |
54.6% | With caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 2h; | The mixture of Intermediate III (400 mg, 1.8 mmol), <strong>[1237535-78-2]5-fluoro-3,4-dihydro-1,8-naphthyridin-2(1H)-one</strong> (250 mg, 1.5 mmol) and cesium carbonate (801 mg, 2.3 mol) in DMF (20 mL) was stirred at 120 C. for 2 hrs. The reaction was diluted with water (10 mL) and extracted with ethyl acetate (2×10 mL). The combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluted with EtOAc:PE=3:1) to obtain the title compound (360 mg, 54.6%) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium tert-butylate; In N,N-dimethyl-formamide; at 100℃; for 5h; | The mixture of (1 R, 1 aR, 6b S)-ethyl 5 -hydroxy- 1 a,6b-dihydro- 1 H-cyclopropa [b]benzofuran-1-carboxylate (2.2 g, 0.01 mol) which was separated the product from Step F in synthesis of Compound 1.1 by Chiral SFC (column: Chiralpak AD-H), 5-fluoro-3,4-dihydro- 1,8- naphthyridin- 2(1H)-one (1.67 g, 0.01 mol) and t-BuOK (1.45 g, 0.013 mol) in DMF (10 mL)was stirred at 100 C for 5 hours. The reaction was cooled to room temperature and filtered through a celite pad. The filtrate was concentrated to half of original volume. Water (30 mL) was added dropwise and a solid was precipitated out of the solution. The solid was filtered and dried in air. The title compound (3.5 g, crude) was obtained as a black solid. MS: M/e 367 (M+1). | |
With potassium tert-butylate; In N,N-dimethyl-formamide; at 100℃; for 5h;Inert atmosphere; | The mixture of (lR,laR,6bS)-ethyl 5-hydroxy-la,6b-dihydro-lH-cyclopropa [b]benzofuran-l-carboxylate (2.2 g, 0.01 mol) which was the product from Step G in synthesis of Intermediate I by Chiral SFC (column: Chiralpak AD-H), 5-fluoro-3,4-dihydro-l,8- naphthyridin- 2(lH)-one (1.67 g, 0.01 mol) and t-BuOK (1.45 g, 0.013 mol) in DMF (10 mL) was stirred at 100 C for 5 hours. The reaction was cooled to room temperature and filtered through a celite pad. The filtrate was concentrated to half of original volume. Water (30 mL) was added dropwise and a solid was precipitated out of the solution. The solid was filtered and dried in air. The title compound (3.5 g, crude) was obtained as a black solid. MS: M/e 367 (M+l)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 2h; | The mixture of the product from step H (90 mg, 0.38 mmol), 5-fluoro-3,4- dihydro-1,8- naphthyridin-2(lH)-one (64 mg, 0.38 mmol) and cesium carbonate (188 mg, 0.58mmol) in DMF (5 mL) was stirred at 120 C for 2 hrs. The reaction was diluted with water (10 mL) and extracted with ethyl acetate (2x20 mL). The combined organic phase was washed with brine (20 mL), dried over sodium sulfate anhydrous and concentrated under reduced pressure. The residue was used in next step without further purification. | |
With caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 2h; | Example 2: Synthesis of compounds 2.1-2.37 Step I: (±)-exo-3-methyl-5-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)oxy)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-1-carboxylic acid ethyl ester The product of Step H (90mg, 0.38mmol), <strong>[1237535-78-2]5-fluoro-3,4-dihydro-1,8-naphthyridin-2(1H)-one</strong> (64mg, 0.38mmol) and cesium carbonate (188mg, 0.58mmol) in DMF (5mL) was stirred at 120 C for 2 hours. The reaction solution was washed with water (10 mL) then diluted and extracted with ethyl acetate (2 × 20mL). The combined organic phases were washed with brine (20mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was used without further purification in the next reaction. | |
With caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 2h; | The mixture of the product from step H (90 mg, 0.38 mmol), <strong>[1237535-78-2]5-fluoro-3,4-dihydro-1,8-naphthyridin-2(1H)-one</strong> (64 mg, 0.38 mmol) and cesium carbonate (188 mg, 0.58 mmol) in DMF (5 mL) was stirred at 120 C. for 2 hrs. The reaction was diluted with water (10 mL) and extracted with ethyl acetate (2×20 mL). The combined organic phase was washed with brine (20 mL), dried over sodium sulfate anhydrous and concentrated under reduced pressure. The residue was used in next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 2h; | The mixture of the product from step A (577 mg, 2.3 mmol), <strong>[1237535-78-2]5-fluoro-3,4-dihydro-1,8-naphthyridin-2(1H)-one</strong> (377 mg, 2.3 mmol) and cesium carbonate (1.1 g, 3.4 mmol) in DMF (20 mL) was stirred at 120 C. for 2 hrs. The reaction was diluted with water (40 mL) and extracted with ethyl acetate (2×30 mL). The combined organic phase was washed with brine (40 mL), dried over sodium sulfate anhydrous and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluted with EtOAc:PE=1:5-1:1) to afford the title compound (320 mg, 80%) as a white solid. |
320 mg | With caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 2h; | Example 2: Synthesis of compounds 2.1-2.37 Step B: (±)-exo-4-chloro-5-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)oxy)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-1-carboxylic acid ethyl ester The product of Step A (577mg, 2.3mmol), <strong>[1237535-78-2]5-fluoro-3,4-dihydro-1,8-naphthyridin-2(1H)-one</strong> (377mg, 2.3mmol) and cesium carbonate (1.1g, 3.4mmol) in DMF (20mL) was stirred at 120 C for 2 hours. The reaction solution was washed with water (40 mL) then diluted and extracted with ethyl acetate (2 × 30mL). The combined organic phases were washed with brine (40mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (eluting with EtOAc: PE = 1: 5 ~ 1: 1 elution) to give the target compound as a white solid (320mg, 80%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; In N,N-dimethyl-formamide; at 150℃; for 2h;Irradiation; | Step 8: (3S)-3-[4-phenyl-1-(2-trimethylsilylethoxymethyl)imidazol-2-yl]-2,3-dihydro-1 ,4-benzodioxin-6-ol (115 mg, 0.27 mmol) , 5-fluoro-3,4-dihydro-1 H-1 ,8-naphthyridin-2-one (45 mg, 0.27 mmol) and Cs2C03 (220.63 mg, 0.68 mmol) in DMF (2 mL) was irradiated at 150 C for 2 hrs. The resultant was partitioned between EtOAc (50 mL) and water (50 mL). To the aqueous layer was added NH4CI (until pH to ~ 5) and the aqueous layer was extracted with EtOAc (5 x 50 mL). The combined organic layers were washed with brine (3 x 50 mL), dried (Na2S04), filtered and concentrated in vacuo. The residue was redissolved in EtOAc (100 mL), washed with brine (2 x 100 mL), dried (Na2S04), filtered and concentrated in vacuo to provide crude 5-[[(3S)-3-[4-phenyl-1-(2- trimethylsilylethoxymethyl)imidazol-2-yl]-2,3-dihydro-1 ,4-benzodioxin-6-yl]oxy]-3,4-dihydro-1 H-1 ,8- naphthyridin-2-one (105 mg, 68 % yield) as an orange-brown solid. LC/MS: (ES+, Short): RT 2.08 min, m/z 571.3 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 2h; | Example 1: Synthesis of compounds 1.1-1.3 Step F: (±)-exo-3-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)oxy)-1,1a,6,6a-tetrahydrocyclopropa[a]inden-1-carboxylic acid ethyl ester <strong>[1237535-78-2]5-fluoro-3,4-dihydro-1,8-naphthyridin-2(1H)-one</strong> (1.5g, 9mmol) and cesium carbonate (6g, 18mmol) in DMF (30mL) was added to a solution of the product from step E (2.0g, 9mmol). The mixture was stirred at 120C for 2 hours. The reaction mixture was washed with water (30mL). The reaction was diluted and extracted with ethyl acetate (2 × 40mL). The combined organic extracts were washed with saturated brine (50mL), concentrated under reduced pressure, and purified by silica gel chromatography (ethyl acetate:petroleum ether = 1: 5 to 1:1 elution) to give the target compound as a white solid (1.4g, 42%). |
42% | With caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 2h; | The mixture of the product from step E (2.0 g, 9 mmol), <strong>[1237535-78-2]5-fluoro-3,4-dihydro-1,8-naphthyridin-2(1H)-one</strong> (1.5 g, 9 mmol) and cesium carbonate (6 g, 18 mmol) in DMF (30 mL) was stirred at 120 C. for 2 hours. The reaction was diluted with water (30 mL) and extracted with ethyl acetate (2×40 mL). The combined organic phase was washed with brine (50 mL), dried over sodium sulfate anhydrous and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluted with EtOAc:PE=1:5-1:1) to obtain the title compound (1.4 g, 42%) as a white solid. |
Tags: 1237535-78-2 synthesis path| 1237535-78-2 SDS| 1237535-78-2 COA| 1237535-78-2 purity| 1237535-78-2 application| 1237535-78-2 NMR| 1237535-78-2 COA| 1237535-78-2 structure
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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.
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