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CAS No. : | 55453-87-7 | MDL No. : | |
Formula : | C16H12O4 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | QFGMXJOBTNZHEL-UHFFFAOYSA-N |
M.W : | 268.26 | Pubchem ID : | 41448 |
Synonyms : |
HP 549
|
Num. heavy atoms : | 20 |
Num. arom. heavy atoms : | 12 |
Fraction Csp3 : | 0.12 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 72.4 |
TPSA : | 63.6 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.21 cm/s |
Log Po/w (iLOGP) : | 1.99 |
Log Po/w (XLOGP3) : | 2.43 |
Log Po/w (WLOGP) : | 2.29 |
Log Po/w (MLOGP) : | 1.72 |
Log Po/w (SILICOS-IT) : | 3.23 |
Consensus Log Po/w : | 2.33 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -3.35 |
Solubility : | 0.121 mg/ml ; 0.000451 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.41 |
Solubility : | 0.105 mg/ml ; 0.00039 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -4.87 |
Solubility : | 0.00359 mg/ml ; 0.0000134 mol/l |
Class : | Moderately soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 0.0 |
Synthetic accessibility : | 3.13 |
Signal Word: | Danger | Class: | 6.1 |
Precautionary Statements: | P201-P202-P260-P264-P270-P280-P301+P310+P330-P308+P313-P405-P501 | UN#: | 2811 |
Hazard Statements: | H301-H361-H372 | Packing Group: | Ⅲ |
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 |
---|---|---|
96.4% | Stage #1: With trifluoroacetic anhydride In chlorobenzene at 20℃; for 4 h; Stage #2: at -10 - 0℃; for 0.666667 h; |
The whole quantity of the 2-(4-carboxymethylphenoxymethyl)benzoic acid obtained in the above Step 4 and 200 ml of chlorobenzene were charged into a 500-ml four-necked flask, 75.0 g (0.3753 mol) of trifluoroacetic anhydride was added thereto, and the mixture was stirred at about 20°C for 4 hours. Subsequently, 2.3 g (0.0162 mol) of BF3-etherate complex was added dropwise thereto at -10 to 0°C over 10 minutes, then the mixture was stirred for 30 minutes. An aqueous phase was then separated, and the organic layer was washed with 200 ml of water. The washed organic layer was added to a solution of 7.2g of sodium hydroxide dissolved in 300 ml of water, and stirred for 30 minutes. An aqueous phase was then separated. To the separated aqueous layer, 2.0 g of activated carbon was added, stirred for 30 minutes, and filtered though a Buchner funnel to separate activated carbon. The activated carbon was washed on a Buchner funnel with 10 ml of water. A mixture of the filtrate and the cleaning solution was maintained at about 40°C, and a mixed solution of 11.3 g (0.1876 mol) of acetic acid and 50 ml of water was added dropwise thereto over 30 minutes. After the dropwise addition was completed, the mixture was cooled to 0 to 10°C, filtered through a Buchner funnel to collect crystals, and washed with 200 ml of water. The washed crystals were dried under reduced pressure to obtain 42.0 g of the title compound, (11-oxo-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid). The yield (yield from 2-(4-carboxymethylphenoxymethyl)benzoic acid) was 96.4percent, and the purity as measured by HPLC was 99.9percent.(HPLC conditions) Column: Inertsil ODS-5 μm (4.6 mm ID x 15 cm)Mobile Phase: 0.02percent trifluoroacetic acid aqueous solution/acetonitrile = 5/5 --> 3/7 (30 minutes)Detection Wavelength: UV 254 nm(Physical Property Data) 1H NMR (400 MHz, DMSOd6) δ 3.63 (s, 2H), 5.30 (s, 2H), 7.07 (d, J = 8.0 Hz, 2H), 7.48 (t, J = 3.6 Hz, 1H), 7.55 (d-d, J = 7.9 Hz, 2H), 7.67 (t, J = 7.6 Hz, 1H), 7.78 (d, J = 7.6 Hz, 1H), 7.97 (d, J = 2.0 Hz, 1H) |
71.3% | Stage #1: With trifluorormethanesulfonic acid; trifluoroacetic anhydride In toluene at 20 - 35℃; for 1 h; Stage #2: With water In toluene |
Example 2; Synthesis of the Intermediate 6,11-dihydro-11-oxo-dibenz[b,e]oxepin-2-acetic acid (Olo-IM2) To a suspension of 4-(2-carboxybenzyloxy)phenylacetic acid (Olo-IM1) (300.09 g, 1.04 mol; assay: 99.0percent) and trifluoromethane sulfonic acid (4.77 g, 0.03 mol; assay: 98.0percent) in toluene (1122 g) was added slowly trifluoroacetic anhydride (255.18 g, 1.20 mol; assay: 99.0percent) at 20-35° C. The brown solution was stirred after complete addition of trifluoroacetic anhydride for 1 hour at 20-25° C. and the mixture was then hydrolyzed with water (99.0 g). Afterwards, the mixture was distilled under normal pressure until the steam temperature was 105-110° C. (1191 g two-phase distillate). The residue was diluted with toluene (261 g) and the suspension was heated to reflux. The dark solution was then cooled to 75° C. and seeded with crystals of 6,11-dihydro-11-oxo-dibenz[b,e]oxepin-2-acetic acid (Olo-IM2). The suspension was stirred after cooling to 20-25° C. for additional 1-2 hours at this temperature. The product was filtered off, washed with cyclohexane (600 g) and water (390 g) and dried under vacuum (20 h, 50° C.) to give 6,11-dihydro-11-oxo-dibenz[b,e]oxepin-2-acetic acid (Olo-IM2) (yield: 203.21 g, 0.76 mol, 73.0percent; HPLC assay >99.5percent, HPLC purity: 99.62percent). This product was then recrystallized from a mixture of cyclohexane (700 g) and toluene (1892 g). After filtration the wet product was washed with cyclohexane (466 g) and dried under vacuum (15 h, 70° C.) to give slightly gray colored 6,11-dihydro-11-oxo-dibenz[b,e]oxepin-2-acetic acid (Olo-IM2) (yield: 198.4 g, 0.74 mol, 97.6percent; HPLC assay >99.5percent, HPLC purity: 99.90percent; overall yield: 71.3percent). |
69.9% | at 80 - 90℃; for 2 h; Large scale | The 10 kg acetic anhydride heated to 70-80°C, batch by adding 2 kg intermediate II, after adding to 80-90 °C stirring 2h, cooling to room temperature, to the reaction solution slowly and 40L water, precipitating a large amount of the yellow solid, stirring for 30 min, filtration, recrystallization with isopropanol/water, shall be intermediate III1.31kg, yield: 69.9percent, purity of 99.1percent. |
0.8 kg | With acetic acid In cyclohexane at 70 - 85℃; | 15 mg of HAClL, cyclohexane 0. 5 L and 4- (2-hydroxybenzyloxy) phenylacetic acid were charged into a reaction vessel, stirred and the reaction was stirred at 70-85 ° C for 2-4 hours. Stir under the conditions of adding appropriate amount of drinking water, stirring, filtering, drinking water to wash the solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79.3% | Stage #1: With potassium hydroxide In methanol at 20℃; for 1 h; Stage #2: Reflux Stage #3: at 80℃; for 2 h; |
Reaction flask was added p-hydroxyphenyl acetic acid (150mmol) 22.67g, potassium hydroxide (200mmol) 11.22g, 90ml of methanol, stirred for 1 hour at room temperature, was added 2- (chloromethyl) benzoic acid (100mmol) 17.06g, heated at reflux The reaction, after the reaction was monitored by TLC, the solvent was distilled off under reduced pressure, 200ml of dichloromethane was added to dissolve, washed with water, dried, concentrated, Eaton reagent was added 7.5percent (mass concentration) 200ml, was heated to 80 deg.] C, stirred for 2 hours, the reaction was completed after addition of saturated sodium carbonate solution, filtration, and recrystallized from ethanol to give Isoxepac (79.3mmol) 21.27g, yield 79.3percent, HPLC purity of 99.9percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36.7 g (85.2%) | With thionyl chloride; In N-methyl-acetamide; tetrachloromethane; | EXAMPLE 3 6,11-Dihydro-11-oxodibenz[b,e]oxepin-2-acetyl chloride A stirred, cooled suspension of 40.23 g (0.15 mol) of 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetic acid, 150 ml of sieve dried CH2 Cl2 and 3 drops of dimethylformamide was treated for a few minutes with 19.62 g (0.165 mol) of thionyl chloride. After total addition the suspension was stirred for 30 minutes with cooling. The suspension was then intermittently warmed until gas evolution ceased. The resultant solution was cooled and concentrated to an oil which crystallized on trituration with hexane to afford 41.96 g of a crude material. Recrystallization from 100 ml of CCl4 afforded 36.7 g (85.2percent) of crystals of 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetyl chloride, m.p. 95°-98.5° C. ANALYSIS: Calculated for C16 H11 ClO3: 67.03percentC; 3.87percentH; Found: 67.57percentC; 4.09percentH |
36.7 g (85.2%) | With thionyl chloride; In N-methyl-acetamide; tetrachloromethane; | EXAMPLE 3 6,11-Dihydro-11-oxodibenz[b,e]oxepine-2-acetyl chloride A stirred, cooled suspension of 40.23 g (0.15 mol) of 6,11-dihydro-11-oxodibenz[b,e]oxepine-2-acetic acid, 150 ml of sieve dried CH2 Cl2 and 3 drops of dimethylformamide was treated for a few minutes with 19.62 g (0.165 mol) of thionyl chloride. After total addition the suspension was stirred for 30 minutes with cooling. The suspension was then intermittently warmed until gas evolution ceased. The resultant solution was cooled and concentrated to an oil which crystallized on trituration with hexane to afford 41.96 g of a crude material. Recrystallization from 100 ml of CCl4 afforded 36.7 g (85.2percent) of crystals of 6,11-dihydro-11-oxodibenz[b,e]oxepine-2-acetyl chloride, m.p. 95°-98.5° C. ANALYSIS: Calculated for C16 H11 ClO3: 67.03percentC, 3.87percentH. Found: 67.57percentC, 4.09percentH. |
With thionyl chloride; In toluene; at 90℃; for 4h; | A suspension of l l-oxo-6,l l-dihydro-dibenzo-[b,e]-oxepin-2-acetic acid (47 g, 0.1752 mol) in toluene was heated at 900C. Thionyl chloride (22.9 g, 0.1927 mol) was added and the mixture was stirred for 4 hours at 900C.After complete conversion, solvent and excess of reagent was removed by distillation and the residual was diluted with THF, then, added to a 30percent wt ammonia solution in water (85.5 ml) at 15°C. Title compound of formula III was isolated by filtration at 00C (44.3 g, 95percent yield). |
With thionyl chloride; In dichloromethane; for 5h;Reflux; | Example 1:Step I: Preparation of N, N-dimethyl-2-(l l-oxo-6, 11-dihydrodibenz [b, e] oxepin-2- yl) acetamide.Charged 200 gm of 1 l-oxo-6, 11-dihydrodibenz [b, e] oxepin-2-acetic acid) in 1000 ml of dichloromethane. Charged 82.0 ml of thionyl chloride maintaining temperature at 25 - 30°C. Raised the temperature of the reaction mass to reflux and maintained five hours. Cooled the reaction mass to 0°C and started passing of dimethyl amine gas in the reaction mass to attain pH of 9.5 to 10.0 maintaining the temperature at 0 - 20 °C. Concentrated the reaction mass under vacuum to remove solvent dichloromethane. Charged 400 ml of DM water and cooled the water slurry of the product to 20 - 30°C and maintained under stirring for one hour. Filtered the solid product N, N-dimethyl-2-(l l-oxo-6, 11- dihydrodibenz [b, e] oxepin-2-yl) acetamide and dried till constant weight. Yield = 204 - 210 gm |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.4% | The whole quantity of the 2-(4-carboxymethylphenoxymethyl)benzoic acid obtained in the above Step 4 and 200 ml of chlorobenzene were charged into a 500-ml four-necked flask, 75.0 g (0.3753 mol) of trifluoroacetic anhydride was added thereto, and the mixture was stirred at about 20°C for 4 hours. Subsequently, 2.3 g (0.0162 mol) of BF3-etherate complex was added dropwise thereto at -10 to 0°C over 10 minutes, then the mixture was stirred for 30 minutes. An aqueous phase was then separated, and the organic layer was washed with 200 ml of water. The washed organic layer was added to a solution of 7.2g of sodium hydroxide dissolved in 300 ml of water, and stirred for 30 minutes. An aqueous phase was then separated. To the separated aqueous layer, 2.0 g of activated carbon was added, stirred for 30 minutes, and filtered though a Buchner funnel to separate activated carbon. The activated carbon was washed on a Buchner funnel with 10 ml of water. A mixture of the filtrate and the cleaning solution was maintained at about 40°C, and a mixed solution of 11.3 g (0.1876 mol) of acetic acid and 50 ml of water was added dropwise thereto over 30 minutes. After the dropwise addition was completed, the mixture was cooled to 0 to 10°C, filtered through a Buchner funnel to collect crystals, and washed with 200 ml of water. The washed crystals were dried under reduced pressure to obtain 42.0 g of the title compound, (11-oxo-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid). The yield (yield from 2-(4-carboxymethylphenoxymethyl)benzoic acid) was 96.4percent, and the purity as measured by HPLC was 99.9percent.(HPLC conditions) Column: Inertsil ODS-5 mum (4.6 mm ID x 15 cm)Mobile Phase: 0.02percent trifluoroacetic acid aqueous solution/acetonitrile = 5/5 --> 3/7 (30 minutes)Detection Wavelength: UV 254 nm(Physical Property Data) 1H NMR (400 MHz, DMSOd6) delta 3.63 (s, 2H), 5.30 (s, 2H), 7.07 (d, J = 8.0 Hz, 2H), 7.48 (t, J = 3.6 Hz, 1H), 7.55 (d-d, J = 7.9 Hz, 2H), 7.67 (t, J = 7.6 Hz, 1H), 7.78 (d, J = 7.6 Hz, 1H), 7.97 (d, J = 2.0 Hz, 1H) | |
71.3% | Example 2; Synthesis of the Intermediate 6,11-dihydro-11-oxo-dibenz[b,e]oxepin-2-acetic acid (Olo-IM2) To a suspension of 4-(2-carboxybenzyloxy)phenylacetic acid (Olo-IM1) (300.09 g, 1.04 mol; assay: 99.0percent) and trifluoromethane sulfonic acid (4.77 g, 0.03 mol; assay: 98.0percent) in toluene (1122 g) was added slowly trifluoroacetic anhydride (255.18 g, 1.20 mol; assay: 99.0percent) at 20-35° C. The brown solution was stirred after complete addition of trifluoroacetic anhydride for 1 hour at 20-25° C. and the mixture was then hydrolyzed with water (99.0 g). Afterwards, the mixture was distilled under normal pressure until the steam temperature was 105-110° C. (1191 g two-phase distillate). The residue was diluted with toluene (261 g) and the suspension was heated to reflux. The dark solution was then cooled to 75° C. and seeded with crystals of 6,11-dihydro-11-oxo-dibenz[b,e]oxepin-2-acetic acid (Olo-IM2). The suspension was stirred after cooling to 20-25° C. for additional 1-2 hours at this temperature. The product was filtered off, washed with cyclohexane (600 g) and water (390 g) and dried under vacuum (20 h, 50° C.) to give 6,11-dihydro-11-oxo-dibenz[b,e]oxepin-2-acetic acid (Olo-IM2) (yield: 203.21 g, 0.76 mol, 73.0percent; HPLC assay >99.5percent, HPLC purity: 99.62percent). This product was then recrystallized from a mixture of cyclohexane (700 g) and toluene (1892 g). After filtration the wet product was washed with cyclohexane (466 g) and dried under vacuum (15 h, 70° C.) to give slightly gray colored 6,11-dihydro-11-oxo-dibenz[b,e]oxepin-2-acetic acid (Olo-IM2) (yield: 198.4 g, 0.74 mol, 97.6percent; HPLC assay >99.5percent, HPLC purity: 99.90percent; overall yield: 71.3percent). | |
69.9% | With acetic anhydride; at 80 - 90℃; for 2h;Large scale; | The 10 kg acetic anhydride heated to 70-80°C, batch by adding 2 kg intermediate II, after adding to 80-90 °C stirring 2h, cooling to room temperature, to the reaction solution slowly and 40L water, precipitating a large amount of the yellow solid, stirring for 30 min, filtration, recrystallization with isopropanol/water, shall be intermediate III1.31kg, yield: 69.9percent, purity of 99.1percent. |
With PPA; In water; acetic acid; | (e) As an alternative to step (d) above, 43.7 g. of polyphosphoric acid are added to 10.0 g. of 4-(2-carboxybenzyloxy)-phenylacetic acid in 35 ml. of glacial acetic acid. The mixture is vigorously stirred at 76° C. for 12/3 hours and then hydrolyzed with 250 ml of water, the temperature being kept at 40° C. The precipitate which separates is collected and, when recrystallized from 2-propanol-water, provides pale yellow crystals, m.p. 137°-138°, of 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetic acid. Analysis: Calculated for C16 H12 O4: 71.64percent C; 4.51percent H. Found: 71.58percent C; 4.58percent H. | |
With acetic acid; at 70 - 75℃; for 2.5h;Product distribution / selectivity; | Example 12: Preparation of ll-oxo-6,ll-dihydrobenz[b,e]oxepin-2-acetic acid formula-2.A mixture of polyphosphoric acid (385 g), 2-((4-(carboxymethyl)phenoxy) methyl)benzoic acid (110 g) and acetic acid (330 ml) was heated to 70-75°C and stirred for 2 1/2 hours at same temperature. After completion of the reaction, the reaction mixture was cooled to 25-30°C, further to 10-15°C. Quenched the reaction mixture with water at 10-15°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 30 minutes at same temperature. Filtered the precipitated solid, washed with water and dried. Ethylacetate (300 ml) was added to the obtained solid and heated the reaction mixture to 70-75°C and then stirred for 15 minutes at same temperature. Carbon (6 g) was added to the reaction mixture and stirred for 15 minutes. Filtered the reaction mixture through hyflow bed and washed with ethyl acetate. Cooled the obtained filtrate to 0-5 °C and stirred for 1 hour at same temperature. Filtered the precipitated solid, washed with cyclohexane and then dried to get the title compound.Yield: 55 gmsMR: 137-138°C. | |
0.8 kg | With acetic acid; In cyclohexane; at 70 - 85℃; | 15 mg of HAClL, cyclohexane 0. 5 L and 4- (2-hydroxybenzyloxy) phenylacetic acid were charged into a reaction vessel, stirred and the reaction was stirred at 70-85 ° C for 2-4 hours. Stir under the conditions of adding appropriate amount of drinking water, stirring, filtering, drinking water to wash the solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
REFERENCE EXAMPLE 7 (Raw material 7) Methyl 11-methylene-6,11-dihydrodibenz-[b,e]oxepin-2-acetate The desired product is obtained by substituting 11-oxo-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid for methyl 11-oxo-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate in Reference example 6. Colorless oily matter NMR (CDCl3, delta, ppm): 3.48(s, 2H), 3.61(s, 3H), 5.05 (s, 2H), 5.20(s, 1H), 5.62(s, 1H), 6.59-7.43 (m, 7H) IR (neat, cm-1): 2950, 1740, 1615, 1490, 1010 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; | EXAMPLE 33 2-(6,11-Dihydrodibenz[b,e]oxepin-2-yl)ethanol A solution of 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetic acid (100 g) in 450 ml dry tetrahydrofuran (THF) at -5° C. was treated with a 1M solution of boran-THF complex (373 ml in THF) under a nitrogen blanket. After stirring at ambient temperature for 72 hours, the reaction was quenched with methanol then diluted with water. Evaporation of the organic phase left an oily biphase which was basified with saturated sodium bicarbonate and extracted into dichloromethane. The organic phase was dried and evaporated to an oil which was purified by flash chromatography to give 14 g of 2-(6,11-dihydrodibenz[b,e]oxepin-2-yl)ethanol as an oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.61 g (25.9%) | (6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)acetate A stirred ice-water chilled solution of 5.08 g (0.02 mol) of 2-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)ethanol of Example 1, 11 ml of KOH-dried pyridine and 10 ml of sieve dried CH2 Cl2 was treated over ten minutes with a solution of 6.31 g (0.022 mol) of 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetyl chloride of Example 3. After total addition the solution was stirred for one hour with cooling and then one hour at ambient temperature. Aqueous quenching, extraction with CH2 Cl2 and washing with 5percent HCl, water, and 5percent NaHCO3 afforded 8.74 g of a foam which was a mixture of the starting alcohol and the desired ester. A cooled solution of the foam, 10 ml of KOH-dried pyridine and 10 ml of CH2 Cl2 was treated over a few minutes with a solution of 3.15 g (0.011 mol) of the acid chloride (Example 3) and 10 ml of CH2 Cl2. After total addition the solution was stirred overnight (about 16 hours) at ambient temperature and was quenched and extracted as previously described to afford 9.39 g of a powder after azeotropic distillation of toluene. The material was purified by high pressure liquid chromatography using 1percent ethyl acetate in CH2 Cl2 to afford 5.82 g of a viscous oil. The oil was purified again by high pressure liquid chromatography to afford 2.61 g (25.9percent) of a tacky amorphous solid of 2-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)ethyl (6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)acetate after vacuum drying at 60°-100° C. ANALYSIS: Calculated for C32 H24 O6: 76.18percentC; 4.79percentH; Found: 76.19percentC; 5.17percentH |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16.5 g (94%) | In N-methyl-acetamide; | EXAMPLE 12 Methyl(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)acetoxyacetate A mixture of 15 g (0.052 m) of 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetic acid in 100 ml of dimethylformamide and 3.87 g (0.028 m) of K2 CO3 was warmed to an internal temperature of 50° C. in an atmosphere of nitrogen for 1.5 hours. To this mixture, 9.41 g (0.062 m) of methyl bromoacetate was added dropwise and the mixture was held at 50° C. overnight. The reaction mixture was poured into water and extracted with ether. The ether extract was washed with 5percent NaHCO3 and water, dried over Na2 SO4, filtered and evaporated to give 16.5 g (94percent) of an oil of methyl(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)acetoxyacetate. ANALYSIS: Calculated for C19 H16 O6: 67.05percentC; 4.74percentH; Found: 66.88percentC; 4.74percentH |
16.5 g (94%) | In N-methyl-acetamide; | EXAMPLE 12 Methyl-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)acetoxyacetate A mixture of 15 g (0.052 m) of 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetic acid in 100 ml of dimethylformamide and 3.87 g (0.028 m) of K2 CO3 was warmed to an internal temperature of 50° C. in an atmosphere of nitrogen for 1.5 hours. To this mixture, 9.41 g (0.062 m) of methyl bromoacetate was added dropwise and the mixture kept at 50° C. overnight. The reaction mixture was poured into water and extracted with ether. The ether extract was washed with 5percent NaHCO3 and water, dried over Na2 SO4, filtered and evaporated to give 16.5 g (94percent) of an oil of methyl-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)acetoxyacetate. ANALYSIS: Calculated for C19 H16 O6: 67.05percentC. 4.74percentH. Found: 66.88percentC, 4.74percentH. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | toluene-4-sulfonic acid;Reflux; | 10 g (0.037 moles) of 6,11-dihydro-11-oxodibenz[b,e] oxepin-2-acetic acid were dissolved in 150 ml of isopropanol (iPrOH) and 2 g (0.01 moles) of p-toluenesulfonic acid (p-TsOH) were added to this solution. The resulting solution was heated under reflux, distilling 100 ml of iPrOH from the reaction medium. The reaction was cooled to 40-45°C and 1 ml (0.007 ml) of Et3N was added. Then, the reaction mixture was left to cool to 20-25°C and stirring was maintained at this temperature for 30 minutes. Then, the suspension was left to cool to 5-10°C, it was filtered and the resulting product was washed with iPrOH. 11 g (0.035 moles, 96percent) of a white solid identified as the compound of the title were obtained, the spectroscopic properties of which are: 1H-NMR (CDCl3, 400 MHz), delta: 1.21 (d, 6H); 3.59 (s, 2H); 4.12 (m, 1H); 5.11 (s, 2H), 6.97 (d, 1H); 7.29 (d, 1H); 7.38 (m, 2H); 7.47 (m, 1H); 7.84 (d, 1H); 8.08 (d, 1H) ppm. 13C-NMR (CDCl3, 400 MHz), delta: 21.78 (2); 40.22; 68.35; 73.55; 120.95; 125.10; 127.93; 129.18; 129.42; 132.34; 132.72; 135.55; 136.31; 140.39; 160.40; 170.90; 171.37; 190.71 ppm. MS, M++1: 311.12 |
EXAMPLE 22 Isopropyl 6,11-Dihydro-11-oxodibenz[b,e]oxepin-2-acetate Reaction of 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetic acid with 2-propanol as described in Example 4 provides isopropyl 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetate as colorless crystals, m.p. 67°-68.5° C. Analysis: Calculated for C19 H18 O4: 73.53percent C; 5.85percent H. Found: 73.59percent C; 5.92percent H. |
Yield | Reaction Conditions | Operation in experiment |
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With sulfuric acid; In methanol; | EXAMPLE 4 Methyl 6,11-Dihydro-11-oxodibenz[b,e]oxepin-2-acetate A mixture of 42 g. of 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetic acid, 750 ml. of methanol, and 17 ml. of concentrated sulfuric acid is refluxed for 24 hours. The reaction mixture is diluted with water and extracted with benzene. After drying over magnesium sulfate, the benzene is concentrated to an oil. The precipitate resulting from addition of hexane is recrystallized from benzene-methanol to provide colorless crystals, m.p. 74°-76°, of methyl 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetate. Analysis: Calculated for C17 H14 O4: 72.33percent C; 5.00percent H. Found: 72.47percent C; 5.11percent H. |
Yield | Reaction Conditions | Operation in experiment |
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With thionyl chloride; In N-methyl-acetamide; chloroform; | (a) A mixture of 5.4 g. of 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetic acid, 2.4 g. of thionyl chloride, 10 ml. of chloroform and 1 ml. of dimethylformamide is heated for one hour under reflux. The excess thionyl chloride is distilled under reduced pressure. The above acid chloride is dissolved in chloroform and the solution saturated with ammonia. The precipitate is filtered and the chloroform is concentrated to an oil. Recrystallization from acetonitrile provides white crystals, m.p. 157°-158°, of 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetamide. Analysis: Calculated for C16 H13 NO3: 71.90percent C; 4.90percent H. Found: 71.89percent C; 4.83percent H. | |
With thionyl chloride; ammonia; In tetrahydrofuran; ethanol; water; | Step C 6,11-Dihydro-11-oxodibenz[b,e]oxepin-2-acetamide Reflux for 20 minutes a mixture of 5.0 gm. of the acid from Step B and 40 ml. of thionyl chloride. Evaporate to dryness under vacuum. Evaporate twice with 30 ml. portions of carbon tetrachloride. Dissolve the residue in 20 ml. of tetrahydrofuran and add the solution dropwise to a cooled and stirred saturated solution (ice-bath) of ammonia in 60 ml. of tetrahydrofuran. Pass ammonia through the solution simultaneously. Continue stirring at room temperature for an additional 15 minutes. Evaporate the mixture to dryness. Add a mixture of 12 ml. of ethanol and 60 ml. of water and stir the suspension for 30 minutes. Separate the solids, wash with water, then with ethanol and finally with ether to obtain the title product. |
Yield | Reaction Conditions | Operation in experiment |
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1.42 g (22.3%) | With BH3; borane; In tetrahydrofuran; methanol; hexane; water; ethyl acetate; toluene; | EXAMPLE 1 2-(6,11-Dihydro-11-oxodibenz[b,e]oxepin-2-yl)ethanol A stirred solution (-17° C.) of 6.71 g (0.025 mol) of 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetic acid and 18 ml of anhydrous tetrahydrofuran was treated dropwise over 15 minutes with 24 ml of 1.06M borane in tetrahydrofuran solution (approximately 0.025 mol BH3). After total addition, the cooling bath was allowed to equilibrate overnight (about 16 hours) to ambient temperature. The resultant stirred, chilled (5° C.) solution was treated with 5 ml of methanol, diluted with 50 ml of water and concentrated on a rotary evaporator at 40° C. to remove the organic solvents. The residue was diluted with water (70 ml) and CH2 Cl2 (70 ml) and was washed with 5percent NaHCO3 solution until the aqueous phase had a pH of 8. The organic phase was dried (Na2 SO4) and then filtered. The resultant organic phase was concentrated to an oil (5.51 g) which was dried by azeotropic distillation of toluene (70 ml). A portion of the oil was dissolved in 8 ml of anhydrous ethyl acetate, diluted to the cloud point with hexane (7 ml) and was then treated dropwise with ethyl acetate (0.6 ml) until a clear solution was obtained. The solution was subjected to high pressure liquid chromatography with hexane/ethyl acetate (60:40). The product-containing fractions were combined and concentrated to an oil (2.08 g). On standing at 5° C., some crystals formed and were stirred into the oil. On trituration of the mixture with hexane the oil solidified. The material was isolated by vacuum filtration, washed with hexane and dried in vacuo at ambient temperature to afford 1.42 g (22.3percent) of a solid of 2-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)ethanol, m.p. 78°-81.5° C. ANALYSIS: Calculated for C16 H14 O3: 75.57percentC; 5.55percentH; Found: 75.73percentC; 5.56percentH |
1.42 g (22.3%) | With BH3; borane; In tetrahydrofuran; methanol; hexane; water; ethyl acetate; toluene; | EXAMPLE 1 2-(6,11-Dihydro-11-oxodibenz[b,e]oxepin-2-yl)ethanol A stirred solution (-17° C.) of 6.71 g (0.025 mol) of 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetic acid and 18 ml of anhydrous tetrahydrofuran was treated dropwise over 15 minutes with 24 ml of 1.06M borane in tetrahydrofuran solution (approximately 0.025 mol BH3). After total addition, the cooling bath was allowed to equilibrate overnight (about 16 hours) to ambient temperature. The resultant stirred, chilled (5° C.) solution was treated with 5 ml of methanol, diluted with 50 ml of water and concentrated on a rotary evaporator at 40° C. to remove the organic solvents. The residue was diluted with water (70 ml) and CH2 Cl2 (70 ml) and was washed with 5percent NaHCO3 solution until the aqueous phase had a pH of 8. The organic phase was dried (Na2 SO4) and then filtered. The resultant organic phase was concentrated to an oil (5.51 g) which was dried by azeotropic distillation of toluene (70 ml). A portion of the oil was dissolved in 8 ml of anhydrous ethyl acetate, diluted to the cloud point with hexane (7 ml) and was then treated dropwise with ethyl acetate (0.6 ml) until a clear solution was obtained. The solution was subjected to high pressure liquid chromatography with hexane/ethyl acetate (60:40). The product-containing fractions were combined and concentrated to an oil (2.08 g). On standing at 5° C., some crystals formed and were stirred into the oil. On trituration of the mixture with hexane the oil solidified. The material was isolated by vacuum filtration, washed with hexane and dried in vacuo at ambient temperature to afford 1.42 g (22.3percent) of a solid of 2-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)ethanol m.p. 78°-81.5° C. ANALYSIS: Calculated for C16 H14 O3: 75.57percentC, 5.55percentH. Found: 75.73percentC, 5.56percentH. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium borohydrid; In sodium hydroxide; water; | EXAMPLE 19 6,11-Dihydro-11-hydroxydibenz[b,e]oxepin-2-acetic acid A solution of 5.0 g. of 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetic acid in 16 ml. of 5percent sodium hydroxide is added dropwise to a cold solution of 1.36 g. of sodium borohydride in 40 ml. of water. The reaction mixture is stirred at 0° C. for 4 hours, poured onto ice, and acidified with glacial acetic acid. The precipitate is filtered and washed with water to provide colorless crystals, m.p. 132°-133.5° C. of 6,11-dihydro-11-hydroxydibenz[b,e]oxepin-2-acetic acid. Analysis: Calculated for C16 H14 O4: 71.10percent C; 5.22percent H. Found: 71.25percent C; 5.21percent H. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 4 Reaction of 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetic acid, Example 2, with 2-propanol as described in Example 3 provides isopropyl 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetate as colorless crystals, mp 67°-68.5° C. Analysis: Calculated for C19 H18 O4: 73.53percentC; 5.85percentH. Found: 73.59percentC; 5.92percentH. |
Yield | Reaction Conditions | Operation in experiment |
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EXAMPLE 6 Reaction of 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetic acid, Example 2, with n-butanol as described in Example 5 provides n-butyl 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetate. Analysis: Calculated for C20 H20 O4: 74.05percentC; 6.21percentH. Found: 74.08percentC; 6.17percentH. |
Yield | Reaction Conditions | Operation in experiment |
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In methylene chloride-nitromethane; 4-benzyloxy-3-chlorocarbonylphenylacetyl chloride; | E. A sample of 4-benzyloxy-3-carboxyphenylacetic acid is treated with an excess of thionyl chloride at reflux for 2 hours. The excess thionyl chloride is removed in vacuo and the remaining 4-benzyloxy-3-(chlorocarbonyl)phenylacetyl chloride is dissolved in methylene chloride-nitromethane and treated with an equivalent amount of aluminum chloride. The reaction mixture is stirred several hours at room temperature, refluxed for two hours and quenched with dilute hydrochloric acid. The layers are separated, the organic phase dried and evaporated in vacuo to a residue which, on crystallization from isopropyl alcohol yields 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetic acid, mp 137°-138° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.95% | Example 6 (Z)-11-[3-dimethylaminopropylidene]-6,11-dihydrodibenz[b,e]oxepin-2-acetic Acid Hydrochloride (Olopatadine Hydrochloride) Procedure 1 Step a: Preparation of Olopatadine Hydrobromide Under a nitrogen atmosphere a 2500 ml 5-neck flask with a mechanical stirrer was charged with 3-dimethylaminopropyltriphenylphosphonium bromide hydrobromide (Olo-IM4) (299.6 g, 0.584 mol; HPLC assay: 99.4percent) and sodium hydride (70.28 g, 1.757 mol, assay: 60percent). Precooled (4° C.) dry THF (284 g) was added and the suspension was stirred under N2 atmosphere at 20-30° C. for 40 minutes and at 55-60° C. for 3 hours. After 160 g of the solvent from the orange suspension was distilled off under normal pressure, the reaction mixture was cooled to <10° C. Then a solution of 6,11-dihydro-11-oxo-dibenz[b,e]oxepin-2-acetic acid (Olo-IM2) (57.69 g, 0.215 mol, HPLC assay >99.5percent) in dry THF (100 g) was added carefully and the reaction mixture was stirred for 20-30 hours at 20-25° C. The reaction mixture was cooled to <10° C. and a solution of water (25 g) in THF (75 g) was added slowly. After dilution with water (270 g) the two-phase solution was separated and the water layer was concentrated under normal pressure until 286 g distillate was obtained. Prior to concentration of this layer, the pH was checked (at 20-25° C.) to ensure that the pH was not lower than pH 12 (and raised to pH 12 or greater, if necessary, with 30percent aqueous NaOH). The residue was diluted with water (765 g), extracted five times with toluene (500 g each). A solution of 2-methyltetrahydrofuran (490 g) and 2-propanol (90 g) was added and the pH of the water layer was adjusted from 13.8 to 4.3-4.4 by addition of an aqueous hydrobromic acid solution (169.2 g, 1.04 mol; assay: 48percent). The phases were separated and the water phase was extracted three times with a mixture of 2-methyltetrahydrofuran (490 g) and 2-propanol (90 g) each. The combined brown organic layers were evaporated under reduced pressure at 500 mbar until a distillate of 2350 g was obtained. The remaining brown oil was diluted with n-butanol (233 g) and the mixture was evaporated again under reduced pressure at 500 mbar to remove water by azeotropic distillation (275 g two-phase distillate). To the residue, n-butanol (537 g) and seeding material were added, and the slurry was stirred at 75° C. for one hour. The slurry was cooled to 20-25° C., stirred at this temperature for 14 hours and filtered off. The wet product washed with n-butanol (130 g) and dried under vacuum (15 h, 80° C.) to give beige powdery Olopatadine Hydrobromide (yield: 52.11 g, 0.122 mol, 56.9percent; HPLC assay: 98.17percent, HPLC purity: 98.16percent, Z/E-Isomers: 98.5/1.5). In a 750 ml 5-necked flask a suspension of the above-obtained dry product (50.0 g, 0.117 mol; HPLC assay: 98.17percent) in n-butanol (325 g) was heated at 80° C. for one hour (water content of the mixture: 1.87percent). Then the pale beige slurry was slowly cooled to <5° C. and stirred at this temperature for one hour. After filtration the wet product washed with n-butanol (200 g) and dried under vacuum (15 h, 60° C.) to give pale beige Olopatadine Hydrobromide (yield: 48.22 g, 0.114 mol, 96.95percent; HPLC assay: 98.69percent, HPLC purity: 98.60percent, Z/E-Isomers: 98.9/1.1). | |
53.5% | Procedure 2 Step a: Preparation of Olopatadine Hydrobromide Under a nitrogen atmosphere a 1250 ml 4-neck flask with a mechanical stirrer, reflux condenser and internal thermometer was charged with 3-dimethylaminopropyltriphenylphosphonium bromide (Olo-IM4, free base) (283.23 g, 0.648 mol, assay: 98.0percent), sodium hydride (38.40 g, 0.960 mol, assay: 60percent) and dry THF (317 g) at an internal temperature of 20-25° C. The white suspension was heated to 55-60° C. for 2.5 hours whereupon the color changed to orange. After 189 g of the solvent was distilled off under normal pressure, the reaction mixture was cooled to 15-20° C. Then a solution of 6,11-dihydro-11-oxo-dibenz[b,e]oxepin-2-acetic acid (Olo-IM2) (64.39 g, 0.240 mol, HPLC assay >99.5percent) in dry THF (111 g) was added carefully and the reaction mixture was stirred for 40 hours at 20-25° C. The reaction mixture was cooled to 0-5° C. and a solution of water (24 g) in THF (60 g) was added slowly (at 0-20° C.). After dilution with water (290 g) and stirring for 10-15 minutes at 20-25° C., the two-phase solution was separated and the water layer was concentrated under normal pressure until 276 g distillate was obtained. Prior to concentration of this layer, the pH was checked (at 20-25° C.) to ensure that the pH was not lower than pH 12 (and raised to pH 12 or greater, if necessary, with 30percent aqueous NaOH). The residue was cooled to 25-30° C. and extracted first with toluene/n-butanol (9/1, 300 g) and then three times with toluene/n-butanol (9/1, 240 g for each extraction). During these extractions three layers were obtained, whereupon each time the two aqueous layers were separated and extracted again. Afterwards the aqueous layers were extracted once with toluene (200 g). In this case only two layers were obtained during the extraction. Then, n-butanol (240 g) was added to the aqueous layer and at 0-10° C., the pH was adjusted from 12.59 to 4.2-4.6 by addition of an aqueous hydrobromic acid solution (78.65 g, 0.467 mol; assay: 48percent). The mixture was allowed to warm to 20-25° C., and the aqueous layer was separated and extracted again with n-butanol (240.0 g). The combined organic layers were washed with water (120.0 g) and then treated with charcoal (5.0 g). After filtration of the suspension through a celite filter bed (10.0 g) and washing the filter cake with n-butanol (30 g), the combined filtrates were concentrated in vacuum (200 mbar) until the internal temperature rose to 72-75° C. and 330-390 g distillate was obtained. To the resulting suspension was added water (4.27 g) at 65-74° C. and the mixture was cooled within 2-3 hours to an internal temperature of 20-25° C. The suspension was stirred at this temperature for 16 hours and then filtered. The wet product washed with n-butanol (72.0 g) and dried under vacuum for 14 hours at 80° C. to give a beige solid (yield: 54.91 g, 0.128 mol, 53.5percent; HPLC assay: 97.85percent, HPLC purity: 97.80percent, Z/E-Isomers: 98.1/1.9). This product is used for the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
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61.5 - 63.7%Chromat. | This example relates to variation of certain parameters involved in the Wittig reaction and work-up procedure described in step (a) of Procedures 1 and 2 of Example 6 to prepare olopatadine hydrobromide (i.e., Wittig reaction conditions; quenching; washing steps; extraction using nBuOH; and charcoal treatment). As shown in the Tables below, the resultant olopatadine product was analyzed for overall yield. The results that are present in Table 5 show the efficiency and robustness of the process for the preparation and isolation of olopatadine HBr from the reaction mixture. Neither a prolonged stirring time of the Wittig reaction (up to 63 h) nor reaction temperatures up to 30° C. had an adverse influence on the yield of the product or the selectivity of the reaction, and isolation of the products as their HBr salts gave high yields (reaction yield of Z-isomer: 66-67percent and overall yield of olopatadine (Z-isomer) after extraction with nBuOH: 62-64percent). |
Yield | Reaction Conditions | Operation in experiment |
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85.3% | Example 3 Production of t-butyl 11-oxo-6,11-dihydrodibenz[b,e] oxepin-2-acetate Into a 3-L four-necked flask, 200 g (0.746 mol) of 11-oxo-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid and 1500 ml of chlorobenzene were charged, 45.8 g (0.298 mol) of phosphorus oxychloride and 2.7 g (0.149 mol) of water were added thereto, and the mixture was heated to 40°C. Then, 209.2 g (3.728 mol) of isobutene was blown thereinto over about 8 hours. The reaction mixture was poured, with cooling, into an aqueous solution of 206.2 g (1.492 mol) of potassium carbonate dissolved in 800 ml of water, and stirred at about 25°C for 1 hour. An organic layer was then separated. Further, the organic layer was washed with an aqueous solution of 51.5 g (0.323 mol) of potassium carbonate dissolved in 200 ml of water, and then concentrated under reduced pressure to obtain 243 g of crude oil of the title compound. The obtained crude oil was dissolved in 500 ml of methanol, and 10 g of activated carbon was added thereto, stirred at 50°C for 1 hour, and filtered through a Buchner funnel. The activated carbon was then washed with 50 ml of methanol heated to 50°C. The filtrate and the cleaning solution were mixed, and slowly cooled, whereby crystals were precipitated at 30°C. It was further cooled to 10°C, and then filtered through a Buchner funnel. The crystals were washed with 15 ml of methanol cooled to 10°C. The obtained crystals were dried under reduced pressure to obtain 206.2 g (0.636 mol) of the title compound. The yield was 85.3percent, and the purity as measured by HPLC was 99.4percent. Melting point 68.8°C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79.9% | Into a 1-L four-necked flask, 60.4 g (0.225 mol) of the 11-oxo-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid obtained according to the method of Example 1 and 300 ml of toluene were charged, 49.6g (0.236 mol) of trifluoroacetic anhydride was added thereto, and the mixture was stirred at about 20°C for 1 hour. Then, 100 ml of t-butanol was added thereto, stirred at about 20°C for 2 hours, and further stirred at 80°C for 2 hours. The mixture was cooled to about 20°C, 600 ml of water was added thereto and stirred for 20 minutes, and then an organic layer was separated. The organic layer was washed with 400 ml of water, and then washed with a solution of 6.2g (0.045 mol) of potassium carbonate dissolved in 100 ml of water. To the washed organic layer, 3.0 g of activated carbon was added, stirred, and then filtered though a Buchner funnel to separate activated carbon. The activated carbon was washed on a Buchner funnel with 50 ml of toluene. The filtrate and the cleaning solution were mixed, and concentrated under reduced pressure to obtain 58.3 g of the title compound. The apparent yield was 79.9percent, and the purity as measured by HPLC was 99.1percent.(HPLC conditions) Column: Inertsil ODS-5 mum (4.6 mm ID x 15 cm)Mobile Phase: 0.02percent trifluoroacetic acid aqueous solution/acetonitrile = 5/5 --> 3/7 (30 minutes)Detection Wavelength: UV 254 nm(Physical Property Data) 1H NMR (400 MHz, CDCl3) delta 1.45 (s, 9H), 3.55 (s, 2H), 5.17 (s, 2H), 7.02 (d, J = 8.4, 1H), 7.40-7.48 (m, 3H), 7.54 (t, J = 6.4 Hz, 1H), 7.89 (d, J = 6.4 Hz, 1H), 8.11 (d, J = 2.4 Hz, 1H) |
Yield | Reaction Conditions | Operation in experiment |
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60% | 8 g (0.029 moles) of 6,11-dihydro-11-oxodibenz[b,e] oxepin-2-acetic acid were dissolved in 30 ml of acetonitrile and 0.15 ml of DMF were added to this solution. 2.3 ml (0.032 moles) of thionyl chloride were added to the resulting solution at 20-25°C. Once the reaction had ended, the reaction mixture is slowly poured over an aqueous solution of 40percent Me2NH (14.4 g, 0.32 ml) cooled at 0-5°C and stirring was maintained at this temperature for 30 minutes. Subsequently, the organic part was distilled under reduced pressure and 80 ml of methylene chloride were added. The phases were decanted, separating the organic phase. The solvent was distilled, obtaining an oil with the product of the title with a yield of 60percent. |
Yield | Reaction Conditions | Operation in experiment |
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98% | toluene-4-sulfonic acid; In toluene;Reflux; | 10 g (0.037 moles) of 6,11-dihydro-11-oxodibenz[b,e] oxepin-2-acetic acid were dissolved in 100 ml of toluene and 2 g (0.01 moles) of p-toluenesulfonic acid (p-TsOH) and 17.5 ml (0.169 moles) of benzyl alcohol were added to this solution. The reaction was equipped with a Dean-Stark, a mixture of water/toluene thus being distilled. The reaction was maintained until 0.7 ml of water were collected. The reaction was left to cool to 20-25°C, at which temperature 1.5 ml (0.011 moles) of Et3N were added. The resulting solution was concentrated under reduced pressure until obtaining a residue which was dissolved in isopropanol (50 ml), giving rise to a suspension. The obtained suspension was stirred at 20-25°C for 30 minutes, then being cooled at 0-5°C. Stirring was maintained at this temperature for 30 minutes. Then, the suspension was filtered and washed, obtaining 12.5 g (0.036 moles, 98percent) of a white solid identified as the compound of the title, the spectroscopic properties of which are: 1H-NMR (CDCl3, 400 MHz), delta: 3.70 (s, 2H); 5.14 (m, 4H), 7.02 (d, 1H), 7.33 (m, 1H); 7.41-7.46 (m, 4H), 7.52 (m, 3H); 7.88 (m, 2H); 8.15 (d, 1H) ppm. 13C-NMR (CDCl3, 400 MHz), delta: 39.95; 66.56; 73.37; 120.88; 124.92; 127.48; 127.64; 128.04 (2); 128.10; 128.39 (2); 129.05; 129.25; 132.32; 132.58; 135.33;135.53; 136.20; 140.60; 160.72; 171.48; 191.01. MS, M++1: 358.12. |
Yield | Reaction Conditions | Operation in experiment |
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93% | toluene-4-sulfonic acid;Reflux; | 10 g (0.037 moles) of 6,11-dihydro-11-oxodibenz[b,e] oxepin-2-acetic acid were dissolved in 50 ml of ethanol (EtOH) and 1 g (0.005 moles) of p-toluenesulfonic acid (p-TsOH) was added to this solution. The resulting solution was heated under reflux, distilling EtOH (10 ml) at atmospheric pressure which was put back immediately in the reaction medium. This operation was repeated several times for 90 minutes. After this time period, the reaction was cooled to 20-25C and 0.54 g (0.005 moles) of potassium acetate were added. Then, it was concentrated under reduced pressure until obtaining a residue on which 40 ml of CH2Cl2 and 10 ml of H2O were added. The mixture was stirred for 5 minutes and decanted, the organic phase being separated from the aqueous phase. The organic phase was concentrated under reduced pressure until obtaining a residue on which 20 ml of ethyl acetate (AcOEt) were added. The resulting suspension was stirred at room temperature (18-22C) for 30 minutes. After this time period the suspension was cooled at 0-5C for 30 minutes, and it was then filtered, washing the obtained solid with AcOEt at 0-5C, which was dried in oven with air circulation at 50-55C, thus obtaining 10.2 g (0.034 moles, 93%) of a white solid identified as the compound of the title, the spectroscopic properties of which are: 1H-NMR (CDCl3, 400 MHz), delta: 1.24 (t, 3H); 3.61 (s, 2H); 4.14 (q, 2H); 5.15 (m, 2H), 7.00 (d, 1H); 7.33 (d, 1H); 7.42 (m, 2H); 7.52 (m, 1H); 7.86 (d, 1H); 8.09 (d, 1H) ppm. 13C-NMR (CDCl3, 400 MHz), delta: 14.28; 40.33; 61.04; 73.68; 121.09; 125.20; 127.87; 128.02; 129.30; 129.54; 132.49; 132.82; 135.64; 136.41; 140.52; 160.50; 171.49; 190.88 ppm. MS, M++1: 297.10. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 4; Preparation of Olopatadine Hydrochloride Form A Through Grignard Reaction(11-oxo-6,11-dihydrodibenzo[b,e]oxepin-2-yl)acetic acid (Compound II, R1H) (22.2 g; 0.0827 mol) was suspended in 216 g (222 mL) of tetrahydrofuran under a nitrogen atmosphere. After stirring the yellow solution for 40 minutes, 102.27 g (0.16471 mol) of 3-dimethylaminopropylmagnesium chloride solution was added over approximately two hours. The reaction mixture was then stirred and maintained at room temperature for 15 hours.Thereafter, 475 mL of aqueous ammonium chloride solution was slowly added to the reaction mixture with continuous stirring. The resulting white aqueous phase and yellow organic phase were then acidified with hydrochloric acid (37percent) with stirring in order to adjust the pH to approximately 1. The mixture was then stirred at room temperature for approximately 15 hours. Next, the mixture was heated to reflux for 2 hours and 45 minutes in order to ensure the complete evolution of the reaction (i.e., complete dehydration). The aqueous and organic phases were then separated, and the aqueous phase was extracted five times with 142 g (160 mL) of tetrahydrofuran. The resulting organics phases were then washed with brine. The phases were then separated, and the solvent of the organic phase was removed by distillation under reduced pressure to yield 46.87 g of an orange residue.Next, 220 g of deionized water and 192 g (220 mL) of isopropyl acetate were added to the residue. The mixture was then stirred for 30 minutes, and the phases were separated. The solvent of the organic phase was then removed by distillation under reduced pressure. Next, 7.9 g (10 mL) of acetone was added to the residue and then removed by distillation under vacuum.The residue obtained was then suspended in 79.1 g (100 mL) of acetone and heated with continuous stirring to reflux for 45 minutes. Thereafter, the resulting suspension was allowed to cool and was stirred overnight at room temperature. The suspension was then filtered, and the resulting yellowish solid was washed with acetone and dried under vacuum at 45° C. to yield 20.55 g of solid. (Global Yield 66.42percent; HPLC Purity: 16.06percent cis, 82.34percent trans; Cis/Trans Ratio: 0.1984).A 1 g portion of the solid obtained was treated with 3.95 g (5 mL) of acetone and 4.05 g (5 mL) of 1-butanol. The mixture was stirred and heated to reflux for 30 minutes and then allowed to cool to 0-5° C. for 2 hours. The suspension was filtered, and the resulting white solid was washed with acetone and dried under vacuum for two hours at 60° C. to yield 0.11 g of olopatadine hydrochloride Form A. (Partial Yield 11.00percent; Global Yield 6.75percent; HPLC Purity: 95.37percent cis, 4.08percent trans; Cis/Trans Ratio: 23.37).Analytical data: HPLC Purity: 95.37percent; XRD (2psi): 6.28°, 11.03°, 12.61°, 15.44°, 17.47°, 18.99°, 19.34°, 19.34°, 20.52°, 24.03°, 25.27°, 28.21° (substantially identical to FIG. 1); IR: substantially identical to FIG. 2; DSC (open pan): substantially identical to FIG. 3. |
Yield | Reaction Conditions | Operation in experiment |
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93% | With sulfuric acid; at 115℃; | EXAMPLE 1; a) Preparation of <strong>[55453-87-7]isoxepac</strong> butyl esterIn a 3 1 flask equipped with a thermometer, stirrer, condenser and Dean-Stark apparatus, add 100 g of <strong>[55453-87-7]Isoxepac</strong> (ll-oxo-6, 11-dihydrodibenzo [b, e] oxepin-2- yl) acetic acid), 1600 ml of n-butanol, 0.2 ml of sulphuric acid. Heat up to boiling temperature (approx. 115°C) and continue stirring at said temperature for at least 2 hours. After stirring for 2 hours, distil 500 ml of solvent at atmospheric pressure. Chill to T=20/25°C, add 10 g of carbon to the reaction mixture, stir at T=20/25°C for 10 minutes and filter through dicalite, washing with 100 ml of n-butanol. Concentrate under vacuum to give an oily residue and add 350 ml of heptane isomers. Chill to T=-15/-20°C so as to crystallise the product. Stir at T=-15/-20°C for 1 hour and filter, washing the crystals obtained with 90 ml of heptane isomers at T=-15/-20°C. Dry the product under vacuum at a temperature of 25°C for at least 8 hours. Yield: 112.5 g, 93percent; Titre by HPLC >;99.5percent, Purity by HPLC >;99.5percentNMR (DMSO d6) : 0.84 (s, 3H), 1.29 (dd,2H), 1.53 (dd, 2H), 3.71 (d,2H), 4.03 (dd,2H), 5.28 (d,2H), 7.07 (d, IH), 7.54 (m, 4H), 7.78 (s,lH), 8.00 (s,lH)). |
93% | With sulfuric acid; at 115℃; for 2h;Dean Stark apparatus; | a) Preparation of <strong>[55453-87-7]Isoxepac</strong> Butyl EsterIn a 3 l flask equipped with a thermometer, stirrer, condenser and Dean-Stark apparatus, add 100 g of <strong>[55453-87-7]Isoxepac</strong> (11-oxo-6,11-dihydrodibenzo[b,e]oxepin-2-yl)acetic acid), 1600 ml of n-butanol, 0.2 ml of sulphuric acid. Heat up to boiling temperature (approx. 115° C.) and continue stirring at said temperature for at least 2 hours.After stirring for 2 hours, distil 500 ml of solvent at atmospheric pressure. Chill to T=20/25° C., add 10 g of carbon to the reaction mixture, stir at T=20/25° C. for 10 minutes and filter through dicalite, washing with 100 ml of n-butanol. Concentrate under vacuum to give an oily residue and add 350 ml of heptane isomers. Chill to T=-15/-20° C. so as to crystallise the product. Stir at T=-15/-20° C. for 1 hour and filter, washing the crystals obtained with 90 ml of heptane isomers at T=-15/-20° C. Dry the product under vacuum at a temperature of 25° C. for at least 8 hours. Yield: 112.5 g, 93percent; Titre by HPLC >99.5percent, Purity by HPLC>99.5percentNMR (DMSO d6): 0.84 (s, 3H), 1.29 (dd,2H), 1.53 (dd,2H), 3.71 (d,2H), 4.03 (dd,2H), 5.28 (d,2H), 7.07 (d,1H), 7.54 (m, 4H),7.78 (s,1H), 8.00 (s,1H)). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 14: Preparation of (Z)-ll-[3-(dimehylamino)propylidene]-6,ll- dihydrodibenz[b,e] oxepin-2-acetic acid hydrochlorideIodine (0.5 g) was added to a mixture of magnesium (43 g) and tetrahydrofuran (150 ml) under nitrogen condition. Heated the reaction mixture to reflux temperature. 3- dimethyl amino propyl chloride (5 ml) followed by 1,2-dibromo ethane (2 g) were added to the reaction mixture at same reflux temperature. A solution of 3 -dimethyl amino propyl chloride (225 g) in tetrahydrofuran (200 ml) was added drop wise to the reaction mixture at reflux temperature and stirred for 1 hour at the same temperature. Cooled the reaction mixture to 25-30°C, further cooled to 5-10°C. A solution of l l-oxo-6,11- dihydrobenz[b,e]oxepin-2-acetic acid (50 g) in tetrahydrofuran (150 ml) was added to the reaction mixture slowly at 5-10°C and stirred for 45 minutes at 5-10°C. Raised the temperature of the reaction mixture to 25-30°C and stirred the reaction mixture for 5 hours at same temperature. After completion of the reaction, the reaction mixture was quenched with aqueous acetic acid. Aqueous hydrochloric acid [hydrochloric acid (300 ml) in water (100 ml)] was added to the reaction mixture at a temperature below 25 °C and stirred for 10 minutes at 25-30°C. Toluene was added to the reaction mixture and stirred for 10 minutes. Both the toluene and aqueous layers were separated and the aqueous layer was washed with toluene. Both the toluene layers were combined and washed with hydrochloric acid. Both the aqueous layer and hydrochloric acid layers were combined. Heated the aqueous layer to 90-95 °C and stirred for 24 hours at same temperature Cooled the reaction mixture to 25-30°C and dichloromethane was added to the reaction mixture. Stirred the reaction mixture for 15 minutes at 25-30°C. Both the organic and aqueous layers were separated and the aqueous layer was extracted with dichloromethane. Both the dichloromethane layers were combined and then dried with sodium sulfate. Distilled off the solvent completely under reduced pressure and co- distilled with acetone. Acetone was added to the reaction mixture and stirred for 45 minutes at 25-30°C. Filtered the precipitated solid, washed with acetone and then dried to get the title compound.Yield: 30 grams; Purity by HPLC: 98.9percent (Z-isomer) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79.7% | Production of 11-hydroxy-11- (3-dimethylaminopropyl)-6, 11-dihydrodibenz[b,e]oxepin-2-acetic acidTo a tetrahydrofuran (47 mL) solution in which 10 g (37.3 mmol) of 11-oxo-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid was dissolved, 160 mL (corresponding to 117 mmol) of a THF/toluene solution of 3-dimethylaminopropyl magnesium chloride was added dropwise at 5 to 18°C for 65 minutes. THF (94 mL) was added during dropping.The solution was stirred at 14 to 18°C for 1 hour, and acetic acid (15 mL) was added dropwise to the reaction liquid.Further, water (40 mL) was poured into the reaction liquid.The reaction liquid was stood still to separate an organic layer therefrom.An aqueous layer (lower layer) was stood still over one night so that crystals were deposited.The crystals were filtered, washed with cool water (30 mL) having a temperature of about 5°C, and dried under reduced pressure to obtain 10.56 g of a title compound.The yield of the compound was 79.7percent.Melting Point: 203.5°C1H NMR (400 MHz, CDCl3) delta 1.51-1.60 (m, 2H), 2.07-2.11 (m, 1H), 2.49-2.53 (m, 1H), 2.72 (s, 6H), 2.81-2.88 (m, 1H), 2.93-2.99 (m, 1H), 3.50 (s, 2H), 3.73-3.77 (m, 1H), 5.04 (d, J= 15.6 Hz, 1H), 5.46 (d, J=15.6Hz, 1H), 7.09 (d, J=8.0Hz, 2H), 7.24-7.38 (m, 3H), 7.61 (d, J= 2.0 Hz, 1H), 7.89 (dd, J= 8.0, 0.8 Hz, 1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With thionyl chloride; at 0 - 20℃; for 24.5h; | 2-(11-Oxo-6,11-dihydrodibenzo[b,e]oxepin-2-yl)acetic acid (5;5.00 g, 18.65 mmol) was dissolved in MeOH (100 mL) and cooled to 0 °C. SOCl2 (2.06 mL, 27.98 mmol) was added dropwise over 30min and the resulting solution was stirred at r.t. for 24 h. The solvent was evaporated almost to dryness and the residue was partitioned between CH2Cl2 (50 mL) and sat. aq NaHCO3 (50 mL). The organic layer was separated, dried (Na2SO4), filtered, and concentrated under reduced pressure to give <strong>[55453-87-7]isoxepac</strong> ester, which was used without further purification. To a stirred mixture of <strong>[55453-87-7]isoxepac</strong> ester (5.00 g, 17.66 mmol) and Zn (3.44 g, 53 mmol) in DMF (50 mL) was added allyl bromide (1.66 mL, 19.43 mmol) at 0 °C. After 2 h, the mixture was filtered to remove the excess Zn. Aq 10percent HCl (20 mL) wasadded and the organic layer was separated. The aqueous layer was extracted with small portions of EtOAc (3 × 20 mL), the combined organic extracts were dried (Na2SO4), filtered, and concentrated underreduced pressure. The resulting liquid was purified by column chromatography (PE?EtOAc, 8:2) to give 4 | |
With thionyl chloride; at 0 - 25℃; for 24.5h; | [0019] 2-(1 1-oxo-6,1 1-dihydrodibenzo{b,ejoxepin-2-yl)acetic acid (5 g, 18.65 mmol) was dissolved in methanol (100 mL) and cooled at 0CC. Thionyl chloride (2.06 mL, 27.98 mmol) was added dropwise during a half hour period and the solution was stirredat room temperature (25°C) for 24 h. The solvent was evaporated almost to dryness and the residue was partitioned between dichloromethane (50 mL) and saturated sodium bicarbonate solution (50 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, giving ketoester, which was used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; at 20℃; for 1h;Inert atmosphere; | At room temperature and under an argon atmosphere, a solution of 6,1 1-dihydro-li- oxo-dibenz[b,e]oxepin-2-acetic acid (5.0 g, 18.64 mmol, I eq) in anhydrous THF (20 ml) was prepared. N,O-bis(trimethyl-silyl)acetamide (4.56 ml, 18.64 mmol, 1 eq) was added and the solution stirred for 1 hour. At room temperature and under an argon atmosphere, a suspension of 3-dimethylaminopropyltriphenylphosphoniumbromide hydrobromide (23.7 g, 46.6 mmol, 2.5 eq) in anhydrous THF (80 ml) was prepared. To this suspension the previously prepared solution of trimethylsilyl ester was then added, followed by the sodium hydride (60percent in mineral oil, 6.08 g, 152.1 mmol, 7.85 eq). The resulting mixture was heated at 60°C for 3 hours and the consumption of the starting material was followed by LC-MS. The reaction mixturewas cooled to 0°C and carefully quenched with 40 ml of THF/H20 1/1 (v/v). After dilution with water (100 ml), the mixture was washed with toluene (100 ml) and two times with 2-methylTllF (100 ml). The aqueous phase was acidified to pH 1 with 37percent hydrochloric acid (8 ml) and then washed with toluene (100 ml). Sodium acetate was added up to pH 5 and the aqueous phase was extracted two times withmixture of 2-methylTHF/2-propanol 2:1 (v/v) (300 ml). The organic layer wasevaporated under reduced pressure. The crude material (8.7 g) was taken up with acetone (90 ml) and acidified with 37percent hydrochloric acid, obtaining the precipitation of the cis isomer of olopatadine hydrochloride. The white solid was filtered and washed with acetone. Yield = 55percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.120 kg | Taking example 2 step 4 the obtained intermediate IV (Z/E = 65.12/32 . 82) 2 kg (5.9mol) dissolved in 10L acetone, dropping 600mL8NHCl, precipitating a large amount of white solid. After the add, continue to stir 1h, filtering, because 2L acetone washing, drying the white solid obtained 1120g, olopatadine hydrochloride for the final product, the yield is 56percent. (Purity 99.79percent, Z/E=99.79/0 . 08) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18.6 kg (36.6mol) 3-dimethylamino propyl triphenylporphyrin phosphorus hydrobromide and 90L non-water mixing and stirring THF, under the protection of nitrogen, is added in batches 3.18 kg (79.8mol) NaH, temperature control 20-40°C, after adding, the temperature rising to 50-60°C, reaction 4h, then adding 3 kg (11.4mol) intermediate (III), stirring the mixture at room temperature for overnight, cooling to 0-15°C, slowly adding 60L water, using ethyl acetate (30L × 3) extraction. PH=8 for adjusting the HCl aqueous phase, the n-butanol extraction product (12L × 2), with an organic layer 6L a water washing, concentrating under reduced pressure nearly dry, add 12L ethyl acetate stirring 1h, filtering, to obtain 2.36 kg intermediate IV (Z/E = 65.12/32 . 82), yield: 62.5percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.5% | Under nitrogen was added to the reaction flask N, of N- dimethylamino-chloropropane hydrochloride (150mmol) 23.71g ,, was added potassium bromide (300mmol) 35.7g, stirred for 1 hour, hexamethylphosphoramide (200mmol) 35.84g, dimethyl sulfoxide 150ml, was heated at reflux, the reaction was stirred for 2 hours. after completion of the reaction, dimethyl sulfoxide was dissolved in 30ml of <strong>[55453-87-7]Isoxepac</strong> (100mmol) 26.83g of the solution, first at room temperature for 1 hour, then 20 reaction temperature, after completion of the reaction the reaction solution was added 150ml of water, the solvent was removed by distillation under reduced pressure, the residue was added 30percent hydrochloric acid was dissolved in ethanol, the crystallization is added petroleum ether, filtered and washed to obtain olopatadine hydrochloride (90.5 mmol) 33.84g, yield 90.5percent, HPLC purity 99.3percent, E-type content of 0.05percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81.2% | Lithium naphthalene reagent preparation Lithium metal (0.4 g, 60 mmol) was added to anhydrous naphthalene (2.6 g, 20 mmol) under nitrogen protection In the temperature control 20-25 ° C stirring 2h lithium naphthalene reagent.Preparation of highly active organozinc reagent Under nitrogen protection, 3-bromo-N,N-dimethylpropanamine (5.0 g, 30 mmol) was added to the reaction flask, anhydrous tetrahydrofuran (32 ml), and the mixture was stirred and cooled to 10-20 °C. Zinc bromide (13.5 g, 60 mmol) was added in batches, stirred for 10 minutes, and the above-mentioned naphthalene lithium reagent was added dropwise. After the reaction temperature was stabilized, the mixture was heated to reflux (65-70° C.), and the reaction was stirred for 5-6 h. The resulting reaction solution is a highly active organozinc reagent.Preparation of Crude Olopatadine <strong>[55453-87-7]Isoxepac</strong>(4.0g, 15mmol) was dissolved in tetrahydrofuran (12ml), dissolved and clarified, and the temperature was controlled at 0-10°C.In the above high activity organozinc reagent, after about 0.5 h, the reaction mixture was heated to 20-25° C. and stirred for 16 h. The end point of the reaction was followed by HPLC, and the purity was 94.0percent. The reaction solution was cooled, and 25 ml of water was added for extraction. The pH of the aqueous phase was adjusted to pH 4.0 to 4.4. The aqueous phase was washed with n-hexane, methyl tert-butyl ether, and ethyl acetate, respectively, and n-butanol was extracted with 20 ml×4 of water to decolorize. Evaporated under reduced pressure to give 4.4 g of oil, with a purity of 96.0percent.Refined OlrotidineTo the above-obtained oily substance, n-butanol (20 ml) was added, heated to 75-80°C, and stirred for 15 minutes.But to 5-10 ° C, stirring crystallized 1h, filtered and dried to give 3.6g olopatadine, yield 81.2percent, purity 99.2percent. |
Tags: 55453-87-7 synthesis path| 55453-87-7 SDS| 55453-87-7 COA| 55453-87-7 purity| 55453-87-7 application| 55453-87-7 NMR| 55453-87-7 COA| 55453-87-7 structure
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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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