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CAS No. : | 42017-89-0 | MDL No. : | MFCD00792461 |
Formula : | C17H15ClO4 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | MQOBSOSZFYZQOK-UHFFFAOYSA-N |
M.W : | 318.75 | Pubchem ID : | 64929 |
Synonyms : |
FNF acid;NSC 281318;Procetofenic acid;Trilipix
|
Num. heavy atoms : | 22 |
Num. arom. heavy atoms : | 12 |
Fraction Csp3 : | 0.18 |
Num. rotatable bonds : | 5 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 84.05 |
TPSA : | 63.6 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | Yes |
CYP2C9 inhibitor : | Yes |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.47 cm/s |
Log Po/w (iLOGP) : | 2.41 |
Log Po/w (XLOGP3) : | 3.91 |
Log Po/w (WLOGP) : | 3.81 |
Log Po/w (MLOGP) : | 2.86 |
Log Po/w (SILICOS-IT) : | 3.78 |
Consensus Log Po/w : | 3.35 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -4.35 |
Solubility : | 0.0141 mg/ml ; 0.0000443 mol/l |
Class : | Moderately soluble |
Log S (Ali) : | -4.94 |
Solubility : | 0.00362 mg/ml ; 0.0000114 mol/l |
Class : | Moderately soluble |
Log S (SILICOS-IT) : | -5.4 |
Solubility : | 0.00128 mg/ml ; 0.00000402 mol/l |
Class : | Moderately soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.14 |
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 |
---|---|---|
91% | Stage #1: With potassium hydroxide In ethanol for 16 h; Heating / reflux Stage #2: With hydrogenchloride In water |
To a solution of 104 (5.00 g, 12.2 mmol) in ethanol (150 mL) was added a solution of potassium hydroxide (2.74 g, 48.9 mmol) in ethanol (50 mL) and the reaction mixture was heated at reflux and stirred for 16 h. Ethanol was removed under vacuum and water (200 mL) was added. The aqueous solution was washed with diethyl ether (2 x 100 mL) and acidified to pH 1 with 2 N HCl. The acidic aqueous solution was then extracted with ethyl acetate (2 x 150 mL) and the combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to provide 105 (3.57 g, 91percent) as an off-white solid: 1H NMR (300 MHz, CD3OD) δ 7.75-7.70 (m, 4H), 7.52 (d, J = 8.6 Hz, 2H), 6.96 (d, J = 9.0 Hz, 2H), 1.65 (s, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | Stage #1: for 2 h; Heating / reflux Stage #2: for 8 h; Heating / reflux |
A mixture of 4-chloro-4'-hydroxybezophenone (116 g, 0.500 mole) and sodium hydroxide (120 g, 3.00 mole) in acetone (1 L) was heated to reflux for 2 hours. The heating was stopped and the heating source was removed. A mixture of chloroform (179 g, 1.50 mole) in acetone (300 mL) was added drop-wise. The reaction mixture was stirred overnight without heating. The mixture was heated to reflux for 8 hours and then allowed to cool to room temperature. The precipitate was removed by filtration and washed with acetone (100 mL). The filtrate was concentrated under reduced pressure to give a brown oil. Water (200 mL) was added to the brown oil and was acidified (to pH=l) with IN hydrochloric acid. The precipitate, which formed was filtered and dried under high vacuum. The remaining yellow solid (268 g) was recrystallized from toluene in 4 batches (400 mL toluene each). After filtration and drying under high vacuum, the experiment produced fenofibric acid (116 g, 73percent yield) as a light yellow solid. 'H NMR (300 MHz, DMSO-d6): 6 = 13.22 (1H, s, br), 7.72 (4H, d, J= 8.4 Hz), 7.61 (2H, d, J= 7. 8 Hz), 6.93 (2H, d, J= 7. 8 Hz), 1.60 (6H, s). "C NMR (75 MHz, DMSO-d6) : 5 = 192.96, 174.18, 159.35, 136.84, 136.12, 131.67, 131.02, 129.12, 128. 43, 116. 91,78. 87,25. 13. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.95 g | With water; sodium hydroxide In ethanol at 25℃; | 2) Diluted with 32mL ethanol in the concentrated residue.Temperature control to 25°CTo dissolve the system,Then add 1mol/L sodium hydroxide aqueous solution 10mL, keep warm until reaction is complete,Vacuum filtration,The filtrate was slowly adjusted to pH 4 with 6M hydrochloric acid.Stirring and crystallization,Vacuum filtration,The filter cake was washed with 30 mL water.Vacuum dryingThat is, crude 2-[4-(4-chlorobenzoyl)phenoxy]-2-methylpropionic acid;3) Add the above 2.0g crude product to a 50mL single-mouth bottle, add 30mL acetone, stir and heat to reflux to dissolve,Incubate for 0.5 hour, stop heating, naturally cool to room temperature, crystallize for 8 hours, filter under reduced pressure, filter cake rinse with a little acetone, 55°C vacuum drying, an off-white solid.Add the above white solid 1.2g to a 50mL single-mouth bottle, add 18mL of ethyl acetate, stir and heat backFlow to dissolve, keep warm for 0.5 hour, stop heating, heat filter, naturally cool the filtrate to room temperature, crystallize for 8 hours, filter under reduced pressure, filterThe cake was rinsed with a small amount of ethyl acetate and dried under vacuum at 55° C. to give 0.95 g of an off-white solid, ie 2-[4-(4-chlorobenzoyl)phenoxyBase]-2-methylpropionic acid refined product, purity 99.92percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15% | Stage #1: With lithium hydroxide monohydrate; water In tetrahydrofuranReflux Stage #2: With hydrogenchloride In tetrahydrofuran; water |
Example 12 - Formula 139 - Compounds 12a 12bIntermediate B: 2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropanoic acid To a stirred solution of compound A (1 .0 g, 2.77 mmol) in THF (10 mL) was added LiOH-H&20 (0.7 g, 16.6 mmol) and H20 (10 mL). The resulting mixture was heated at reflux overnight then quenched with a 1 M aqueous HCI solution and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine, dried over MgS04 and concentrated under reduced pressure. The residue was purified by flash chromatography (CH2Cl2/MeOH, 15/1 , v/v) to give 2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropanoic acid (130 mg, 15percent) as a white solid.LC-MS (Agilent): Rt 3.00 min; m/z calculated for Ci7H15CI04 [M+H]+ 319.07, found 319.1 . |
15% | With lithium hydroxide monohydrate; water In tetrahydrofuranReflux | To a stirred solution of compound A (1.0 g, 2.77 mmol) in THF (10 mL) was added LiOH.H2O (0.7 g, 16.6 mmol) and H2O (10 mL). The resulting mixture was heated at reflux overnight then quenched with a 1 M aqueous HCl solution and extracted with EtOAc (10 mL*3). The combined organic layers were washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (CH2Cl2/MeOH, 15/1, v/v) to give 2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropanoic acid (130 mg, 15percent) as a white solid. LC-MS (Agilent): Rt 3.00 min; m/z calculated for C17H15ClO4 [M+H]+ 319.07. found 319.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | Stage #1: With triethylamine In ethanol Stage #2: Reflux |
Charge 10 gm fenofibric acid and 90 ml absolute ethanol and 4.5 ml triethylamine in to 250 ml RBF. Stir it for 10-15 minutes to get clear solution. Charge in to 250 ml RBF and charge 4.4 gm choline chloride. Heat it up to reflux temperature to get clear solution. Filter it through hyflo bed and wash it with absolute ethanol (10 ml). Cool it up to ambient temperature. Stir it for 12-15 hours at ambient temperature. Cool it at 0-5° C and stir for 2 hours at 0-5° C. Filter it and suck dry it. Charge wet cake in to 250 ml RBF and 50 ml absolute ethanol. Stir it for one hour at ambient temperature. Filter it and wash it with 10 ml absolute ethanol. Dry it at 50-60° C. Dry wt. - 8.0 gm (yield: -75percent). |
75% | Stage #1: With triethylamine In ethanol for 10 - 15 h; Stage #2: Reflux |
Example-1 Preparation of Choline Salt of Fenofibric Acid Charge 10 gm fenofibric acid and 90 ml absolute ethanol and 4.5 ml triethylamine in to 250 ml RBF. Stir it for 10-15 minutes to get clear solution. Charge in to 250 ml RBF and charge 4.4 gm choline chloride. Heat it up to reflux temperature to get clear solution. Filter it through hyflo bed and wash it with absolute ethanol (10 ml). Cool it up to ambient temperature. Stir it for 12-15 hours at ambient temperature. Cool it at 0-5° C. and stir for 2 hours at 0-5° C. Filter it and suck dry it. Charge wet cake in to 250 ml RBF and 50 ml absolute ethanol. Stir it for one hour at ambient temperature. Filter it and wash it with 10 ml absolute ethanol. Dry it at 50-60° C. Dry wt.-8.0 gm (yield: ~75percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With magneticnanosolidsuperacid; In cyclohexane; water; at 83 - 85℃; | In the ring with a water separator, reflux condenser, thermometer, 250 mL reaction flask fenofibrate (I) (20.0 g, 0.063 mol),isopropanol (28.0 g, 0.467 mol),with aqua cyclonexane 10 mL of hexane and magnetic nano solid superacid SO 4 / Fe 3 O 4 -Al 2 O3 -ZrO 2 -Nd 2 O 3 0.36 g, warmed to 83-85 C reflux, TLC monitoring of the reaction . After completion of the reaction, thecatalyst was separated magnetically, recovery of the catalyst. The reaction solution was cooled to 0-10 C, stirred crystallization, filtration, the filter cake rinsed with isopropanol and dried to give a white solid 22.1 g, yield 97.0%. Products byNMR, MS, IR and their structures were confirmed for our target product. |
96.6% | EXAMPLE; In a dual-jacket reactor of 250 mL (reactor A), 60 g of <strong>[42017-89-0]fenofibric acid</strong> (1 eq.; 0.188 moles) are introduced and 120 mL of isopropanol (2 volumes). The reaction mixture is heated with reflux. The reaction mixture is heterogeneous. To this suspension, are added 29.11 g of thionyl chloride (1.3 eq.; 0.245 moles) over 3 hours. The reaction mixture is homogenized while adding thionyl chloride in order to obtain a yellow solution. At the end of the addition, the reaction medium is maintained under reflux for about 4 hours (the reaction kinetics are followed by HPLC).In a reactor B, 28.58 g of K2CO3 (1.1 eq.; 0.21 mole) are introduced and 120 mL of water (2 volumes). The mixture is heated to 60-65 C.The contents of reactor A are hot-poured into the reactor B within about 1 hour. The reactor A is rinsed with 15 mL of isopropanol which are transferred to reactor B. The mixture is stirred for a minimum of 5 minutes. Stirring is stopped and the mixture is left to decant. The lower aqueous phase is removed. 134 mL of water are added to the alcoholic phase, while maintaining the temperature of the reaction mass at 60-65 C. The reaction mass is cooled to 50 C. and initiated with a few mg of fenofibrate. The mixture is maintained for about 30 minutes at 50 C. The medium crystallizes. The temperature is lowered to 0-5 C. within 2 hours and then maintained for a minimum of 30 minutes at this temperature (0-5 C.). The mixture is filtered. The cake is washed three times with 70 mL of water. It is dried for one night at 60 C. in a ventilated oven. 65.61 g of dry product are thereby obtained (yield=96.6%).Analytical results:HPLC (area %)Fenofibrate=99.98%<strong>[42017-89-0]Fenofibric acid</strong>=0.02%. | |
92.4% | With macroporous strong acid cation exchange resin D001; In water; toluene; at 110℃; | The <strong>[42017-89-0]Fenofibric acid</strong> is obtained by condensation, acidification and purification of 4-hydroxy-4-chlorobenzophenone with acetone and chloroform under the conditions of sodium hydroxide as a catalyst. <strong>[42017-89-0]Fenofibric acid</strong> (63.75 g, 0.2 mol) was added to a 500 ml flask. Isopropyl alcohol 69ml and water with toluene 100ml, After stirring and heating, after the reaction liquid reaches the specified temperature, the initial acid value of the reaction liquid is sampled and measured. At the same time, 10 g of the catalyst was added to the four-necked flask, and the timing was started, and the acid value was measured at regular intervals. In a boiling state, the water formed by the reaction is azeotropically distilled off with toluene.The aqueous phase was separated in a water separator and toluene was refluxed.As the reaction progresses, the temperature of the reaction solution gradually increases, and the temperature of the reaction solution is controlled to be within 110 C. After the reaction for a certain period of time, the reaction is stopped. The reaction solution was cooled, filtered, and neutralized with a mass concentration of 3% to 4% sodium hydroxide solution to pH = 7 to 8, and allowed to stand for stratification. The upper layer is dried with an appropriate amount of anhydrous sodium sulfate until clarification, and the clear liquid is taken. The toluene with water is distilled off under normal pressure and then under reduced pressure, and the distilled toluene is recycled. The material was cooled to 50 C, dissolved in isopropanol, cooled, filtered, and dried to obtain a yellowish crystalline powder, which was purified with isopropyl alcohol.A white solid of 66.69 g was obtained, and the esterification yield was 92.4% (based on fenofibrate acid), and the content was 99.9%. |
87.70% | With sulfuric acid; In toluene; at 110℃;Green chemistry; | A four-necked flask, each of which has an electric stirring bar, a thermometer, a third port with a reflux condenser and a water separator, and a fourth port for feeding; To the four-necked flask was added 60 g of toluene, 18 g of isopropyl alcohol and 6 g of concentrated sulfuric acid. Then, 60 g of <strong>[42017-89-0]fenofibric acid</strong> was added with stirring, and the mixture was stirred at 400r to 500r / min using an electric stir bar, 110 C heated to reflux, so that the reaction of water from the water separator, toluene, a small amount of water and isopropyl alcohol through the reflux condenser flow back to the four-necked flask, when the reaction to the water and then enter the water separator to stop heating Stirring, the esterification reaction after leaving the liquid with 60 ~ 70 hot water washing, so that impurities and liquid layer, to retain the upper layer of material and toluene mixture, remove the lower water and impurities, and then to the liquid And the unreacted fenofibrate acid was neutralized by stirring, the alkali aqueous layer and the feed liquid were separated, and the alkali layer was neutralized with hydrochloric acid to pH = 3 to 4, Norbert acid, dried as raw material recovery; separation of alkaline water after the liquid with 60 ~ 70 hot water washing, so that impurities and liquid layer, the upper material and toluene mixed organic phase, the lower layer of NaOH The organic phase was separated and the organic phase was separated. The separated organic phase was placed in a three-necked flask equipped with a stir bar, a thermometer and a ball-type condensing tube, respectively, and subjected to atmospheric distillation to remove water and partially toluene , When the temperature rose to 115 after the relative vacuum to maintain the -0.08 ~ -0.1MPa, under vacuum distillation in addition to toluene; cooling to 60 , adding 150g isopropyl alcohol, 1g of medicinal activated carbon, heated to reflux 30min after the heat Filtration, cooling to 15 C, to obtain white-like fenofibrate, the product yield of 87.70%, prepared fenofibrate melting point of 79.4 ~ 80.3 . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | A mixture of 4-chloro-4'-hydroxybezophenone (116 g, 0.500 mole) and sodium hydroxide (120 g, 3.00 mole) in acetone (1 L) was heated to reflux for 2 hours. The heating was stopped and the heating source was removed. A mixture of chloroform (179 g, 1.50 mole) in acetone (300 mL) was added drop-wise. The reaction mixture was stirred overnight without heating. The mixture was heated to reflux for 8 hours and then allowed to cool to room temperature. The precipitate was removed by filtration and washed with acetone (100 mL). The filtrate was concentrated under reduced pressure to give a brown oil. Water (200 mL) was added to the brown oil and was acidified (to pH=l) with IN hydrochloric acid. The precipitate, which formed was filtered and dried under high vacuum. The remaining yellow solid (268 g) was recrystallized from toluene in 4 batches (400 mL toluene each). After filtration and drying under high vacuum, the experiment produced fenofibric acid (116 g, 73% yield) as a light yellow solid. 'H NMR (300 MHz, DMSO-d6): 6 = 13.22 (1H, s, br), 7.72 (4H, d, J= 8.4 Hz), 7.61 (2H, d, J= 7. 8 Hz), 6.93 (2H, d, J= 7. 8 Hz), 1.60 (6H, s). "C NMR (75 MHz, DMSO-d6) : 5 = 192.96, 174.18, 159.35, 136.84, 136.12, 131.67, 131.02, 129.12, 128. 43, 116. 91,78. 87,25. 13. | |
With sodium hydroxide; | The Fenofibric acid is obtained by condensation, acidification and purification of 4-hydroxy-4-chlorobenzophenone with acetone and chloroform under the conditions of sodium hydroxide as a catalyst. Fenofibric acid (63.75 g, 0.2 mol) was added to a 500 ml flask. Isopropyl alcohol 69ml and water with toluene 100ml, After stirring and heating, after the reaction liquid reaches the specified temperature, the initial acid value of the reaction liquid is sampled and measured. At the same time, 10 g of the catalyst was added to the four-necked flask, and the timing was started, and the acid value was measured at regular intervals. In a boiling state, the water formed by the reaction is azeotropically distilled off with toluene.The aqueous phase was separated in a water separator and toluene was refluxed.As the reaction progresses, the temperature of the reaction solution gradually increases, and the temperature of the reaction solution is controlled to be within 110 C. After the reaction for a certain period of time, the reaction is stopped. The reaction solution was cooled, filtered, and neutralized with a mass concentration of 3% to 4% sodium hydroxide solution to pH = 7 to 8, and allowed to stand for stratification. The upper layer is dried with an appropriate amount of anhydrous sodium sulfate until clarification, and the clear liquid is taken. The toluene with water is distilled off under normal pressure and then under reduced pressure, and the distilled toluene is recycled. The material was cooled to 50 C, dissolved in isopropanol, cooled, filtered, and dried to obtain a yellowish crystalline powder, which was purified with isopropyl alcohol.A white solid of 66.69 g was obtained, and the esterification yield was 92.4% (based on fenofibrate acid), and the content was 99.9%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.4% | With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 0 - 20℃; for 3h; | 31.8 g of 2-methyl-2-(4-(4-chlorobenzoyl)phenoxy)propionic acid was dissolved in 200 mL of dichloromethane, 1 mL of N,N-dimethylformamide was added and stirred, and 19.0 g of oxalyl chloride was added dropwise thereto at 0 C. The reaction was carried out at room temperature for 3 hours. The methylene chloride was removed to give 30.8 g of 2-methyl-2-(4-(4-chlorobenzoyl)phenoxy)propionyl chloride in a yield of 91.4%. |
83.2% | With thionyl chloride; In Petroleum ether; benzene; | (a) 2-[4-(4-Chlorobenzoyl)-phenoxy]-2-methylpropionyl chloride 18.6 ml (0.25 mol) of thionyl chloride are added to a solution of 31.85 g (0.10 mol) of <strong>[42017-89-0]2-[4-(4-chlorobenzoyl)-phenoxy]-2-methylpropionic acid</strong> in 100 ml of anhydrous benzene and the mixture is then heated under reflux for 1 hour 30 minutes. After cooling, the solvent and the excess chlorinating agent are driven off under reduced pressure. The residual chestnut-coloured crystalline mass is taken up in petroleum ether. After filtering, washing and drying, 28 g of the expected acid chloride are obtained, in the form of a beige powder. Instanteous melting point (Kofler) = 80-81 C. Yield = 83.2%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 96h; | L-hydroxyproline-<strong>[42017-89-0]fenofibric acid</strong> ester To a mixture of <strong>[42017-89-0]fenofibric acid</strong> (24. 9 g, 78.1 mmol), N-carbobenzyloxy-L- hydroxyproline t-butyl ester (Boc-Hyp-OtBu, 20. 4 g, 71.0 mmole, prepared in accordance with the procedure in the literature), EDC (16.3 g, 85.2 mmol), and DMAP (1.04 g, 8.52 mmol) cooled in an ice-water bath was added anhydrous dichloromethane (200 mL) dropwise. After the addition was complete, the ice bath was removed and the reaction mixture was stirred under an argon atmosphere at room temperature for 20 hours. After 20 hours, additional EDC (1.63 g, 8.52 mmol) was added and the experiment was allowed to stir over the weekend at room temperature under an argon atmosphere. After 4 days the solution was washed with water (200 mL) and brine (200 mL). After drying over sodium sulfate and filtration, the solution was concentrated under reduced pressure. The remaining yellow oil (49.4 g) was purified by column chromatography on silica gel (500 g, 0.035-0. 070 mm, 6 nm pore diameter), eluting with heptane/ethyl acetate (2: 1). After concentration of the product containing fractions under reduced pressure and drying under high vacuum until the weight was constant, the experiment produced the protected L-hydroxyproline-<strong>[42017-89-0]fenofibric acid</strong> ester SPIB0020301 (26.4 g, 63% yield) as a colorless oil. 'H NMR (300 MHz, CDC13): 8 = 7.76 (2H, d, J= 8. 1 Hz), 7.73 (2H, d, J= 8.1 Hz), 7.46 (2H, d, J= 8. 1 Hz), 6. 84 (2H, d, J= 8. 1 Hz), 5.32 (1H, m), 4.13 (0. 38H, t, J= 7. 8 Hz), 4.00 (0.62H, t, J= 7. 8 Hz), 3.67 (1.62H, m), 3.46 (0. 38H, d, J=12. 6 Hz), 2.29 (1H, m), 2.15 (1H, m), 1.68 (3H, s), 1.66 (3H, s), 1.44-1. 38 (18H, m). '3C NMR (75 MHz, CDC13) : 8 193. 88, 172. 98, 171.14, 159.25, 153.48, 138. 23, 136.16, 131.99, 131.08, 130.36, 128. 44,117. 03,116. 91,81. 48,80. 32,80. 20,79. 19, 74.03, 73.26, 58. 23,51. 88,51. 58,36. 33,35. 31,31. 92,28. 29, 28. 00,25. 89,24. 95 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 20h; | To a mixture of <strong>[42017-89-0]fenofibric acid</strong> (11.6 g, 36.3 mmol), N-carbobenzyloxy-L-serine t-butyl ester (Boc-Ser-OtBu, 8.62 g, 33.0 mmol), EDC (7. 59 g, 39.6 mmol), and DMAP (484 mg, 3.96 mmol) cooled in an ice-water bath was added anhydrous dichloromethane (150 mL) dropwise. After the addition was complete, the ice bath was removed and the reaction mixture was stirred under an argon atmosphere at room temperature for 20 hours. After 20 hours, the additional dichloromethane (200 mL) was added and the solution was washed with water (2x200 mL) and brine (200 mL). After drying over sodium sulfate and filtration, the solution was concentrated under reduced pressure. The remaining yellow oil (21.2 g) was purified by column chromatography on silica gel (400 g, 0.035-0. 070 mm, 6 nm pore diameter), eluting with heptane/ethyl acetate (3: 1). After concentration of the product-containing fractions under reduced pressure and drying under high vacuum until the weight was constant, the experiment produced the protected L-serine-<strong>[42017-89-0]fenofibric acid</strong> ester SPIB0020101 (16.2 g, 87% yield) as a light yellow oil. 'H NMR (300 MHz, CDC13) : 8 = 7.75 (2H, d, J= 9. 0 Hz), 7.72 (2H, d, J= 9. 0 Hz), 7.45 (2H, d, J= 8. 7 Hz), 6.86 (2H, d, J= 8. 7 Hz), 5.04 (1H, d, J= 6. 9 Hz), 4.55-4. 42 (3H, m), 1.66 (3H, s), 1.65 (3H, s), 1.43 (9H, s), 1.39 (9H, s). 3C NMR (75 MHz, CDC13) : 8 = 193. 92,172. 99,168. 07,159. 24,154. 87, 138. 24, 136.19, 131.94, 131.06, 130.40, 128.41, 117.26, 82.88, 80.13, 79.24, 65.44, 53.44, 28.27, 27.92, 25.70, 25.30. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 96h; | To a mixture of <strong>[42017-89-0]fenofibric acid</strong> (25.5 g, 79.9 mmol), N-carbobenzyloxy-L-threonine t- butyl ester (Boc-Thr-OtBu, 20.0 g, 72.6 mmol, prepared by the literature method), EDC (16.7 g, 87.1 mmol), and DMAP (1.06 g, 8.71 mmol) cooled in an ice-water bath was added anhydrous dichloromethane (200 mL), dropwise. After the addition was complete, the ice bath was removed and the reaction mixture was stirred under an argon atmosphere at room temperature for 20 hours. After 20 hours, additional EDC (1.39 g, 7.26 mmol) was added and the experiment was allowed to stir over the weekend at room temperature under an argon atmosphere. After 4 days, additional dichloromethane (300 mL) was added and the solution was washed with water (300 mL) and brine (300 mL). After drying over sodium sulfate and filtration, the solution was concentrated under reduced pressure. The remaining yellow oil (53.5 g) was purified by column chromatography on silica gel (500 g, 0.035-0. 070 mm, 6 nm pore diameter), eluting with heptane/ethyl acetate (3: 1). After concentration of the product-containing fractions under reduced pressure and drying under high vacuum until the weight was constant, the experiment produced the protected L-threonine-<strong>[42017-89-0]fenofibric acid</strong> ester SPIB0020201 (34.1 g, 82% yield) as a white foam. IH NMR (300 MHz, CDC13) : 8 = 7.74 (2H, d, J= 8. 4 Hz), 7.72 (2H, d, J= 8. 4 Hz), 7.45 (2H, d, J= 8. 4 Hz), 6.87 (2H, d, J= 8. 4 Hz), 5.47 (1H, m), 4.98 (1H, d, J= 9.9 Hz), 4,31 (1H, d, J= 9.9 Hz), 1.65 (3H, s), 1.64 (3H, s), 1.45 (9H, s), 1.42 (9H, s), 1.22 (3H, d, J= 6.3 Hz). "C NMR (75 MHz, CDC13) : 8 = 193. 94,172. 14,168. 70,159. 26,155. 62,138. 28, 136.18, 131.90, 131.08, 130.37, 128.43, 117.40, 82. 70,80. 17,79. 38,72. 02,57. 46, 28. 30, 27.99, 26.44, 24.79, 16.90. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; dicyclohexyl-carbodiimide; | <strong>[42017-89-0]Fenofibric acid</strong> is esterified with 3-bromopropanol (n=l) in the presence of dicyclohexylcarbodiimide (DCC) and 4-dimethylamino pyridine (DMAP). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; | Coupling of fenofbric acid (1) with EDC / HOBT in Dichloromethane followed by t-butylglycine gave t-butyl protected 118 in 79% yield after chromatography (ethyl acetate/hexane) 1H-NMR (CDCl3): delta 7.74 (d, 2H, J= 9 Hz), 7.72 (d, 2H, J= 9 Hz), 7.53 (d, 2H, J= 8 Hz), 7.10 (d, 2H, J= 8 Hz), 3.83 (s, 2H), 1.60 (s, 6H), 1.45 (s, 9H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dichloromethane; at 0 - 50℃;Purification / work up; | EXAMPLES; Example 1; Preparation of Fenofibric Acid Polymorph Form A and Form B, CrystallizationPreparation of <strong>[42017-89-0]fenofibric acid</strong> polymorphs from single solvent or binary solvent crystallization is achieved according to the conditions shown in Table 1 below. TABLE 1 Material Primary Amount Solvent Anti-solvent Form (mg) (mL) (mL) (XRPD/Raman) 13.0 DCM 0.5 - - A 9.5 DCM 0.5 water 7.0 A 12.5 DCM 0.5 heptane 0.5 A 15.7 DCM 0.5 c-hexane 0.5 A 11.6 benzene 3.2 - - B 9.1 benzene 3.0 water 5.0 B 9.2 benzene 3.0 heptane 4.0 A 11.1 benzene 3.0 c-hexane 5.0 A 14.9 toluene 7.0 - - B 15.2 toluene 9.0 water 11.0 B 15.5 toluene 9.0 heptane 13.0 A 13.0 toluene 9.0 c-hexane 13.0 B 15.1 xylenes 5.0 - - B 10.9 xylenes 7.0 water 13.0 B 11.3 xylenes 7.0 heptane 12.0 A 12.5 xylenes 7.0 c-hexane 12.0 A - Single solvent crystallizationsThe crystallizations are performed in vials using primary solvents which exhibited moderate to low solubility of the <strong>[42017-89-0]fenofibric acid</strong> Form A. About 9-15 milligrams (mg) of <strong>[42017-89-0]fenofibric acid</strong> Form A is dissolved in select solvents at 50 C. (Table 1). For the binary solvent crystallizations, anti-solvents including water, heptane or c-hexane are then slowly added until precipitation is observed or until the maximum volume capacity of the vial is reached. The resulting mixtures or solutions are then stirred for five minutes and then cooled rapidly to 0 C. in a refrigerator. If precipitation is observed, the solids are filtered and dried overnight under vacuum at ambient temperature. If no precipitation is observed, the solvent(s) are evaporated under a gentle flow of nitrogen and the residue dried overnight under vacuum.All solids are analyzed by XRPD and Raman spectroscopy under the following conditions:The XRPD patterns are obtained with a Shimadzu XRD-6000 according to the following conditions: Samples for x-ray powder diffraction (XRPD) are analyzed ?as is?. Samples are placed on Si zero-return ultra-micro sample holders and analyzed using the following conditions: X-ray tube: Cu Kalpha, 40 kV, 40 mA Slits Divergence Slit 1.00 deg Scatter Slit 1.00 deg Receiving Slit 0.30 mm Scanning Scan Range 3.0-45.0 deg Scan Mode Continuous Step Size 0.04 Scan Rate 2/min Raman spectra are obtained using a Kaiser RXN1 Raman Macroscope according to the following conditions: Raman source: 785 nm laser Spot Size: 1.2 mm Single Exposure time: 12 seconds Co-additions: 16 Enabled Exposure options: Cosmic Ray filtering, Dark subtraction, Intensity calibration Varying the cooling rate for the crystallization is explored for the crystallization process. Approximately 30 mg of <strong>[42017-89-0]fenofibric acid</strong> Form A is dissolved to form a clear solution in a minimal amount of primary solvent at 55 C. The clear solution is passed through a Millipore Millex-HV 0.45 muM syringe filter into a pre-heated vial. For the single solvent crystallizations, the vials are allowed to stir using a magnetic stir bar at 55 C. for 10 minutes and either placed in a refrigerator at 0 C. (rapid cooling, Table 2) or cooled at a rate of 20 C. per hour to room temperature (slow cooling, Table 3). Following cooling, the vials are allowed to stand for 16 hours. For the binary solvent crystallizations, an anti-solvent (water, heptane, or c-hexane) is slowly added to promote precipitation. The vials are then stirred and rapidly cooled using the procedures described for the single solvent crystallizations. If precipitation is observed, the solids are filtered and dried under vacuum (30 inches Hg) at ambient temperature. If no precipitation occurs, the solvent(s) are evaporated under a gentle flow of nitrogen and the residue dried overnight under vacuum (30 inches Hg) at room temperature. The resulting solids are analyzed by XRPD or Raman spectroscopy. TABLE 2 Material Primary Amount Solvent Anti-solvent Form (mg) (mL) (mL) (XRPD/Raman) 32.1 MeOH 3.3 - - A 30.1 Acetone 1.5 - - A 28.2 t-AmOH 3.3 - - A + peaks 34.1 MEK 5.2 - - A + peaks 32.6 DMA 1.5 - - A + peaks 34.2 toluene 14.25 - - A + B 31.6 DME 5.2 Water 7.5 A 30.3 IPA 5.2 Water 7.5 A 34.5 dioxane 7.1 Water 7.5 A 32.2 EtOAc 7.1 Water 7.5 B 27.3 DMA 5.2 Water 7.5 A 30.9 MeOH 3.3 Water 7.5 A 34.1 EtOH 3.3 Water 7.5 A 29.8 Acetone 1.5 Water 7.5 A + B 30 MeCN 1.5 Water 7.5 A 31.3 Dioxane 3.3 Heptane 7.5 B 33.8 Benzene 9 Heptane 12 A 33.3 toluene 18 Heptane 26 A 30.4 MeOH 7.1 Heptane 7.5 A 32.9 DMSO 1.5 Heptane 7.5 A 30.4 DMA 1.5 Heptane 7.5 A 28.6 DCM 1 c-hexane 1 A 30.8 toluene 18 c-hexane 26 A - Single solvent crystallizations TABLE 3 Material Amount Primary Solvent Form (mg) (mL) Anti-solvent (mL) (XRPD/Raman) 29.2 MeOH 3.3 - - A 31.8 Acetone 1.5 - - A 33.1 t-AmOH 3.3 - - B 28.9 MEK 5.2 - - B 29.1 DMA 1.5 - - A + B 27 toluene 14 - - A + peaks 33.3 DME 5.2 Water 7.5 A 27.7 IPA 5.2 Water 7.5 A 31.5 dioxane 7.1 Water 7.5 A + B 33.2 EtOAc 7.1 Water 7.5 A + peaks 29.9 DMA 5.2 Water 7.5 A 28.5 MeOH 3.3 Water 7.5 A 27.8 EtOH 3.3 Water 7.5 A + B 35 Acetone 1.5 Water 7.5 A + B 30.5 MeCN 1.5 Water 7.5 A + peaks 26.7 Dioxane 3.3 He... |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dicyclohexyl-carbodiimide;dmap; In dichloromethane; at 20℃; for 2h; | To a solution of 105 (980 mg, 3.1 mmol) andp- nitrophenol (535 mg, 3.83 mmol) in CH2Cl2 (80 mL) was added N,N- dicyclohexylcarbodiimide (833 mg, 4.04 mmol) and 4-dimethylaminopyridine (92 mg, 0.75 mmol), and the mixture was stirred at room temperature for 2 h. The reaction mixture was directly passed through a plug of silica gel eluting with 8:1 hexanes/EtOAc. The crude white solid 114 (1.50 g) was used directly in the next coupling step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 16h; | To a suspension of 105 (126 mg, 0.397 mmol) in CH2Cl2 (20 mL) was added EDCetaC1 (83 mg, 0.433 mmol), HOBT (59 mg, 0.433 mmol), (/^-fluoxetine (132, 125 mg, 0.361 mmol), and triethylamine (44 mg, 0.433 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with CH2Cl2 (20 mL), washed with water (20 mL) and br sine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the residue by flash column chromatography (silica gel, 7:3 hexanes/EtOAc) provided 11 (160 mg, 66%) as a white amorphous solid: 1H NMR (300 MHz, CDCl3) delta 7.72-7.65 (m, 4H), 7.44-7.38 (m, 4H), 7.34- 7.25 (m, 4H), 6.91-6.81 (m, 4H), 5.15-5.1 1 (m, IH), 3.54-3.48 (m, 2H), 3.08-2.91 (m, 3H), 2.34-2.09 (m. 2H), 1 .68-1.65 (m, 6H); 13C NMR (75 MHz, CDCl3) delta 170.3, 157.4, 138.4, 136.5, 134.3, 130.3, 129.2, 128.4, 127.09, 126.9, 126.6, 126.1 , 124.9, 124.8, 123.7, 123.5, 1 14.4, 1 13.7, 79.5, 76.4, 45.6, 34.0, 33.6, 23.8, 23.7; ESI m/z 632 [M+MeOH]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 4h; | To a suspension of 105 (78 mg, 0.24 mmol) in CH2Cl2 (5 mL) was added EDC-HCl (46 mg, 0.24 mmol), HOBT (36 mg, 0.27 mmol), 122 (52 mg, 0.16 mmol), and triethylamine (25 mg, 0.25 mmol). The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with CH2Cl2 (5 mL), washed with water (5 mL) and br sine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the residue by flash column chromatography (silica gel, 7: 1 hexanes/EtOAc) provided 9 (75 mg, 75%) as an amorphous solid: 1H NMR (300 MHz, CDCl3) delta 7.71-7.66 (m, 4H), 7.47-7.42 (m, 2H), 7.37-7.32 (m, 2H), 7.31-7.22 (m, 5H), 7.13 (s, 1 H), 6.89-6.79 (m, 4H), 5.31 (dd, J = 9.6, 1.8 Hz, 1 H), 2.27 (dd, J = 15.3, 9.8 Hz, IH), 2.15 (dd, J= 15.2, 2.0 Hz, IH), 1.60 (s, 3H), 1.52 (s, 3H), 1.51 (s, 3H), 1.48 (s, 3H); 13C NMR (75 MHz, CDCl3) delta 194.1 , 173.4, 159.4, 159.4, 158.6, 141.0, 136.1 , 131.8, 131.4, 131.2, 129.0, 128.6, 128.0, 126.9, 126.8, 126.8, 126.7, 126.0, 125.4, 123.5, 123.0, 1 19.3, 1 15.8, 82.1, 77.7, 53.3, 49.9, 27.9, 25.9, 25.8, 24.7; ESI m/z 646 [M+Na]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | To a solution of 104 (5.00 g, 12.2 mmol) in ethanol (150 mL) was added a solution of potassium hydroxide (2.74 g, 48.9 mmol) in ethanol (50 mL) and the reaction mixture was heated at reflux and stirred for 16 h. Ethanol was removed under vacuum and water (200 mL) was added. The aqueous solution was washed with diethyl ether (2 x 100 mL) and acidified to pH 1 with 2 N HCl. The acidic aqueous solution was then extracted with ethyl acetate (2 x 150 mL) and the combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to provide 105 (3.57 g, 91%) as an off-white solid: 1H NMR (300 MHz, CD3OD) delta 7.75-7.70 (m, 4H), 7.52 (d, J = 8.6 Hz, 2H), 6.96 (d, J = 9.0 Hz, 2H), 1.65 (s, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
~ 75% | Charge 10 gm <strong>[42017-89-0]fenofibric acid</strong> and 90 ml absolute ethanol and 4.5 ml triethylamine in to 250 ml RBF. Stir it for 10-15 minutes to get clear solution. Charge in to 250 ml RBF and charge 4.4 gm choline chloride. Heat it up to reflux temperature to get clear solution. Filter it through hyflo bed and wash it with absolute ethanol (10 ml). Cool it up to ambient temperature. Stir it for 12-15 hours at ambient temperature. Cool it at 0-5 C and stir for 2 hours at 0-5 C. Filter it and suck dry it. Charge wet cake in to 250 ml RBF and 50 ml absolute ethanol. Stir it for one hour at ambient temperature. Filter it and wash it with 10 ml absolute ethanol. Dry it at 50-60 C. Dry wt. - 8.0 gm (yield: -75%). | |
~ 75% | Example-1 Preparation of Choline Salt of Fenofibric Acid Charge 10 gm <strong>[42017-89-0]fenofibric acid</strong> and 90 ml absolute ethanol and 4.5 ml triethylamine in to 250 ml RBF. Stir it for 10-15 minutes to get clear solution. Charge in to 250 ml RBF and charge 4.4 gm choline chloride. Heat it up to reflux temperature to get clear solution. Filter it through hyflo bed and wash it with absolute ethanol (10 ml). Cool it up to ambient temperature. Stir it for 12-15 hours at ambient temperature. Cool it at 0-5 C. and stir for 2 hours at 0-5 C. Filter it and suck dry it. Charge wet cake in to 250 ml RBF and 50 ml absolute ethanol. Stir it for one hour at ambient temperature. Filter it and wash it with 10 ml absolute ethanol. Dry it at 50-60 C. Dry wt.-8.0 gm (yield: ~75%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | Example 4 Preparation of (4Z,7Z,10Z,13Z,16Z,19Z)-N-(2-(2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropanamido)ethyl)docosa-4,7,10,13,16,19-hexaenamide In a typical run, <strong>[42017-89-0]2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropanoic acid</strong>, (<strong>[42017-89-0]fenofibric acid</strong>, 5.2 g, 16.3 mmol) was taken up in CH2Cl2 (80 mL) along with oxalyl chloride (1.4 mL, 16.3 mmol). After 20 muL of DMF was added, the resulting reaction mixture was stirred at room temperature for 3 h, until all gas evolution had ceased, and then concentrated under reduced pressure. The resulting acid chloride was taken up in 100 mL of CH2Cl2 and cooled to 0 C. A solution containing tert-butyl 2-aminoethylcarbamate (2.60 g, 16.3 mmol) and triethylamine (3.4 mL) in 15 mL of CH2Cl2 was added dropwise at 0 C. over a period of 20 min. The resulting reaction mixture was warmed to room temperature and stirred for 18 h. It was then quenched with brine and the two layers were separated. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (95% CH2Cl2, 5% MeOH) afforded tert-butyl 2-(2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropanamido)ethylcarbamate (3.00 g, 40%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 18h; | tert-Butyl 2-(2-aminoethoxy)ethylcarbamate (300 mg, 1.47 mmol) was taken up in CH2Cl2 (15 mL) along with <strong>[42017-89-0]2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropanoic acid</strong> (<strong>[42017-89-0]fenofibric acid</strong>, 467 mg, 1.47 mmol) and EDCI (310 mg, 1.47 mmol). The resulting reaction mixture was stirred at room temperature for 18 h. It was then brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (9:1 CH2Cl2/MeOH) to afford tert-butyl 2-(2-(2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropanamido)ethoxy)ethylcarbamate (260 mg, 35%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In acetonitrile; at 20℃; for 18h; | tert-Butyl 2-((2-aminoethyl)(methyl)amino)ethylcarbamate (270 mg, 1.24 mmol) was taken up in CH3CN (10 mL) along with <strong>[42017-89-0]2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropanoic acid</strong> (396 mg, 1.24 mmol) and EDCI (260 mg, 1.36 mmol). The resulting reaction mixture was stirred at room temperature for 18 h and then diluted with EtOAc (30 mL). The organic layer was washed with saturated aqueous NaHCO3, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (5% MeOH-CH2Cl2) to afford tert-butyl 2-((2-(2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropanamido)ethyl)(methyl)amino)ethylcarbamate (260 mg, 40%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 18h; | tert-Butyl 2-(2-(2-aminoethyl)disulfanyl)ethylcarbamate (350 mg, 1.39 mmol) was taken up in CH2Cl2 (15 mL) along with <strong>[42017-89-0]2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropanoic acid</strong> (442 mg, 1.39 mmol) and EDCI (290 mg, 1.53 mmol). The resulting reaction mixture was stirred at room temperature for 18 h and diluted with EtOAc (50 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue is purified by silica gel chromatography (CH2Cl2) to afford tert-butyl 2-(2-(2-(2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropanamido)ethyl)disulfanyl)ethylcarbamate (264 mg, 34%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With potassium carbonate; In N,N-dimethyl acetamide; at 65℃; | A solution of 4-chloromethyl-5-1,3-dioxolen-2-one(2.94 g, 20 mmol) was added to <strong>[42017-89-0]fenofibric acid</strong>(3.18 g, 10 mmol) and K2CO3 (2.76 g, 20 mmol) inN,N-dimethylacetamide (64 mL) at room temperatureat such a rate that the reaction maintained an internaltemperature of 60-65 C overnight. The reaction mixturewas cooled to 0 C and water (100 mL) was added slowly.The resulting mixture was stirred at room temperature for1.5 h, extracted with ethyl acetate (100 mL), and washedwith brine (150 mL × 3). The solvent was distilled offunder reduced pressure to obtain a residue. The residue waspurified further by column chromatography to give the titlecompounds. The following compounds were synthesizedaccording to this procedure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.9% | Example I 2-[4-(4-Chlorobenzoyl)phenoxy]-2-methylpropanoic acid, 1-methylethyl ester 1 kg (3.14 mol) of <strong>[42017-89-0]fenofibric acid</strong> (II), 500 ml of dimethyl sulfoxide and 1 l of isopropyl acetate were charged into a jacketed 5 l reactor under nitrogen. 433.5 g (3.14 mol) of potassium carbonate were then added, with stirring at ambient temperature, and the reaction mixture was brought to 85-90 C. for 45 min. The temperature of the reaction mixture was subsequently reduced to approximately 80 C. and 354 ml (3.77 mol) of 2-bromopropane and then 100 ml of isopropyl acetate were added over a period of 50 min. The mixture was kept stirring at 85-95 C. for 5 hours and then slightly cooled to approximately 80 C. In-process monitoring showed that the degree of conversion to give fenofibrate was approximately 99.5%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | Intermediate C: 2-(4-((4-Chlorophenyl)(hydroxy)methyl)phenoxy)-2-methylpropan-1 -olTo a stirred solution of intermediate B (500 mg, 1 .57 mmol) in dry THF (10 mL) at 0 C under nitrogen was added a solution of borane in THF (1 M, 4.7 mL, 4.7 mmol) dropwise. The resulting mixture was heated at 50 C for 3 h then cooled to 0 C, quenched with MeOH and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine, dried over MgS04 and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (Pet. ether/EtOAc, 5/1 to 2/1 , v/v) to give 2-(4-((4- chlorophenyl)(hydroxy)methyl)phenoxy)-2-methylpropan-1 -ol (452 mg, 94%) as a white solid.LC-MS (Agilent): Rt 3.00 min; m/z calculated for Ci7H19CI03 [M+Na]+ 329.1 , found 329.0. | |
94% | With borane-THF; In tetrahydrofuran; at 0 - 50℃; for 3h;Inert atmosphere; | To a stirred solution of intermediate B (500 mg, 1.57 mmol) in dry THF (10 mL) at 0 C. under nitrogen was added a solution of borane in THF (1 M, 4.7 mL, 4.7 mmol) dropwise. The resulting mixture was heated at 50 C. for 3 h then cooled to 0 C., quenched with MeOH and extracted with EtOAc (10 mL*3). The combined organic layers were washed with brine, dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (Pet. ether/EtOAc, 5/1 to 2/1, v/v) to give 2-(4-((4-chlorophenyl)(hydroxy)methyl)phenoxy)-2-methylpropan-1-ol (452 mg, 94%) as a white solid. LC-MS (Agilent): Rt 3.00 min; m/z calculated for C17H19ClO3 [M+Na]+ 329.1. found 329.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | General procedure: To a cooled mixture (0-5C) of proper acids (1.0 mmol) in dry dichloromethane (15 mL), 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride (EDC, 1.0 mmol, 177.0 mL) and 4-dimethylaminopyridine (DMAP, 1.0 mmol, 122.2 mg) were added, under stirring in a nitrogen atmosphere. After 15 min, methanesulfonamide (1.1 mmol) was added, and the mixture was allowed to warm to room temperature. After stirring overnight, the reaction was diluted with dichloromethane (15 mL), washed with 2N HCl (3Chi30 mL), dried on Na2SO4. After evaporation of solvent under reduced pressure, crude products were purified on silica gel (eluent dichloromethane/methanol 9:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.32 g | With dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 4h; | 2 g of <strong>[42017-89-0]2-methyl-2-(4-(4-chlorobenzoyl)phenoxy)propanoic acid</strong>, 1.2 g of dicyclohexylcarbodiimide, 0.5 g of 2-amino-1-(4-hydroxyphenyl)ethyl ketone and 60 ml of dichloromethane were placed into the 100 ml single-neck flask, reacted for 4 hours at room temperature, evaporated to dryness, then purified through chromatography on silica gel column, to give the target compound (1.32 g). MS (ESI): 752(M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
820 mg | With dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 4h; | 1 g of <strong>[42017-89-0]2-methyl-2-(4-(4-chlorobenzoyl)phenoxy)propanoic acid</strong>, 0.57 g of dicyclohexylcarbodiimide, 0.5 g of 2-amino-1-(4-hydroxyphenyl)ethyl ketone and 60 ml of dichloromethane were placed into the 100 ml single-neck flask, reacted for 4 hours at room temperature, evaporated to dryness, then purified through chromatography on silica gel column, to give the target compound (820 mg). MS (ESI): 452 (M+H+). 1H-NMR: 7.8-7.85 (2H, d), 7.7-7.8 (4H, m), 7.6(1H, m), 7.42-7.53 (2H, d), 7.04-7.13 (2H, d), 6.9-7, 1 (2H, d), 6.84 (1H, s), 4.7 (2H, d), 1.65 (6H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
820 mg | With dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 4h; | Experiment 3 Preparation of Compound 03 [0080] 1 g of <strong>[42017-89-0]2-methyl-2-(4-(4-chlorobenzoyl)phenoxy)propanoic acid</strong>, 0.57 g of dicyclohexylcarbodiimide, 0.5 g of 2-amino-1-(4-hydroxyphenyl)ethyl ketone and 60 ml of dichloromethane were placed into the 100 ml single-neck flask, reacted for 4 hours at room temperature, evaporated to dryness, then purified through chromatography on silica gel column, to give the target compound (820 mg). MS (ESI): 452 (M+H+). 1H-NMR: 7.8-7.85 (2H, d), 7.7-7.8 (4H, m), 7.6 (1H, m), 7.42-7.53 (2H, d), 7.04-7.13 (2H, d), 6.9-7, 1 (214, d), 6.84 (1H, s), 4.7 (2H, d), 1.65 (6H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.32 g | With dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 4h; | Experiment 4 Preparation of Compound 04 [0081] 2 g of <strong>[42017-89-0]2-methyl-2-(4-(4-chlorobenzoyl)phenoxy)propanoic acid</strong>, 1.2 g of dicyclohexylcarbodiimide, 0.5 g of 2-amino-1-(4-hydroxyphenyl)ethyl ketone and 60 ml of dichloromethane were placed into the 100 ml single-neck flask, reacted for 4 hours at room temperature, evaporated to dryness, then purified through chromatography on silica gel column, to give the target compound (1.32 g). MS (ESI): 752 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | A. Synthesis of chloromethyl 2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropanoate 1 A mixture of <strong>[42017-89-0]2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropanoic acid</strong> (10.0 g, 31.4 mmol), sodium bicarbonate (13.2 g, 47.1 mmol, 1.5 eq) and tetrabutylammonium hydrogensulfate (2.1 g, 6.3 mmol, 0.2 eq) in water (150 mL) was stirred at room temperature for 15 min. Dichloromethane (150 mL) was added and the mixture was cooled in ice. Chloromethyl sulfochloridate (4.2 mL, 47.1 mmol, 1.5 eq) was added and the mixture was stirred overnight at room temperature. The layers were separated, the organic phase was washed with water (50 mL) and brine, then dried over sodium sulfate. The drying agent was filtered off and the solution was concentrated by rotary evaporation to leave a thick oil. Hexane (50 mL) and seeds were added and rotary evaporation was continued at room temperature to leave chloromethyl 2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropanoate 1 as a white solid (11.6 g, 101% yield). 1H-NMR (CDCl3) delta 7.73 (d, 2H), 7.70 (d, 2H), 7.44 (d, 2H), 6.87 (d, 2H), 5.77, (s, 2H), 1.70 (s, 6H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: CDI (10.0 mmol) was dissolved in N,N-dimethylformamide (DMF) (20 mL) and to this solution a solution of the carboxylic acids 14a and d (10.0 mmol) in DMF (2 mL) was added dropwise. Subsequently, the reaction mixture was stirred at room temperature for 1 h. Then, H2S was bubbled gently through the reaction mixture for 2 h. Sulfuric acid (0.5 M, 40 mL) was added and the mixture was extracted with ethyl acetate. The organic layer was dried with magnesium sulfate (MgSO4), filtered, and concentrated to yield 16a,d, 14a, d, 16a, and d (2.0 mmol). They were dissolved inTHF (10 mL), anhydrous K2CO3 (4.0 mmol) and 2-bromo-4-hydroxyacetophenone 11 (2.0 mmol) were added, and the mixture was stirred for 4 h at room temperature. Dilute HCl was added, and the mixture was extracted with ethyl acetate, washed with brine, dried over MgSO4, filtered, and concentrated, and the residue was purified by chromatography to afford target compounds 17a, d, 18a, and d. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 12h; | General procedure: To a solution of 2-bromo-4-hydroxyacetophenone 11 (20.0 mmol) in tetrahydrofuran (THF) (50 mL), hexamethylenetetramine (20.0 mmol) was added and stirred for 3 h at room temperature, and then the precipitated hexamethylenetetramine adduct 12 was filtered out. The adduct 12 was then heated with ethanol (80 mL) and concentrated HCl (8 mL) for 1 h at 45 C. After cooling, the inorganics were filtered out, the mixture was washed with ethanol (20 mL), and the solvent was distilled out completely under reduced pressure to obtain the desired compound 13. Then 14a-d (2.0 mmol), triethylamine (4.0 mmol), and EDCI·HCl (4.0 mmol), followed by HOBT (4.0 mmol), were added to a stirred solution of 13 (2.0 mmol) in CH2Cl2 (10 mL) and the mixture was stirred for 12 h at room temperature. Saturated Na2CO3 was added, the mixture was extracted with ethyl acetate, and the extracts were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by chromatography to give target compounds 15a-d. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 12h; | General procedure: To a solution of 2-bromo-4-hydroxyacetophenone 11 (20.0 mmol) in tetrahydrofuran (THF) (50 mL), hexamethylenetetramine (20.0 mmol) was added and stirred for 3 h at room temperature, and then the precipitated hexamethylenetetramine adduct 12 was filtered out. The adduct 12 was then heated with ethanol (80 mL) and concentrated HCl (8 mL) for 1 h at 45 C. After cooling, the inorganics were filtered out, the mixture was washed with ethanol (20 mL), and the solvent was distilled out completely under reduced pressure to obtain the desired compound 13. Then 14a-d (2.0 mmol), triethylamine (4.0 mmol), and EDCI·HCl (4.0 mmol), followed by HOBT (4.0 mmol), were added to a stirred solution of 13 (2.0 mmol) in CH2Cl2 (10 mL) and the mixture was stirred for 12 h at room temperature. Saturated Na2CO3 was added, the mixture was extracted with ethyl acetate, and the extracts were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by chromatography to give target compounds 15a-d. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 12h; | General procedure: To a solution of 2-bromo-4-hydroxyacetophenone 11 (20.0 mmol) in tetrahydrofuran (THF) (50 mL), hexamethylenetetramine (20.0 mmol) was added and stirred for 3 h at room temperature, and then the precipitated hexamethylenetetramine adduct 12 was filtered out. The adduct 12 was then heated with ethanol (80 mL) and concentrated HCl (8 mL) for 1 h at 45 C. After cooling, the inorganics were filtered out, the mixture was washed with ethanol (20 mL), and the solvent was distilled out completely under reduced pressure to obtain the desired compound 13. Then 14a-d (2.0 mmol), triethylamine (4.0 mmol), and EDCI·HCl (4.0 mmol), followed by HOBT (4.0 mmol), were added to a stirred solution of 13 (2.0 mmol) in CH2Cl2 (10 mL) and the mixture was stirred for 12 h at room temperature. Saturated Na2CO3 was added, the mixture was extracted with ethyl acetate, and the extracts were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by chromatography to give target compounds 15a-d. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 12h; | General procedure: To a solution of 2-bromo-4-hydroxyacetophenone 11 (20.0 mmol) in tetrahydrofuran (THF) (50 mL), hexamethylenetetramine (20.0 mmol) was added and stirred for 3 h at room temperature, and then the precipitated hexamethylenetetramine adduct 12 was filtered out. The adduct 12 was then heated with ethanol (80 mL) and concentrated HCl (8 mL) for 1 h at 45 C. After cooling, the inorganics were filtered out, the mixture was washed with ethanol (20 mL), and the solvent was distilled out completely under reduced pressure to obtain the desired compound 13. Then 14a-d (2.0 mmol), triethylamine (4.0 mmol), and EDCI·HCl (4.0 mmol), followed by HOBT (4.0 mmol), were added to a stirred solution of 13 (2.0 mmol) in CH2Cl2 (10 mL) and the mixture was stirred for 12 h at room temperature. Saturated Na2CO3 was added, the mixture was extracted with ethyl acetate, and the extracts were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by chromatography to give target compounds 15a-d. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 12h; | DMAP (2.0 mmol) and EDCI·HCl (40.0 mmol) were added to a solution of 1-(tert-butoxycarbonyl) piperazine 23 (20.0 mmol) and carboxylic acid 14d (20.0 mmol) in CH2Cl2 (125 mL). The reaction mixture was stirred at room temperature for 12 h and then washed with dilute HCl and water. The organic layer was dried over MgSO4, filtered, and the filtrate concentrated in vacuo to provide 24. Compound 24 (2.0 mmol) was dissolved in THF (10 mL), TFA (1 mL) was added, and the resulting mixture shaken at room temperature for 24 h. The reaction mixture was concentrated at reduced pressure and basified with NaOH solution (until pH 10), extracted with CH2Cl2, dried over MgSO4, filtered, and evaporated at reduced pressure, and then the residue was purified by chromatography to afford 25. K2CO3 (4.0 mmol) and 11 (2.0 mmol) were added to a solution of 25 (2.0 mmol) in THF (10 mL), and the reaction mixture was stirred at room temperature for 12 h, filtered, and evaporated at reduced pressure. The residue was then purified by chromatography to afford target compound 26. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 12h; | General procedure: To a solution of 2-bromo-4-hydroxyacetophenone 11 (20.0 mmol) in tetrahydrofuran (THF) (50 mL), hexamethylenetetramine(20.0 mmol) was added and stirred for 3 h at room temperature, and then the precipitated hexamethylenetetramine adduct 12 was filtered out. The adduct 12 was then heated with ethanol (80 mL) and concentrated HCl (8 mL) for 1 h at 45 C. After cooling, the inorganics were filtered out, the mixture was washed with ethanol (20 mL), and the solvent was distilled out completely under reduced pressure to obtain the desired compound 13. Then 14a-d (2.0 mmol), triethylamine (4.0 mmol), and EDCI·HCl (4.0 mmol), followed by HOBT (4.0 mmol), were added to a stirred solution of 13 (2.0 mmol) in CH2Cl2 (10 mL) and the mixture was stirred for 12 h at room temperature. Saturated Na2CO3 was added, the mixture was extracted with ethyl acetate, and the extracts were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by chromatography to give target compounds 15a-d. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In tetrahydrofuran; at 20℃; for 4h; | General procedure: CDI (10.0 mmol) was dissolved in N,N-dimethylformamide (DMF) (20 mL) and to this solution a solution of the carboxylic acids 14a and d (10.0 mmol) in DMF (2 mL) was added dropwise. Subsequently, the reaction mixture was stirred at room temperature for 1 h. Then, H2S was bubbled gently through the reaction mixture for 2 h. Sulfuric acid (0.5 M, 40 mL) was added and the mixture was extracted with ethyl acetate. The organic layer was dried with magnesium sulfate (MgSO4), filtered, and concentrated to yield 16a ,d, 14a, d, 16a, and d (2.0 mmol). They were dissolved in THF (10 mL), anhydrous K2CO3 (4.0 mmol) and 2-bromo-4-hydroxyacetophenone 11 (2.0 mmol) were added, and the mixture was stirred for 4 h at room temperature. Dilute HCl was added, and the mixture was extracted with ethyl acetate, washed with brine, dried over MgSO4, filtered, and concentrated, and the residue was purified by chromatography to afford target compounds 17a, d, 18a, and d. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | General procedure: To a cooled mixture (0-5C) of starting carboxylic acids (1.0mmol) in dry dichloromethane (15mL), 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride (EDC, 1.0mmol, 177muL) and 4-dimethylaminopyridine (DMAP, 1.0mmol, 122mg) were added, under stirring in a nitrogen atmosphere. After 15min, p-substituted benzenesulfonamides (1.1mmol) were added and the mixture was allowed to warm to room temperature. After stirring overnight, the reaction mixture was diluted with dichloromethane (15mL), washed with 2N HCl (3×30mL), dried on Na2SO4. After evaporation of solvent under reduced pressure, crude products were purified on silica gel (eluent dichloromethane/methanol 9:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With glucose-6-phosphate dehydrogenase; glucose-6-phosphate; recombinant carbonyl reducing enzyme CBR1; nicotinamide adenine dinucleotide phosphate; magnesium chloride; In methanol; aq. phosphate buffer; at 37℃; for 0.5h;pH 7.4;Enzymatic reaction; | The carbonyl reduction of <strong>[42017-89-0]fenofibric acid</strong> was assessed usingpooled human liver cytosolic and microsomal fractions (0.5 mg/mLfinal protein concentration) or using recombinant enzymes(0.2 mg/mL final protein concentration). The incubation mixtureconsisted of 20 mL of enzyme source, 20 mL of an NADPHregeneratingsystem (final concentrations: 0.8 mM NADP+, 6 mMglucose-6-phosphate, 0.35 units glucose-6-phosphate dehydrogenase,3mMMgCl2), 50 mL of 0.1Msodium phosphate buffer (pH 7.4)and 10 mL of <strong>[42017-89-0]fenofibric acid</strong>. The reaction was initiated by theaddition of <strong>[42017-89-0]fenofibric acid</strong> and performed for 30 min at 37 C.Controls without added enzyme source (i.e., without the liverfraction or the recombinant enzyme) were included in each incubation.The controls showed no or negligible formation of reduced<strong>[42017-89-0]fenofibric acid</strong>. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.13 g | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; | 3,4-dibenzyloxyphenethyl alcohol (1.00 g, 3.26 mmol), <strong>[42017-89-0]fenofibric acid</strong> (1.56 g, 4.89 mmol) and DMAP (0.08 g, 0.65 mmol) were added to DMF (20 mL) after 5 min, EDCI · HCl (0.94 g, 4.89 mmol) was added and the mixture was stirred at room temperature. The reaction was complete and the reaction was washed twice with 5% NaHCO3 solution and saturated brine, dried over anhydrous Na2SO4 and concentrated to give 2.13 g of a yellow oil which was directly added to the next reaction. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | To a mixed solution of methylene chloride / N, N-dimethylacetamide 20/1 (63 ml) at room temperature was added SOCl 2 (2.76 g, 0.02 mol) 2-methylpropanoic acid (3.18 g, 0.01 mol) was added to the mixture, and the mixture was stirred at room temperature for 2 hours. " (E) -4- (3,5-dimethoxystyryl) phenol (5.12 g, 0.02 mol) was added and the reaction was warmed to 60-65 & lt; The mixture was stirred overnight on the road. The reaction mixture was cooled to 0 & lt; 0 & gt; C and slowly added 100 ml of purified water. Get The crude mixture was stirred at room temperature for 0.5 h. Extract with 100 ml of ethyl acetate and wash 3 times with 150 ml of brine Followed by distillation under reduced pressure. Purification by column chromatography (30% ethyl acetate in hexanes) gave 65% yield as a white Obtained a color solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With potassium carbonate; In N,N-dimethyl acetamide; at 60 - 65℃; for 12h; | N, N-dimethylacetamide (64 mL) was added at room temperature, 2- (4- (4-chlorobenzoyl) phenoxy) -2-methylpropanoic acid (3.18 g, 0.01 mol) And K2CO3 (2.76 g, 0.02 mol) 2-bromomethyl acetate (3.12 g, 0.02 mol) was added thereto. [0064] The reaction product was stirred at a temperature of 60 to 65 for 12 hours or longer. The reaction mixture was cooled to 0 C and slowly added purified water (100 mL). The resulting mixture was stirred at room temperature for 0.5 hour. The mixture was extracted with 100 ml of ethyl acetate, washed three times with 150 ml of brine, and distilled under reduced pressure. Column chromatography (n-hexane: ethyl acetate 3: 1 mixed solvent as eluent), and then concentrated under reduced pressure to obtain a pale cream solid. Yield 75%. |
Tags: 42017-89-0 synthesis path| 42017-89-0 SDS| 42017-89-0 COA| 42017-89-0 purity| 42017-89-0 application| 42017-89-0 NMR| 42017-89-0 COA| 42017-89-0 structure
A473645[ 856676-23-8 ]
2-Hydroxy-N,N,N-trimethylethanaminium 2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropanoate
Reason: Free-salt
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H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
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