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CAS No. : | 1246213-45-5 |
Formula : | C26H30N2O5 |
M.W : | 450.53 |
SMILES Code : | O=C(OC1=CC(NC(C2=CNC3=C(C=CC=C3)C2=O)=O)=C(C(C)(C)C)C=C1C(C)(C)C)OC |
* 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 |
---|---|---|
With pyridine;2-propane phosphonic acid anhydride; In 2-methyltetrahydrofuran; at 47.5℃; for 8h;Product distribution / selectivity; | 4-Oxo-l,4-dihydroquinoline-3-carboxylic acid, 26, (1.0 eq) and 5-amino-2,4-di- tert-butylphenyl methyl carbonate, 32, (1.1 eq) were charged to a reactor. 2-MeTHF (4.0 vol, relative to the acid) was added followed by T3P.(R). 50percent solution in 2-MeTHF (1.7 eq). The T3P charged vessel was washed with 2-MeTHF (0.6 vol). Pyridine (2.0 eq) was then added, and the resulting suspension was heated to 47.5 +/- 5.0 0C and held at this temperature for 8 hours. A sample was taken and checked for completion by HPLC. Once complete, the resulting mixture was cooled to 25.0 0C +/- 2.5 0C. 2-MeTHF was added (12.5 vol) to dilute the mixture. The reaction mixture was washed with water (10.0 vol) 2 times. 2-MeTHF was added to bring the total volume of reaction to 40.0 vol (-16.5 vol charged). To this solution was added NaOMe/MeOH (1.7 equiv) to perform the methanolysis. The reaction was stirred for no less than 1.0 hour, and checked for completion by HPLC. Once complete, the reaction was quenched with 1 N HCl (10.0 vol), and washed with 0.1 N HCl (10.0 vol). The organic solution was polish filtered to remove any particulates and placed in a second reactor. The filtered solution was concentrated at no more than 350C (jacket temperature) and no less than 8.00C (internal reaction temperature) under reduced pressure to 20 vol. CH3CN was added to 40 vol and the solution concentrated at no more than 35 0C (jacket temperature) and no less than 8.00C (internal reaction temperature) to 20 vol. The addition of CH3CN and concentration cycle was repeated 2 more times for a total of 3 additions of CH3CN and 4 concentrations to 20 vol. After the final concentration to 20 vol, 16.0 vol of CH3CN was added followed by 4.0 vol of H2O to make a final concentration of 40 vol of 10percent H2O/CH3CN relative to the starting acid. This slurry was heated to 78.00C +/- 5.00C (reflux). The slurry was then stirred for no less than 5 hours. The slurry was cooled to 0.00C +/- 5 0C over 5 hours, and filtered. The cake was washed with 0.0 0C +/- 5.0 0C CH3CN (5 vol) 4 times. The resulting solid (compound 34) was dried in a vacuum oven at 50.0 0C +/- 5.0 0C. 1H NMR (400 MHz, DMSO-<;/6) delta 12.8 (s, IH), 11.8 (s, IH), 9.2 (s, IH), 8.9 (s, IH), 8.3 (s, IH), 7.2 (s, IH), 7.9 (t, IH), 7.8 (d, IH), 7.5 (t, IH), 7.1 (s, IH), 1.4 (s, 9H), 1.4 (s, 9H). | |
With pyridine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; In 2-methyltetrahydrofuran; at 47.5℃; for 8h;Product distribution / selectivity; | Preparation of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (1) 4-Oxo-1,4-dihydroquinoline-3-carboxylic acid, 26, (1.0 eq) and 5-amino-2,4-di-tert-butylphenyl methyl carbonate, 32, (1.1 eq) were charged to a reactor. 2-MeTHF (4.0 vol, relative to the acid) was added followed by T3P.(R). 50percent solution in 2-MeTHF (1.7 eq). The T3P charged vessel was washed with 2-MeTHF (0.6 vol). Pyridine (2.0 eq) was then added, and the resulting suspension was heated to 47.5+/-5.0° C. and held at this temperature for 8 hours. A sample was taken and checked for completion by HPLC. Once complete, the resulting mixture was cooled to 25.0° C.+/-2.5° C. 2-MeTHF was added (12.5 vol) to dilute the mixture. The reaction mixture was washed with water (10.0 vol) 2 times. 2-MeTHF was added to bring the total volume of reaction to 40.0 vol (16.5 vol charged). To this solution was added NaOMe/MeOH (1.7 equiv) to perform the methanolysis. The reaction was stirred for no less than 1.0 hour, and checked for completion by HPLC. Once complete, the reaction was quenched with 1 N HCl (10.0 vol), and washed with 0.1 N HCl (10.0 vol). The organic solution was polish filtered to remove any particulates and placed in a second reactor. The filtered solution was concentrated at no more than 35° C. (jacket temperature) and no less than 8.0° C. (internal reaction temperature) under reduced pressure to 20 vol. CH3CN was added to 40 vol and the solution concentrated at no more than 35° C. (jacket temperature) and no less than 8.0° C. (internal reaction temperature) to 20 vol. The addition of CH3CN and concentration cycle was repeated 2 more times for a total of 3 additions of CH3CN and 4 concentrations to 20 vol. After the final concentration to 20 vol, 16.0 vol of CH3CN was added followed by 4.0 vol of H2O to make a final concentration of 40 vol of 10percent H2O/CH3CN relative to the starting acid. This slurry was heated to 78.0° C.+/-5.0° C. (reflux). The slurry was then stirred for no less than 5 hours. The slurry was cooled to 0.0° C.+/-5° C. over 5 hours, and filtered. The cake was washed with 0.0° C.+/-5.0° C. CH3CN (5 vol) 4 times. The resulting solid (compound 1) was dried in a vacuum oven at 50.0° C.+/-5.0° C. 1H NMR (400 MHz, DMSO-d6) delta 12.8 (s, 1H), 11.8 (s, 1H), 9.2 (s, 1H), 8.9 (s, 1H), 8.3 (s, 1H), 7.2 (s, 1H), 7.9 (t, 1H), 7.8 (d, 1H), 7.5 (t, 1H), 7.1 (s, 1H), 1.4 (s, 9H), 1.4 (s, 9H). | |
With pyridine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; In 2-methyltetrahydrofuran; ethyl acetate; at 45 - 50℃; for 15h; | Compound A (1.0 eq.) and Compound B (1.1 eq.) were charged to a reactor. 2- MeTHF (4.0 vol., relative to Compound A) was added followed by T3P® 50percent solution in EtOAc (2.5 eq.). The T3P charge vessel was washed with 2-MeTHF (3.5 vol.). Pyridine (2.0 eq.) was then charged. The resulting suspension was heated to 45.0 to 50.0 °C and held at thistemperature for 15 hours. A sample was taken and checked for completion by HPLC. Once complete, the resulting mixture was cooled to 20.0 °C +/- 5.0 °C. 2-MeTHF was charged (12.5 vol.) to dilute the mixture. The reaction mixture was washed with water (10.0 vol.) 3 times. 2- MeTHF was charged to bring the total volume of reaction to 40.0 vol. (-16.5 vol. charged). Residual water was removed by continuous distillation at 35.0 °C +/- 5 °C from 40 vol. to 30 vol. with 2-MeTHF until in-process control testing using the Karl Fisher method shows the water content to be no more than 1.0percent w/w. The solution was cooled to 20.0 °C +/- 5.0 °C. To this solution was charged NaOMe/MeOH (1.7 equiv) to perform the hydrolysis of the carbonate. The reaction was stirred for no less than 1.0 hours, and checked for completion by HPLC. Once complete, the reaction was quenched with 1 N HC1 / H20 (10.0 vol.), and washed with 0.1 N HC1 (10.0 vol.). The organic solution was polish filtered to remove any particulates and placed in a second flask. The filtered solution was concentrated at 25.0 °C +/- 5.0 °C under reduced pressure to 20 vol. CCN was added to 40 vol. and the solution concentrated at 25.0 °C +/- 5.0 °C to 20 vol. The addition of CCN and concentration was repeated 2 more times for a total of 3 additions of CH3CN and 4 concentrations to 20 vol. After the final concentration to 20 vol., 16.0 vol. of CH3CN was charged followed by 4.0 vol. of H20 to make a final concentration of 40 vol. of 10percent H2O/CH3CN relative to Compound A. This slurry was refluxed for 5 hours. The slurry was cooled to 20.0 °C +/- 5 °C and filtered. The cake was washed with CH3CN (5 vol.) 2 times. The resulting solid was dried in a vacuum oven at 50.0 °C +/- 5.0 °C until a constant weight is attained |
With pyridine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; In 2-methyltetrahydrofuran; at 47.5℃; for 8h; | 4-Oxo-l ,4-dihydroquinoline-3-carboxylic acid (26) (1.0 eq) and 5-amino-2,4-di-tert- butylphenyl methyl carbonate (32) (1.1 eq) were charged to a reactor. 2-MeTHF (4.0 vol, relative to the acid) was added followed by T3P® 50percent solution in 2-MeTHF (1.7 eq). The T3P charged vessel was washed with 2-MeTHF (0.6 vol). Pyridine (2.0 eq) was then added, and the resulting suspension was heated to 47.5 +/- 5.0 °C and held at this temperature for 8 hours. A sample was taken and checked for completion by HPLC. Once complete, the resulting mixture was cooled to 25.0 °C +/- 2.5 °C. 2-MeTHF was added (12.5 vol) to dilute the mixture. The reaction mixture was washed with water (10.0 vol) 2 times. 2-MeTHF was added to bring the total volume of reaction to 40.0 vol (-16.5 vol charged). To this solution was added NaOMe/MeOH (1.7 equiv) to perform the methano lysis. The reaction was stirred for no less than 1.0 hour, and checked for completion by HPLC. Once complete, the reaction was quenched with 1 N HCl (10.0 vol), and washed with 0.1 N HCl (10.0 vol). The organic solution was polish filtered to remove any particulates and placed in a second reactor. The filtered solution was concentrated at no more than 45 °C (jacket temperature) and no less than 8.0 °C (internal reaction temperature) under reduced pressure to 20 vol. CH3CN was added to 40 vol and the solution concentrated at no more than 45 °C (jacket temperature) and no less than 8.0 °C (internal reaction temperature) to 20 vol. The addition of CH3CN and concentration cycle was repeated 2 more times for a total of 3 additions of CH3CN and 4 concentrations to 20 vol. After the final concentration to 20 vol, 16.0 vol of CH3CN was added followed by 4.0 vol of H20 to make a final concentration of 40 vol of 10percent H20/CH3CN relative to the starting acid. This slurry was heated to 78.0 °C +/- 5.0 °C (reflux). The slurry was then stirred for no less than 5 hours. The slurry was cooled to 0.0 °C +/- 5 °C over 5 hours, and filtered. The cake was washed with 0.0 °C +/- 5.0 °C CH3CN (5 vol) 4 times. The resulting solid (Compound 1) was dried in a vacuum oven at no more than 50.0 °C. 1H NMR (400 MHz, DMSO-< ) delta 12.8 (s, 1H), 11.8 (s, 1H), 9.2 (s, 1H), 8.9 (s, 1H), 8.3 (s, 1H), 7.2 (s, 1H), 7.9 (t, 1H), 7.8 (d, 1H), 7.5 (t, 1H), 7.1 (s, 1H), 1.4 (s, 9H), 1.4 (s, 9H). | |
With pyridine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; In 2-methyltetrahydrofuran; ethyl acetate; at 45 - 50℃; for 15h; | Compound A (1.0 eq.) and Compound B (1.1 eq.) were charged to a reactor. 2-MeTHF (4.0 vol., relative to Compound A) was added followed by T3P® 50percent solution in EtOAc (2.5 eq.). The T3P charge vessel was washed with 2-MeTHF (3.5 vol.). Pyridine (2.0 eq.) was then charged. The resulting suspension was heated to 45.0 to 50.0° C. and held at this temperature for 15 hours. A sample was taken and checked for completion by HPLC. Once complete, the resulting mixture was cooled to 20.0° C.+/-5.0° C. 2-MeTHF was charged (12.5 vol.) to dilute the mixture. The reaction mixture was washed with water (10.0 vol.) 3 times. 2-MeTHF was charged to bring the total volume of reaction to 40.0 vol. (-16.5 vol. charged). Residual water was removed by continuous distillation at 35.0° C.+/-5° C. from 40 vol. to 30 vol. with 2-MeTHF until in-process control testing using the Karl Fisher method shows the water content to be no more than 1.0percent w/w. The solution was cooled to 20.0° C.+/-5.0° C. To this solution was charged NaOMe/MeOH (1.7 equiv) to perform the hydrolysis of the carbonate. The reaction was stirred for no less than 1.0 hours, and checked for completion by HPLC. Once complete, the reaction was quenched with 1 N HCl/H2O (10.0 vol.), and washed with 0.1; N HCl (10.0 vol.). The organic solution was polish filtered to remove any particulates and placed in a second flask. The filtered solution was concentrated at 25.0° C.+/-5.0° C. under reduced pressure to 20 vol. CH3CN was added to 40 vol. and the solution concentrated at 25.0° C.+/-5.0° C. to 20 vol. The addition of CH3CN and concentration was repeated 2 more times for a total of 3 additions of CH3CN and 4 concentrations to 20 vol. After the final concentration to 20 vol., 16.0 vol. of CH3CN was charged followed by 4.0 vol. of H2O to make a final concentration of 40 vol. of 10percent H2O/CH3CN relative to Compound A. This slurry was refluxed for 5 hours. The slurry was cooled to 20.0° C.+/-5° C. and filtered. The cake was washed with CH3CN (5 vol.)2 times. The resulting solid was dried in a vacuum oven at 50.0° C.+/-5.0° C. until a constant weight is attained. | |
With pyridine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; In 2-methyltetrahydrofuran; at 47.5℃; for 8h; | [00339] 4-0xo-1,4-dihydroquinoline-3-carboxylic acid, 26, (1.0 eq) and 5-amino-2,4-di-tertbutylphenylmethyl carbonate, 32, (1.1 eq) were charged to a reactor. 2-MeTHF (4.0 vol, relative to the acid) was added followed by T3P® 50percent solution in 2-MeTHF (1.7 eq). The T3P chargedvessel was washed with 2-MeTHF (0.6 vol). Pyridine (2.0 eq) was then added, and the resultingsuspension was heated to 47.5 +/- 5.0 oc and held at this temperature for 8 hours. A sample wastaken and checked for completion by HPLC. Once complete, the resulting mixture was cooled to25.0 oc +/- 2.5 °C. 2-MeTHF was added (12.5 vol) to dilute the mixture. The reaction mixturewas washed with water (10.0 vol) 2 times. 2-MeTHF was added to bring the total volume ofreaction to 40.0 vol (~16.5 vol charged). To this solution was added NaOMe/MeOH (1.7 equiv)to perform the methanolysis. The reaction was stirred for no less than 1.0 hour, and checked forcompletion by HPLC. Once complete, the reaction was quenched with 1 N HCl (10.0 vol), andwashed with 0.1 N HCl (10.0 vol). The organic solution was polish filtered to remove anyparticulates and placed in a second reactor. The filtered solution was concentrated at no morethan 35 oc (jacket temperature) and no less than 8.0 oc (internal reaction temperature) underreduced pressure to 20 vol. CH3CN was added to 40 vol and the solution concentrated at nomore than 35 oc (jacket temperature) and no less than 8.0 oc (internal reaction temperature) to 20vol. The addition of CH3CN and concentration cycle was repeated 2 more times for a total of 3additions of CH3CN and 4 concentrations to 20 vol. After the final concentration to 20 vol, 16.0vol of CH3CN was added followed by 4.0 vol of H20 to make a final concentration of 40 vol of10percent H20/CH3CN relative to the starting acid. This slurry was heated to 78.0 oc +/- 5.0 oc(reflux). The slurry was then stirred for no less than 5 hours. The slurry was cooled to 0.0 oc +/-5 oc over 5 hours, and filtered. The cake was washed with 0.0 oc +/- 5.0 oc CH3CN (5 vol) 4times. The resulting solid (Compound 2) was dried in a vacuum oven at 50.0 oc +/- 5.0 °C. 1HNMR ( 400 MHz, DMSO-d6) 8 12.8 (s, 1H), 11.8 (s, 1H), 9.2 (s, 1H), 8.9 (s, 1H), 8.3 (s, 1H), 7.2(s, 1H), 7.9 (t, 1H), 7.8 (d, 1H), 7.5 (t, 1H), 7.1 (s, 1H), 1.4 (s, 9H), 1.4 (s, 9H). | |
With pyridine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; In 2-methyltetrahydrofuran; ethyl acetate; at 45 - 50℃; for 15h; | Compound (VII), Form XX Compound A (1.0 eq.) and Compound B (1.1 eq.) were charged to a reactor. 2-MeTHF (4.0 vol., relative to Compound A) was added followed by T3P® 50percent solution in EtOAc (2.5 eq.). The T3P charge vessel was washed with 2-MeTHF (3.5 vol.). Pyridine (2.0 eq.) was then charged. The resulting suspension was heated to 45.0 to 50.0°C and held at this temperature for 15 hours. A sample was taken and checked for completion by HPLC. Once complete, the resulting mixture was cooled to 20.0°C +/- 5.0°C. 2-MeTHF was charged (12.5 vol.) to dilute the mixture. The reaction mixture was washed with water (10.0 vol.) 3 times. 2-MeTHF was charged to bring the total volume of reaction to 40.0 vol. (-16.5 vol. charged). Residual water was removed by continuous distillation at 35.0°C +/- 5°C from 40 vol. to 30 vol. with 2-MeTHF until in-process control testing using the Karl Fisher method shows the water content to be no more than 1.0percent w/w. The solution was cooled to 20.0°C +/- 5.0°C. To this solution was charged NaOMe/MeOH (1.7 equiv) to perform the hydrolysis of the carbonate. The reaction was stirred for no less than 1.0 hours, and checked for completion by HPLC. Once complete, the reaction was quenched with 1 N HCl / H2O (10.0 vol.), and washed with 0.1 N HCl (10.0 vol.). The organic solution was polish filtered to remove any particulates and placed in a second flask. The filtered solution was concentrated at 25.0°C +/- 5.0°C under reduced pressure to 20 vol. CCN was added to 40 vol. and the solution concentrated at 25.0°C +/- 5.0°C to 20 vol. The addition of CCN and concentration was repeated 2 more times for a total of 3 additions of CH3CN and 4 concentrations to 20 vol. After the final concentration to 20 vol., 16.0 vol. of CH3CN was charged followed by 4.0 vol. of H20 to make a final concentration of 40 vol. of 10percent H2O/CH3CN relative to Compound A. This slurry was refluxed for 5 hours. The slurry was cooled to 20.0°C +/- 5°C and filtered. The cake was washed with CH3CN (5 vol.) 2 times. The resulting solid was dried in a vacuum oven at 50.0°C +/- 5.0°C until a constant weight is attained. | |
With pyridine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; In 2-methyltetrahydrofuran; at 42.5 - 52.5℃; for 8h; | [00354] 4-Oxo-l ,4-dihydroquinoline-3-carboxylic acid, 26, (1.0 eq) and 5-amino-2,4-di-tert- butylphenyl methyl carbonate, 32, (1.1 eq) were charged to a reactor. 2-MeTHF (4.0 vol, relative l iotaupsilon to the acid) was added followed by T3P® 50percent solution in 2-MeTHF (1.7 eq). The T3P charged vessel was washed with 2-MeTHF (0.6 vol). Pyridine (2.0 eq) was then added, and the resulting suspension was heated to 47.5 +/- 5.0 °C and held at this temperature for 8 hours. A sample was taken and checked for completion by HPLC. Once complete, the resulting mixture was cooled to 25.0 °C +/- 2.5 °C. 2-MeTHF was added (12.5 vol) to dilute the mixture. The reaction mixture was washed with water (10.0 vol) 2 times. 2-MeTHF was added to bring the total volume of reaction to 40.0 vol (-16.5 vol charged). To this solution was added NaOMe/MeOH (1.7 equiv) to perform the methanolysis. The reaction was stirred for no less than 1.0 hour, and checked for completion by HPLC. Once complete, the reaction was quenched with 1 N HC1 (10.0 vol), and washed with 0.1 N HC1 (10.0 vol). The organic solution was polish filtered to remove any particulates and placed in a second reactor. The filtered solution was concentrated at no more than 35 °C (jacket temperature) and no less than 8.0 °C (internal reaction temperature) under reduced pressure to 20 vol. CH3CN was added to 40 vol and the solution concentrated at no more than 35 °C (jacket temperature) and no less than 8.0 °C (internal reaction temperature) to 20 vol. The addition of CH3CN and concentration cycle was repeated 2 more times for a total of 3 additions of CH3CN and 4 concentrations to 20 vol. After the final concentration to 20 vol, 16.0 vol of CH3CN was added followed by 4.0 vol of H20 to make a final concentration of 40 vol of 10percent H20/CH3CN relative to the starting acid. This slurry was heated to 78.0 °C +/- 5.0 °C (reflux). The slurry was then stirred for no less than 5 hours. The slurry was cooled to 0.0 °C +/- 5 °C over 5 hours, and filtered. The cake was washed with 0.0 °C +/- 5.0 °C CH3CN (5 vol) 4 times. The resulting solid (Compound 2) was dried in a vacuum oven at 50.0 °C +/- 5.0 °C. NMR (400 MHz, DMSO-d6) delta 12.8 (s, 1H), 11.8 (s, 1H), 9.2 (s, 1H), 8.9 (s, 1H), 8.3 (s, 1H), 7.2 (s, 1H), 7.9 (t, 1H), 7.8 (d, 1H), 7.5 (t, 1H), 7.1 (s, 1H), 1.4 (s, 9H), 1.4 (s, 9H). | |
With pyridine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; In 2-methyltetrahydrofuran; at 47.5℃; for 8h; | 4-Oxo-1,4-dihydroquinoline-3-carboxylic acid 26 (1.0 eq) and 5-amino-2,4-di-tert-butylphenyl methyl carbonate 32 (1.1 eq) were charged to a reactor. 2-MeTHF (4.0 vol, relative to the acid) was added followed by T3P® 50percent solution in 2-MeTHF (1.7 eq). The T3P charged vessel was washed with 2-MeTHF (0.6 vol). Pyridine (2.0 eq) was then added, and the resulting suspension was heated to 47.5+/?5.0° C. and held at this temperature for 8 hours. | |
With pyridine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; In 2-methyltetrahydrofuran; at 45 - 50℃; for 15h; | (0444) Compound 1 was prepared as described in WO 2010/18162, US 2010/0267768 and U.S. Pat. No. 8,476,442, which are incorporated by reference herein. The preparation is also described below. (0445) Compound A (1.0 eq.) and Compound B (1.1 eq.) were charged to a reactor. 2-MeTHF (4.0 vol., relative to Compound A) was added followed by T3P® 50percent solution in EtOAc (2.5 eq.). The T3P charge vessel was washed with 2-MeTHF (3.5 vol.). Pyridine (2.0 eq.) was then charged. The resulting suspension was heated to 45.0 to 50.0° C. and held at this temperature for 15 hours. A sample was taken and checked for completion by HPLC. Once complete, the resulting mixture was cooled to 20.0° C.+/?5.0° C. 2-MeTHF was charged (12.5 vol.) to dilute the mixture. The reaction mixture was washed with water (10.0 vol.) 3 times. 2-MeTHF was charged to bring the total volume of reaction to 40.0 vol. (?16.5 vol. charged). Residual water was removed by continuous distillation at 35.0° C.+/?5° C. from 40 vol. to 30 vol. with 2-MeTHF until in-process control testing using the Karl Fisher method shows the water content to be no more than 1.0percent w/w. The solution was cooled to 20.0° C.+/?5.0° C. To this solution was charged NaOMe/MeOH (1.7 equiv) to perform the hydrolysis of the carbonate. The reaction was stirred for no less than 1.0 hours, and checked for completion by HPLC. Once complete, the reaction was quenched with 1 N HCl/H2O (10.0 vol.), and washed with 0.1 N HCl (10.0 vol.). The organic solution was polish filtered to remove any particulates and placed in a second flask. The filtered solution was concentrated at 25.0° C.+/?5.0° C. under reduced pressure to 20 vol. CH3CN was added to 40 vol. and the solution concentrated at 25.0° C.+1-5.0° C. to 20 vol. The addition of CH3CN and concentration was repeated 2 more times for a total of 3 additions of CH3CN and 4 concentrations to 20 vol. After the final concentration to 20 vol., 16.0 vol. of CH3CN was charged followed by 4.0 vol. of H2O to make a final concentration of 40 vol. of 10percent H2O/CH3CN relative to Compound A. This slurry was refluxed for 5 hours. The slurry was cooled to 20.0° C.+/?5° C. and filtered. The cake was washed with CH3CN (5 vol.) 2 times. The resulting solid was dried in a vacuum oven at 50.0° C.+/?5.0° C. until a constant weight is attained. | |
With pyridine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; In 2-methyltetrahydrofuran; ethyl acetate; at 45 - 50℃; for 15h; | [003931 Compound A (1.0 eq.) and Compound B (1.1 eq.) were charged to a reactor. 2-MeTHF (4.0 vol., relative to Compound A) was added followed by T3P® 50percent solution in EtOAc (2.5 eq.). The T3P charge vessel was washed with 2-MeTHF (3.5 vol.). Pyridine (2.0 eq.) was then charged. The resulting suspension was heated to 45.0 to 50.0 °C and held at this temperature for 15 hours. A sample was taken and checked for completion by HPLC. Once complete, the resulting mixture was cooled to 20.0 °C +1- 5.0 °C. 2-MeTHF was charged (12.5 vol.) to dilute the mixture. The reaction mixture was washed with water (10.0 vol.) 3 times. 2-MeTHF was charged to bring the total volume of reaction to 40.0 vol. (-16.5 vol. charged). Residual water was removed by continuous distillation at 35.0 °C +1- 5 °C from 40 vol. to 30 vol. with 2-MeTHF until in-process control testing using the Karl Fisher method shows the water content to be no more than 1.0percent w/w. The solution was cooled to 20.0 °C +1- 5.0 °C. To this solution was charged NaOMe/MeOH (1.7 equiv) to perform the hydrolysis of the carbonate. The reaction was stirred for no less than 1.0 hours, and checked for completion by HPLC. Once complete, the reaction was quenched with 1 N HC1 / H20 (10.0 vol.), and washed with 0.1 N HC1 (10.0 vol.). The organic solution was polish filtered to remove any particulates and placed in a second flask. The filtered solution was concentrated at 25.0 °C +1- 5.0 °C under reduced pressure to 20 vol. CH3CN was added to 40 vol. and the solution concentrated at 25.0 °C +I5.0 °C to 20 vol. The addition of CH3CN and concentration was repeated 2 more times for a total of 3 additions of CH3CN and 4 concentrations to 20 vol. After the final concentration to 20 vol., 16.0 vol. of CH3CN was charged followed by 4.0 vol. of H2O to make a final concentration of 40 vol. of 10percent H20/CH3CN relative toCompound A. This slurry was refluxed for 5 hours. The slurry was cooled to 20.0 °C +1- 5 °C and filtered. The cake was washed with CH3CN (5 vol.) 2 times. The resulting solid was dried in a vacuum oven at 50.0 °C +I. 5.0 °C until a constant weight is attained. |
Yield | Reaction Conditions | Operation in experiment |
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76% | With water; sodium hydroxide; In methanol; at 20℃; for 5h; | To a solution of 2,4-di-tert-butyl-5-(4-oxo-1,4-dihydroquinoline-3-carboxamido)phenyl methyl carbonate 5 (30 mg, 0.06mmol) in MeOH (2 mL) was added NaOH (5.3 mg, 0.13mmol) dissolved in H2O (2 mL), and the reaction mixture was stirred at room temperature for 5h. Reaction mass was evaporated to one third of its volume (temperature not exceeding 40C) and acidified with aq.2N HC1 to pH 2-3. The resulting precipitate was collected by suction filtration give desired compound 7 (19 mg, 76%) as off white solid. 1H NMR (400MHz, DMSO-d6) delta = 12.88 (d, J = 6.6 Hz, 1 H), 11.81 (s, 1 H), 9.20 (s, 1 H), 8.86 (d, J = 6.6 Hz, 1 H), 8.32 (d, J = 7.8 Hz, 1 H), 7.88 - 7.65 (m, 2 H), 7.51 (t, J = 7.5 Hz, 1 H), 7.16 (s, 1 H), 7.10 (s, 1 H), 1.38 (s,9H), 1.36 (s, 9H). |
4-Oxo-l,4-dihydroquinoline-3-carboxylic acid, 26, (1.0 eq) and 5-amino-2,4-di- tert-butylphenyl methyl carbonate, 32, (1.1 eq) were charged to a reactor. 2-MeTHF (4.0 vol, relative to the acid) was added followed by T3P 50% solution in 2-MeTHF (1.7 eq). The T3P charged vessel was washed with 2-MeTHF (0.6 vol). Pyridine (2.0 eq) was then added, and the resulting suspension was heated to 47.5 +/- 5.0 0C and held at this temperature for 8 hours. A sample was taken and checked for completion by HPLC. Once complete, the resulting mixture was cooled to 25.0 0C +/- 2.5 0C. 2-MeTHF was added (12.5 vol) to dilute the mixture. The reaction mixture was washed with water (10.0 vol) 2 times. 2-MeTHF was added to bring the total volume of reaction to 40.0 vol (-16.5 vol charged). To this solution was added NaOMe/MeOH (1.7 equiv) to perform the methanolysis. The reaction was stirred for no less than 1.0 hour, and checked for completion by HPLC. Once complete, the reaction was quenched with 1 N HCl (10.0 vol), and washed with 0.1 N HCl (10.0 vol). The organic solution was polish filtered to remove any particulates and placed in a second reactor. The filtered solution was concentrated at no more than 350C (jacket temperature) and no less than 8.00C (internal reaction temperature) under reduced pressure to 20 vol. CH3CN was added to 40 vol and the solution concentrated at no more than 35 0C (jacket temperature) and no less than 8.00C (internal reaction temperature) to 20 vol. The addition of CH3CN and concentration cycle was repeated 2 more times for a total of 3 additions of CH3CN and 4 concentrations to 20 vol. After the final concentration to 20 vol, 16.0 vol of CH3CN was added followed by 4.0 vol of H2O to make a final concentration of 40 vol of 10% H2O/CH3CN relative to the starting acid. This slurry was heated to 78.00C +/- 5.00C (reflux). The slurry was then stirred for no less than 5 hours. The slurry was cooled to 0.00C +/- 5 0C over 5 hours, and filtered. The cake was washed with 0.0 0C +/- 5.0 0C CH3CN (5 vol) 4 times. The resulting solid (compound 34) was dried in a vacuum oven at 50.0 0C +/- 5.0 0C. 1H NMR (400 MHz, DMSO-<;/6) delta 12.8 (s, IH), 11.8 (s, IH), 9.2 (s, IH), 8.9 (s, IH), 8.3 (s, IH), 7.2 (s, IH), 7.9 (t, IH), 7.8 (d, IH), 7.5 (t, IH), 7.1 (s, IH), 1.4 (s, 9H), 1.4 (s, 9H). | ||
Preparation of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (1) 4-Oxo-1,4-dihydroquinoline-3-carboxylic acid, 26, (1.0 eq) and 5-amino-2,4-di-tert-butylphenyl methyl carbonate, 32, (1.1 eq) were charged to a reactor. 2-MeTHF (4.0 vol, relative to the acid) was added followed by T3P 50% solution in 2-MeTHF (1.7 eq). The T3P charged vessel was washed with 2-MeTHF (0.6 vol). Pyridine (2.0 eq) was then added, and the resulting suspension was heated to 47.5+/-5.0 C. and held at this temperature for 8 hours. A sample was taken and checked for completion by HPLC. Once complete, the resulting mixture was cooled to 25.0 C.+/-2.5 C. 2-MeTHF was added (12.5 vol) to dilute the mixture. The reaction mixture was washed with water (10.0 vol) 2 times. 2-MeTHF was added to bring the total volume of reaction to 40.0 vol (16.5 vol charged). To this solution was added NaOMe/MeOH (1.7 equiv) to perform the methanolysis. The reaction was stirred for no less than 1.0 hour, and checked for completion by HPLC. Once complete, the reaction was quenched with 1 N HCl (10.0 vol), and washed with 0.1 N HCl (10.0 vol). The organic solution was polish filtered to remove any particulates and placed in a second reactor. The filtered solution was concentrated at no more than 35 C. (jacket temperature) and no less than 8.0 C. (internal reaction temperature) under reduced pressure to 20 vol. CH3CN was added to 40 vol and the solution concentrated at no more than 35 C. (jacket temperature) and no less than 8.0 C. (internal reaction temperature) to 20 vol. The addition of CH3CN and concentration cycle was repeated 2 more times for a total of 3 additions of CH3CN and 4 concentrations to 20 vol. After the final concentration to 20 vol, 16.0 vol of CH3CN was added followed by 4.0 vol of H2O to make a final concentration of 40 vol of 10% H2O/CH3CN relative to the starting acid. This slurry was heated to 78.0 C.+/-5.0 C. (reflux). The slurry was then stirred for no less than 5 hours. The slurry was cooled to 0.0 C.+/-5 C. over 5 hours, and filtered. The cake was washed with 0.0 C.+/-5.0 C. CH3CN (5 vol) 4 times. The resulting solid (compound 1) was dried in a vacuum oven at 50.0 C.+/-5.0 C. 1H NMR (400 MHz, DMSO-d6) delta 12.8 (s, 1H), 11.8 (s, 1H), 9.2 (s, 1H), 8.9 (s, 1H), 8.3 (s, 1H), 7.2 (s, 1H), 7.9 (t, 1H), 7.8 (d, 1H), 7.5 (t, 1H), 7.1 (s, 1H), 1.4 (s, 9H), 1.4 (s, 9H). |
With sodium methylate; In 2-methyltetrahydrofuran; methanol; at 20℃; for 1h; | Compound A (1.0 eq.) and Compound B (1.1 eq.) were charged to a reactor. 2- MeTHF (4.0 vol., relative to Compound A) was added followed by T3P 50% solution in EtOAc (2.5 eq.). The T3P charge vessel was washed with 2-MeTHF (3.5 vol.). Pyridine (2.0 eq.) was then charged. The resulting suspension was heated to 45.0 to 50.0 C and held at thistemperature for 15 hours. A sample was taken and checked for completion by HPLC. Once complete, the resulting mixture was cooled to 20.0 C +/- 5.0 C. 2-MeTHF was charged (12.5 vol.) to dilute the mixture. The reaction mixture was washed with water (10.0 vol.) 3 times. 2- MeTHF was charged to bring the total volume of reaction to 40.0 vol. (-16.5 vol. charged). Residual water was removed by continuous distillation at 35.0 C +/- 5 C from 40 vol. to 30 vol. with 2-MeTHF until in-process control testing using the Karl Fisher method shows the water content to be no more than 1.0% w/w. The solution was cooled to 20.0 C +/- 5.0 C. To this solution was charged NaOMe/MeOH (1.7 equiv) to perform the hydrolysis of the carbonate. The reaction was stirred for no less than 1.0 hours, and checked for completion by HPLC. Once complete, the reaction was quenched with 1 N HC1 / H20 (10.0 vol.), and washed with 0.1 N HC1 (10.0 vol.). The organic solution was polish filtered to remove any particulates and placed in a second flask. The filtered solution was concentrated at 25.0 C +/- 5.0 C under reduced pressure to 20 vol. CCN was added to 40 vol. and the solution concentrated at 25.0 C +/- 5.0 C to 20 vol. The addition of CCN and concentration was repeated 2 more times for a total of 3 additions of CH3CN and 4 concentrations to 20 vol. After the final concentration to 20 vol., 16.0 vol. of CH3CN was charged followed by 4.0 vol. of H20 to make a final concentration of 40 vol. of 10% H2O/CH3CN relative to Compound A. This slurry was refluxed for 5 hours. The slurry was cooled to 20.0 C +/- 5 C and filtered. The cake was washed with CH3CN (5 vol.) 2 times. The resulting solid was dried in a vacuum oven at 50.0 C +/- 5.0 C until a constant weight is attained | |
With sodium methylate; In 2-methyltetrahydrofuran; methanol; for 1h; | 4-Oxo-l ,4-dihydroquinoline-3-carboxylic acid (26) (1.0 eq) and 5-amino-2,4-di-tert- butylphenyl methyl carbonate (32) (1.1 eq) were charged to a reactor. 2-MeTHF (4.0 vol, relative to the acid) was added followed by T3P 50% solution in 2-MeTHF (1.7 eq). The T3P charged vessel was washed with 2-MeTHF (0.6 vol). Pyridine (2.0 eq) was then added, and the resulting suspension was heated to 47.5 +/- 5.0 C and held at this temperature for 8 hours. A sample was taken and checked for completion by HPLC. Once complete, the resulting mixture was cooled to 25.0 C +/- 2.5 C. 2-MeTHF was added (12.5 vol) to dilute the mixture. The reaction mixture was washed with water (10.0 vol) 2 times. 2-MeTHF was added to bring the total volume of reaction to 40.0 vol (-16.5 vol charged). To this solution was added NaOMe/MeOH (1.7 equiv) to perform the methano lysis. The reaction was stirred for no less than 1.0 hour, and checked for completion by HPLC. Once complete, the reaction was quenched with 1 N HCl (10.0 vol), and washed with 0.1 N HCl (10.0 vol). The organic solution was polish filtered to remove any particulates and placed in a second reactor. The filtered solution was concentrated at no more than 45 C (jacket temperature) and no less than 8.0 C (internal reaction temperature) under reduced pressure to 20 vol. CH3CN was added to 40 vol and the solution concentrated at no more than 45 C (jacket temperature) and no less than 8.0 C (internal reaction temperature) to 20 vol. The addition of CH3CN and concentration cycle was repeated 2 more times for a total of 3 additions of CH3CN and 4 concentrations to 20 vol. After the final concentration to 20 vol, 16.0 vol of CH3CN was added followed by 4.0 vol of H20 to make a final concentration of 40 vol of 10% H20/CH3CN relative to the starting acid. This slurry was heated to 78.0 C +/- 5.0 C (reflux). The slurry was then stirred for no less than 5 hours. The slurry was cooled to 0.0 C +/- 5 C over 5 hours, and filtered. The cake was washed with 0.0 C +/- 5.0 C CH3CN (5 vol) 4 times. The resulting solid (Compound 1) was dried in a vacuum oven at no more than 50.0 C. 1H NMR (400 MHz, DMSO-< ) delta 12.8 (s, 1H), 11.8 (s, 1H), 9.2 (s, 1H), 8.9 (s, 1H), 8.3 (s, 1H), 7.2 (s, 1H), 7.9 (t, 1H), 7.8 (d, 1H), 7.5 (t, 1H), 7.1 (s, 1H), 1.4 (s, 9H), 1.4 (s, 9H). | |
With methanol; sodium methylate; In 2-methyltetrahydrofuran; | Compound A (1.0 eq.) and Compound B (1.1 eq.) were charged to a reactor. 2-MeTHF (4.0 vol., relative to Compound A) was added followed by T3P 50% solution in EtOAc (2.5 eq.). The T3P charge vessel was washed with 2-MeTHF (3.5 vol.). Pyridine (2.0 eq.) was then charged. The resulting suspension was heated to 45.0 to 50.0 C. and held at this temperature for 15 hours. A sample was taken and checked for completion by HPLC. Once complete, the resulting mixture was cooled to 20.0 C.+/-5.0 C. 2-MeTHF was charged (12.5 vol.) to dilute the mixture. The reaction mixture was washed with water (10.0 vol.) 3 times. 2-MeTHF was charged to bring the total volume of reaction to 40.0 vol. (-16.5 vol. charged). Residual water was removed by continuous distillation at 35.0 C.+/-5 C. from 40 vol. to 30 vol. with 2-MeTHF until in-process control testing using the Karl Fisher method shows the water content to be no more than 1.0% w/w. The solution was cooled to 20.0 C.+/-5.0 C. To this solution was charged NaOMe/MeOH (1.7 equiv) to perform the hydrolysis of the carbonate. The reaction was stirred for no less than 1.0 hours, and checked for completion by HPLC. Once complete, the reaction was quenched with 1 N HCl/H2O (10.0 vol.), and washed with 0.1; N HCl (10.0 vol.). The organic solution was polish filtered to remove any particulates and placed in a second flask. The filtered solution was concentrated at 25.0 C.+/-5.0 C. under reduced pressure to 20 vol. CH3CN was added to 40 vol. and the solution concentrated at 25.0 C.+/-5.0 C. to 20 vol. The addition of CH3CN and concentration was repeated 2 more times for a total of 3 additions of CH3CN and 4 concentrations to 20 vol. After the final concentration to 20 vol., 16.0 vol. of CH3CN was charged followed by 4.0 vol. of H2O to make a final concentration of 40 vol. of 10% H2O/CH3CN relative to Compound A. This slurry was refluxed for 5 hours. The slurry was cooled to 20.0 C.+/-5 C. and filtered. The cake was washed with CH3CN (5 vol.)2 times. The resulting solid was dried in a vacuum oven at 50.0 C.+/-5.0 C. until a constant weight is attained. | |
With methanol; sodium methylate; In 2-methyltetrahydrofuran; for 1h; | [00339] 4-0xo-1,4-dihydroquinoline-3-carboxylic acid, 26, (1.0 eq) and 5-amino-2,4-di-tertbutylphenylmethyl carbonate, 32, (1.1 eq) were charged to a reactor. 2-MeTHF (4.0 vol, relative to the acid) was added followed by T3P 50% solution in 2-MeTHF (1.7 eq). The T3P chargedvessel was washed with 2-MeTHF (0.6 vol). Pyridine (2.0 eq) was then added, and the resultingsuspension was heated to 47.5 +/- 5.0 oc and held at this temperature for 8 hours. A sample wastaken and checked for completion by HPLC. Once complete, the resulting mixture was cooled to25.0 oc +/- 2.5 C. 2-MeTHF was added (12.5 vol) to dilute the mixture. The reaction mixturewas washed with water (10.0 vol) 2 times. 2-MeTHF was added to bring the total volume ofreaction to 40.0 vol (~16.5 vol charged). To this solution was added NaOMe/MeOH (1.7 equiv)to perform the methanolysis. The reaction was stirred for no less than 1.0 hour, and checked forcompletion by HPLC. Once complete, the reaction was quenched with 1 N HCl (10.0 vol), andwashed with 0.1 N HCl (10.0 vol). The organic solution was polish filtered to remove anyparticulates and placed in a second reactor. The filtered solution was concentrated at no morethan 35 oc (jacket temperature) and no less than 8.0 oc (internal reaction temperature) underreduced pressure to 20 vol. CH3CN was added to 40 vol and the solution concentrated at nomore than 35 oc (jacket temperature) and no less than 8.0 oc (internal reaction temperature) to 20vol. The addition of CH3CN and concentration cycle was repeated 2 more times for a total of 3additions of CH3CN and 4 concentrations to 20 vol. After the final concentration to 20 vol, 16.0vol of CH3CN was added followed by 4.0 vol of H20 to make a final concentration of 40 vol of10% H20/CH3CN relative to the starting acid. This slurry was heated to 78.0 oc +/- 5.0 oc(reflux). The slurry was then stirred for no less than 5 hours. The slurry was cooled to 0.0 oc +/-5 oc over 5 hours, and filtered. The cake was washed with 0.0 oc +/- 5.0 oc CH3CN (5 vol) 4times. The resulting solid (Compound 2) was dried in a vacuum oven at 50.0 oc +/- 5.0 C. 1HNMR ( 400 MHz, DMSO-d6) 8 12.8 (s, 1H), 11.8 (s, 1H), 9.2 (s, 1H), 8.9 (s, 1H), 8.3 (s, 1H), 7.2(s, 1H), 7.9 (t, 1H), 7.8 (d, 1H), 7.5 (t, 1H), 7.1 (s, 1H), 1.4 (s, 9H), 1.4 (s, 9H). | |
With sodium methylate; In methanol; for 1h; | Compound (VII), Form XX Compound A (1.0 eq.) and Compound B (1.1 eq.) were charged to a reactor. 2-MeTHF (4.0 vol., relative to Compound A) was added followed by T3P 50% solution in EtOAc (2.5 eq.). The T3P charge vessel was washed with 2-MeTHF (3.5 vol.). Pyridine (2.0 eq.) was then charged. The resulting suspension was heated to 45.0 to 50.0C and held at this temperature for 15 hours. A sample was taken and checked for completion by HPLC. Once complete, the resulting mixture was cooled to 20.0C +/- 5.0C. 2-MeTHF was charged (12.5 vol.) to dilute the mixture. The reaction mixture was washed with water (10.0 vol.) 3 times. 2-MeTHF was charged to bring the total volume of reaction to 40.0 vol. (-16.5 vol. charged). Residual water was removed by continuous distillation at 35.0C +/- 5C from 40 vol. to 30 vol. with 2-MeTHF until in-process control testing using the Karl Fisher method shows the water content to be no more than 1.0% w/w. The solution was cooled to 20.0C +/- 5.0C. To this solution was charged NaOMe/MeOH (1.7 equiv) to perform the hydrolysis of the carbonate. The reaction was stirred for no less than 1.0 hours, and checked for completion by HPLC. Once complete, the reaction was quenched with 1 N HCl / H2O (10.0 vol.), and washed with 0.1 N HCl (10.0 vol.). The organic solution was polish filtered to remove any particulates and placed in a second flask. The filtered solution was concentrated at 25.0C +/- 5.0C under reduced pressure to 20 vol. CCN was added to 40 vol. and the solution concentrated at 25.0C +/- 5.0C to 20 vol. The addition of CCN and concentration was repeated 2 more times for a total of 3 additions of CH3CN and 4 concentrations to 20 vol. After the final concentration to 20 vol., 16.0 vol. of CH3CN was charged followed by 4.0 vol. of H20 to make a final concentration of 40 vol. of 10% H2O/CH3CN relative to Compound A. This slurry was refluxed for 5 hours. The slurry was cooled to 20.0C +/- 5C and filtered. The cake was washed with CH3CN (5 vol.) 2 times. The resulting solid was dried in a vacuum oven at 50.0C +/- 5.0C until a constant weight is attained. | |
With methanol; sodium methylate; In 2-methyltetrahydrofuran; | [00354] 4-Oxo-l ,4-dihydroquinoline-3-carboxylic acid, 26, (1.0 eq) and 5-amino-2,4-di-tert- butylphenyl methyl carbonate, 32, (1.1 eq) were charged to a reactor. 2-MeTHF (4.0 vol, relative l iotaupsilon to the acid) was added followed by T3P 50% solution in 2-MeTHF (1.7 eq). The T3P charged vessel was washed with 2-MeTHF (0.6 vol). Pyridine (2.0 eq) was then added, and the resulting suspension was heated to 47.5 +/- 5.0 C and held at this temperature for 8 hours. A sample was taken and checked for completion by HPLC. Once complete, the resulting mixture was cooled to 25.0 C +/- 2.5 C. 2-MeTHF was added (12.5 vol) to dilute the mixture. The reaction mixture was washed with water (10.0 vol) 2 times. 2-MeTHF was added to bring the total volume of reaction to 40.0 vol (-16.5 vol charged). To this solution was added NaOMe/MeOH (1.7 equiv) to perform the methanolysis. The reaction was stirred for no less than 1.0 hour, and checked for completion by HPLC. Once complete, the reaction was quenched with 1 N HC1 (10.0 vol), and washed with 0.1 N HC1 (10.0 vol). The organic solution was polish filtered to remove any particulates and placed in a second reactor. The filtered solution was concentrated at no more than 35 C (jacket temperature) and no less than 8.0 C (internal reaction temperature) under reduced pressure to 20 vol. CH3CN was added to 40 vol and the solution concentrated at no more than 35 C (jacket temperature) and no less than 8.0 C (internal reaction temperature) to 20 vol. The addition of CH3CN and concentration cycle was repeated 2 more times for a total of 3 additions of CH3CN and 4 concentrations to 20 vol. After the final concentration to 20 vol, 16.0 vol of CH3CN was added followed by 4.0 vol of H20 to make a final concentration of 40 vol of 10% H20/CH3CN relative to the starting acid. This slurry was heated to 78.0 C +/- 5.0 C (reflux). The slurry was then stirred for no less than 5 hours. The slurry was cooled to 0.0 C +/- 5 C over 5 hours, and filtered. The cake was washed with 0.0 C +/- 5.0 C CH3CN (5 vol) 4 times. The resulting solid (Compound 2) was dried in a vacuum oven at 50.0 C +/- 5.0 C. NMR (400 MHz, DMSO-d6) delta 12.8 (s, 1H), 11.8 (s, 1H), 9.2 (s, 1H), 8.9 (s, 1H), 8.3 (s, 1H), 7.2 (s, 1H), 7.9 (t, 1H), 7.8 (d, 1H), 7.5 (t, 1H), 7.1 (s, 1H), 1.4 (s, 9H), 1.4 (s, 9H). | |
With sodium methylate; In 2-methyltetrahydrofuran; methanol; for 1h; | 4-Oxo-1,4-dihydroquinoline-3-carboxylic acid 26 (1.0 eq) and 5-amino-2,4-di-tert-butylphenyl methyl carbonate 32 (1.1 eq) were charged to a reactor. 2-MeTHF (4.0 vol, relative to the acid) was added followed by T3P 50% solution in 2-MeTHF (1.7 eq). The T3P charged vessel was washed with 2-MeTHF (0.6 vol). Pyridine (2.0 eq) was then added, and the resulting suspension was heated to 47.5+/-5.0 C. and held at this temperature for 8 hours. A sample was taken and checked for completion by HPLC. Once complete, the resulting mixture was cooled to 25.0 C.+1-2.5 C. 2-MeTHF was added (12.5 vol) to dilute the mixture. The reaction mixture was washed with water (10.0 vol) 2 times. 2-MeTHF was added to bring the total volume of reaction to 40.0 vol (16.5 vol charged). To this solution was added NaOMe/MeOH (1.7 equiv) to perform the methanolysis. The reaction was stirred for no less than 1.0 hour, and checked for completion by HPLC. Once complete, the reaction was quenched with 1 N HCl (10.0 vol), and washed with 0.1 N HCl (10.0 vol). The organic solution was polish filtered to remove any particulates and placed in a second reactor. The filtered solution was concentrated at no more than 35 C. (jacket temperature) and no less than 8.0 C. (internal reaction temperature) under reduced pressure to 20 vol. CH3CN was added to 40 vol and the solution concentrated at no more than 35 C. (jacket temperature) and no less than 8.0 C. (internal reaction temperature) to 20 vol. The addition of CH3CN and concentration cycle was repeated 2 more times for a total of 3 additions of CH3CN and 4 concentrations to 20 vol. After the final concentration to 20 vol, 16.0 vol of CH3CN was added followed by 4.0 vol of H2O to make a final concentration of 40 vol of 10% H2O/CH3CN relative to the starting acid. This slurry was heated to 78.0 C.+/-5.0 C. (reflux). The slurry was then stirred for no less than 5 hours. The slurry was cooled to 0.0 C.+/-5 C. over 5 hours, and filtered. The cake was washed with 0.0 C.+/-5.0 C. CH3CN (5 vol) 4 times. The resulting solid (Compound 1) was dried in a vacuum oven at 50.0 C.+/-5.0 C. 1H NMR (400 MHz, DMSO-d6) delta 12.8 (s, 1H), 11.8 (s, 1H), 9.2 (s, 1H), 8.9 (s, 1H), 8.3 (s, 1H), 7.2 (s, 1H), 7.9 (t, 1H), 7.8 (d, 1H), 7.5 (t, 1H), 7.1 (s, 1H), 1.4 (s, 9H), 1.4 (s, 9H). | |
With sodium methylate; In 2-methyltetrahydrofuran; methanol; for 1h; | (0444) Compound 1 was prepared as described in WO 2010/18162, US 2010/0267768 and U.S. Pat. No. 8,476,442, which are incorporated by reference herein. The preparation is also described below. (0445) Compound A (1.0 eq.) and Compound B (1.1 eq.) were charged to a reactor. 2-MeTHF (4.0 vol., relative to Compound A) was added followed by T3P 50% solution in EtOAc (2.5 eq.). The T3P charge vessel was washed with 2-MeTHF (3.5 vol.). Pyridine (2.0 eq.) was then charged. The resulting suspension was heated to 45.0 to 50.0 C. and held at this temperature for 15 hours. A sample was taken and checked for completion by HPLC. Once complete, the resulting mixture was cooled to 20.0 C.+/-5.0 C. 2-MeTHF was charged (12.5 vol.) to dilute the mixture. The reaction mixture was washed with water (10.0 vol.) 3 times. 2-MeTHF was charged to bring the total volume of reaction to 40.0 vol. (-16.5 vol. charged). Residual water was removed by continuous distillation at 35.0 C.+/-5 C. from 40 vol. to 30 vol. with 2-MeTHF until in-process control testing using the Karl Fisher method shows the water content to be no more than 1.0% w/w. The solution was cooled to 20.0 C.+/-5.0 C. To this solution was charged NaOMe/MeOH (1.7 equiv) to perform the hydrolysis of the carbonate. The reaction was stirred for no less than 1.0 hours, and checked for completion by HPLC. Once complete, the reaction was quenched with 1 N HCl/H2O (10.0 vol.), and washed with 0.1 N HCl (10.0 vol.). The organic solution was polish filtered to remove any particulates and placed in a second flask. The filtered solution was concentrated at 25.0 C.+/-5.0 C. under reduced pressure to 20 vol. CH3CN was added to 40 vol. and the solution concentrated at 25.0 C.+1-5.0 C. to 20 vol. The addition of CH3CN and concentration was repeated 2 more times for a total of 3 additions of CH3CN and 4 concentrations to 20 vol. After the final concentration to 20 vol., 16.0 vol. of CH3CN was charged followed by 4.0 vol. of H2O to make a final concentration of 40 vol. of 10% H2O/CH3CN relative to Compound A. This slurry was refluxed for 5 hours. The slurry was cooled to 20.0 C.+/-5 C. and filtered. The cake was washed with CH3CN (5 vol.) 2 times. The resulting solid was dried in a vacuum oven at 50.0 C.+/-5.0 C. until a constant weight is attained. | |
With methanol; sodium methylate; for 1h; | [003931 Compound A (1.0 eq.) and Compound B (1.1 eq.) were charged to a reactor. 2-MeTHF (4.0 vol., relative to Compound A) was added followed by T3P 50% solution in EtOAc (2.5 eq.). The T3P charge vessel was washed with 2-MeTHF (3.5 vol.). Pyridine (2.0 eq.) was then charged. The resulting suspension was heated to 45.0 to 50.0 C and held at this temperature for 15 hours. A sample was taken and checked for completion by HPLC. Once complete, the resulting mixture was cooled to 20.0 C +1- 5.0 C. 2-MeTHF was charged (12.5 vol.) to dilute the mixture. The reaction mixture was washed with water (10.0 vol.) 3 times. 2-MeTHF was charged to bring the total volume of reaction to 40.0 vol. (-16.5 vol. charged). Residual water was removed by continuous distillation at 35.0 C +1- 5 C from 40 vol. to 30 vol. with 2-MeTHF until in-process control testing using the Karl Fisher method shows the water content to be no more than 1.0% w/w. The solution was cooled to 20.0 C +1- 5.0 C. To this solution was charged NaOMe/MeOH (1.7 equiv) to perform the hydrolysis of the carbonate. The reaction was stirred for no less than 1.0 hours, and checked for completion by HPLC. Once complete, the reaction was quenched with 1 N HC1 / H20 (10.0 vol.), and washed with 0.1 N HC1 (10.0 vol.). The organic solution was polish filtered to remove any particulates and placed in a second flask. The filtered solution was concentrated at 25.0 C +1- 5.0 C under reduced pressure to 20 vol. CH3CN was added to 40 vol. and the solution concentrated at 25.0 C +I5.0 C to 20 vol. The addition of CH3CN and concentration was repeated 2 more times for a total of 3 additions of CH3CN and 4 concentrations to 20 vol. After the final concentration to 20 vol., 16.0 vol. of CH3CN was charged followed by 4.0 vol. of H2O to make a final concentration of 40 vol. of 10% H20/CH3CN relative toCompound A. This slurry was refluxed for 5 hours. The slurry was cooled to 20.0 C +1- 5 C and filtered. The cake was washed with CH3CN (5 vol.) 2 times. The resulting solid was dried in a vacuum oven at 50.0 C +I. 5.0 C until a constant weight is attained. | |
0.45 g | With methanol; sodium methylate; In 2-methyltetrahydrofuran; for 0.583333h; | Experimental procedure :( Continues process) Example 5: Synthesis of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-l,4- dihydroquinoline-3-carboxamide(4) and synthesis of ivacaftor: (0094) 5-(2-(lH-indol-3-yl)acetamido)-2,4-di-tert-butylphenyl methyl carbonate5 (0.75 g, 1.72 mmol) was dissolved in acetone: water (50 mL, 2: 1), and loaded in syringe. Pump is used to pump this solution in syringe to a Tee junction where other inlet of Tee junction was connected to ozone generator where stream of 03 was passed to the Tee junction at 0 C. Outlet of Tee junction was connected to the continuous flow reactor where reaction takes place. Outlet of the flow reactor is connected to 2-neck round bottom flask. Flow rate of substrate 5 (1.0 mL/min) and O3/O2(1000 mL/min) gas was kept to have 2 sec residence time for overall reaction. One neck is used to evacuate excesses 03 for quenching and from other neck product was transferred to the other round bottom flask under stirring where water (0.1 mL/min) and 2-MeTHF (1.0 mL) was pumped. The mixed solution was then pumped to the separating funnel for layer separation. 2-MeTHF layer was then pumped (0.4 mL/min) to another Tee junction where other inlet of Tee junction was connected to the syringe filled with DMF-DMA in 2-MeTHF (0.4mL/min; 10% v/v). Outlet of Tee connected to the continuous flow reactor to maintain the 40 min residence time. (0095) Outlet of the flow reactor is connected to other Tee junction, which is already connected to other inlet with sodium methoxide in methanol (0.3 mL/min; 2% w/v) solution and the next flow reactor to maintain the residence time of (35 min) and product was collected at the outlet of the flow reactor.The solution collected at outlet was washed with cold IN HC1 (3 mL X 2), brine solution (5 mL), dried over Na2S04 and evaporated to dryness. This crude material was subjected to purification by column chromatography (silica gel 230-400 mesh; 0.3:0.7: MeOH: DCM) to offer desired compound as of white solid (yield: 0.45g; 60%) |