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Chemical Structure| 1182822-31-6 Chemical Structure| 1182822-31-6

Structure of 1182822-31-6

Chemical Structure| 1182822-31-6

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Product Details of [ 1182822-31-6 ]

CAS No. :1182822-31-6
Formula : C16H25NO3
M.W : 279.37
SMILES Code : O=C(OC1=CC(N)=C(C(C)(C)C)C=C1C(C)(C)C)OC
MDL No. :MFCD21606649
InChI Key :NEMQZDZEKFZZJT-UHFFFAOYSA-N
Pubchem ID :46927778

Safety of [ 1182822-31-6 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H335
Precautionary Statements:P261-P280-P301+P312-P302+P352-P305+P351+P338

Application In Synthesis of [ 1182822-31-6 ]

* 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.

  • Downstream synthetic route of [ 1182822-31-6 ]

[ 1182822-31-6 ] Synthesis Path-Downstream   1~4

  • 1
  • [ 1182822-31-6 ]
  • [ 13721-01-2 ]
  • [ 1246213-45-5 ]
YieldReaction ConditionsOperation 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.

  • 2
  • [ 134271-94-6 ]
  • [ 1182822-31-6 ]
  • T3P [ No CAS ]
  • [ 13721-01-2 ]
  • [ 873054-44-5 ]
YieldReaction ConditionsOperation in experiment
With pyridine; hydrogenchloride; sodium methylate; In methanol; water; acetonitrile; An alternative synthesis of Compound 1 is depicted in Scheme 1-7.4-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 20° C.+/-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 and 2-MeTHF (16.5 vol) was charged to the reactor.This solution was charged with 30percent w/w NaOMe/MeOH (1.7 equiv) to perform the methanolysis.The reaction was stirred at 25.0° C.+/-5.0° C. for no less than 1.0 hour, and checked for completion by HPLC. Once complete, the reaction was quenched with 1.2 N HCl/H2O (10.0 vol), and washed with 0.1 N HCl/H2O (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 charged 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 20 to 25° C. over 5 hours, and filtered.The cake was washed with CH3CN (5 vol) heated to 20 to 25° C. 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; hydrogenchloride; sodium methylate; In methanol; water; acetonitrile; 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).
  • 3
  • [ 1182822-31-6 ]
  • [ 13721-01-2 ]
  • [ 873054-44-5 ]
YieldReaction ConditionsOperation in experiment
4-Oxo-l,4-dihydroqiiinoline-3-carboxylic acid (26) (1.0 eq) and 5-amino-2,4-di-tert- butylphenyl methyl carbonate (32) (L I eq) were charged to a reactor, 2- eTHF (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 addedNaOMe/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 45 °C (jacket temperature) and no less than 8.0 °C (internal reaction temperature) under reduced pressure to 20 vol, CCN 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 CCN 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 0 to make a final concentration of 40 vol of 10percent H?Q/CCN 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. H NMR (400 MHz, DMSO-rf6) delta 12.8 (s, lH), 1 1 ,8 (s, lH), 9.2 (s, I H), 8.9 (s, 1H), 8.3 (s, IH), 7.2 (s, 1H), 7.9 (t, IH), 7.8 (d, IH), 7.5 (t, lH), 7.1 (s, 1H), 1.4 (s, 9H), 1.4 (s, 9H).
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. 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 1N HCl (10.0 vol), and washed with 0.1N 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 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 (Ivacaftor) was dried in a vacuum oven at no more than 50.0° 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).
To a solution of 4-Oxo-1,4-dihydroquinoline-3-carboxylic acid (1.0 eq) in 2-Me THE added 5-amino-2,4-di-tert-, butylphenyl methyl carbonate (1.1 eq), Propane phosphonic acid anhydride 50percent solution in 2-MeTHF (1.7 eq) was added, followed by Pyridine (2.0 eq) and the resultant suspension was heated to 45° to 50° C., and held at this same temperature for 8 to 10 hours, until completion of the reaction (checked for completion by HPLC). Once complete, the resulting mixture was cooled to 20-25° C., and 2-MeTHF (12.5 vol) was added to dilute the mixture. The reaction mixture was then washed with water (10.0 vol)., and 2-MeTHF was added to bring the total volume of the reaction to 40.0 vol. To this solution was added NaOMe/MeOH (1.7 equiv) followed by stirring for 1 to 2 hour, where the reaction was 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 filtered and the filtrate concentrated at 35° C. to obtain a residue. The residue was charged in 40:20 acetonitrile and water, the slurry was stirred for 5 to 6 hours and then cooled to 0° C. hours, followed by stirring for 2 hours. The resultant solid was filtered and dried under vacuum to obtain a title compound.
 

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