Name: 873054-44-5|N-(2,4-Di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide|98%
Brand: Ambeed
SKU: A286566
Price: 6.0 USD
Availability: InStock
Rating: 94 (25 reviews)

1
[ 873055-58-4 ]
[ 873054-44-5 ]

Yield	Reaction Conditions	Operation in experiment
52%		N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide To a suspension of 4-oxo-1,4-dihydroquinolin-3-carboxylic acid (35.5 g, 188 mmol) and HBTU (85.7 g, 226 mmol) in DMF (280 mL) was added Et3N (63.0 mL, 451 mmol) at ambient temperature. The mixture became homogeneous and was allowed to stir for 10 min before 5-amino-2,4-di-tert-butyl-phenol (50.0 g, 226 mmol) was added in small portions. The mixture was allowed to stir overnight at ambient temperature. The mixture became heterogeneous over the course of the reaction. After all of the acid was consumed (LC-MS analysis, MH+ 190, 1.71 min), the solvent was removed in vacuo. EtOH was added to the orange solid material to produce a slurry. The mixture was stirred on a rotovap (bath temperature 65 C.) for 15 min without placing the system under vacuum. The mixture was filtered and the captured solid was washed with hexanes to provide a white solid that was the EtOH crystalate. Et2O was added to the material obtained above until a slurry was formed. The mixture was stirred on a rotovapor (bath temperature 25 C.) for 15 min without placing the system under vacuum. The mixture was filtered and the solid captured. This procedure was performed a total of five times. The solid obtained after the fifth precipitation was placed under vacuum overnight to provide 8 N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide as a white powdery solid (38 g, 52%). HPLC ret. time 3.45 min, 10-99% CH3CN, 5 min run; 1H NMR (400 MHz, DMSO-d6) delta 12.88 (s, 1H), 11.83 (s, 1H), 9.20 (s, 1H), 8.87 (s, 1H), 8.33 (dd, J=8.2, 1.0 Hz, 1H), 7.83-7.79 (m, 1H), 7.76 (d, J=7.7 Hz, 1H), 7.54-7.50 (m, 1H), 7.17 (s, 1H), 7.10 (s, 1H), 1.38 (s, 9H), 1.37 (s, 9H); ESI-MS 393.3 m/z [M+H]+. Set forth below is the characterizing data for Compound 1:

Reference： [1]Patent: US2008/90864,2008,A1 .Location in patent: Page/Page column 8; 9

3
[ 873054-44-5 ]
[ 108549-23-1 ]
C₃₈H₄₁N₂O₅P [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 1H-tetrazole; In dichloromethane; acetonitrile; at 20℃; for 2h;	Example 1 [5-[(4-oxo-1H-quinolin-3-yl)carbonylamino]-2,4-ditert-butyl-phenoxy]phosphonic acid dibenzyl ester Tetrazole (0.45 M solution in CH3CN, 1.24 mL, 0.56 mmol) was added to a mixture of N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (78 mg, 0.2 mmol) and dibenzyl diisopropylphosphoramidite (184 muL, 0.56 mmol) in dichloromethane (2 mL) and the reaction was stirred at room temperature for 2 h, then tert-butyl hydroperoxide (5.5M solution in decane, 102 muL, 0.56 mmol) was added and the reaction was stirred at room temperature overnight. The reaction mixture was then partitioned between ethyl acetate and saturated NaHCO3 solution. The organic layer was washed with brine, dried over MgSO4 and concentrated. The residue was adsorbed onto silica gel and purified by column chromatography (silica gel, 50-100% ethyl acetate-hexanes) to yield [5-[(4-oxo-1H-quinolin-3-yl)carbonylamino]-2,4-ditert-butyl-phenoxy]phosphonic acid dibenzyl ester as a clear oil (80 mg, 61%). 1H-NMR (400 MHz, d-DMSO) delta 13.04 (br s, 1H), 12.05 (s, 1H), 8.91 (s, 1H), 8.35 (dd, J=8.1, 1.0 Hz, 1H), 7.88 (s, 1H), 7.82 (m, 1H), 7.77 (d, J=7.7 Hz, 1H), 7.53 (m, 1H), 7.37-7.31 (m, 11H), 5.19 (m, 4H), 1.44 (s, 9H), 1.33 (s, 9H); HPLC ret. time 3.77 min, 30-99% CH3CN, 5 min run; ESI-MS 653.4 m/z [M+H]+.

Reference： [1]Patent: US2009/105272,2009,A1 .Location in patent: Page/Page column 19

4
[ 873054-44-5 ]
[ 1606-01-5 ]
[ 943316-05-0 ]

Yield	Reaction Conditions	Operation in experiment
		To a mixture of N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (3.92 g, 10 mmol), DMAP (8.54 g, 70 mmol) and diethylamino-acetic acid (2.62 g, 20 mmol) in dichloromethane (35 mL) was added N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (5.75 g, 30 mmol). The reaction was stirred at room temperature for 3 days. The reaction mixture was washed with water, dried over MgSO4 and concentrated. The residue was dissolved in DMSO and purified by reverse phase HPLC (10-99% CH3CH-H2O with 0.5% TFA) to yield the product as a TFA salt. A portion of this product (130 mg) was dissolved in dichloromethane and extracted with saturated NaHCO3 solution, dried over MgSO4 and concentrated to yield the freebase; 1H-NMR (400 MHz, d-DMSO) delta 12.93 (br s, 1H), 12.05 (s, 1H), 8.87 (s, 1H), 8.33 (dd, J=8.2, 1.1 Hz, 1H), 7.82 (m, 1H), 7.75 (d, J=7.8 Hz, 1H), 7.52 (m, 1H), 7.42 (s, 1H), 7.39 (s, 1H), 3.63 (s, 2H), 2.66 (q, J=7.1 Hz, 4H), 1.45 (s, 9H), 1.32 (s, 9H), 1.02 (t, J=7.1 Hz, 6H); HPLC ret. time 2.99 min, 10-99% CH3CN, 5 min run; ESI-MS 506.5 m/z (MH+). The freebase was then dissolved in diethyl ether and HCl solution (2M in diethyl ether, 2 equivalents) was added and the solution was concentrated to yield [5-[(4-oxo-1H-quinolin-3-yl)carbonylamino]-2,4-ditert-butyl-phenyl]2-diethylaminoacetate hydrochloride as a light pink solid. 1H-NMR (400 MHz, d-DMSO) delta 13.15 (d, J=6.8 Hz, 1H), 12.09 (s, 1H), 10.13 (s, 1H), 8.83 (d, J=6.8 Hz, 1H), 8.33 (d, J=7.6 Hz, 1H), 7.85-7.78 (m, 2H), 7.58 (s, 1H), 7.53 (m, 1H), 7.44 (s, 1H), 4.66 (m, 2H), 3.28 (m, 4H), 1.46 (s, 9H), 1.34 (s, 9H), 1.27 (t, J=7.3 Hz, 6H); HPLC ret. time 3.01 min, 10-99% CH3CN, 5 min run; ESI-MS 506.5 m/z [M+H]+.

Reference： [1]Patent: US2009/105272,2009,A1 .Location in patent: Page/Page column 21

5
[ 873054-44-5 ]
[ 67-63-0 ]
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide.2-propanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	at -5℃;	40-5Og of Compound 1 was dissolved in hot 2-propanol and cooled to -50C. The resulting slurry was aged overnight. The product was isolated by filtration after 1 hour to provide Form VIII.A sample of Form VIII was analyzed using a plurality of analytical techniques. Figures 29, 30, 31, and 32 respectively depict an experimental XRPD of Form VIII, a TGA trace of Form VIII, a DSC of Form VIII, and a DVS of Form VIII, each of which were obtained using the methods described above.

Reference： [1]Patent: WO2009/38683,2009,A2 .Location in patent: Page/Page column 49

6
[ 873054-44-5 ]
[ 79-31-2 ]
ivacaftor bis(isobutyric acid) solvate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	at 5 - 100℃;	5Og of Compound 1 was dissolved in hot Isobutyric acid 90-100 0C, cooled to 5 0C over several hours, and aged overnight. The resulting slurry was filtered and dried using a rotavap to provide Form V.A sample of Form V was analyzed using a plurality of analytical techniques. Figures 17, 18, 19, and 20 respectively depict an experimental XRPD of Form V, a TGA trace of Form V, a DSC of Form V, and a DVS of Form V, each of which were obtained using the methods described above.

Reference： [1]Patent: WO2009/38683,2009,A2 .Location in patent: Page/Page column 48

7
[ 116-53-0 ]
[ 873054-44-5 ]
[ 1134821-98-9 ]

Yield	Reaction Conditions	Operation in experiment
	at -5 - 110℃;	70g of Compound 1 is dissolved in 4500 ml of hot (1 10 C) 2 Methyl Butyric acid, the solution is then cooled to -5 0C and aged overnight. A sample of Form I was analyzed using a plurality of analytical techniques. Figures 1, 2, 3, and 4 respectively depict an experimental <n="48"/>XRPD of Form C, a TGA trace of Form C, a DSC of Form I, and a DVS of Form I, each of which were obtained using the methods described above.

Reference： [1]Patent: WO2009/38683,2009,A2 .Location in patent: Page/Page column 46; 47

8
[ 873054-44-5 ]
[ 57-55-6 ]
[ 1134821-99-0 ]

Yield	Reaction Conditions	Operation in experiment
	at -5 - 100℃; for 24h;Product distribution / selectivity;	Form II was prepared using the two methods described below.1. 54.58g of Compound 1 was dissolved in 4500 ml of propylene glycol at 100 0C. The solution was slow cooled to -5 0C over 24 hrs, and the solid was then filtered.2. 40g of Compound 1 dissolved in 4500 ml of propylene glycol at +85 0C, solution cooled to -5 0C and aged overnight. Solids filtered and washed with approximately 60 ml acetone to remove excess propylene glycol and then vacuum dried to remove excess acetone.A sample of Form II was analyzed using a plurality of analytical techniques. Figures 5, 6, 7, and 8 respectively depict an experimental XRPD of Form D, a TGA trace of Form II, a DSC of Form II, and a DVS of Form II, each of which were obtained using the methods described above.

Reference： [1]Patent: WO2009/38683,2009,A2 .Location in patent: Page/Page column 47

9
[ 873054-44-5 ]
[ 64-17-5 ]
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide.ethanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	at -5 - 80℃;	40-5Og Compound 1 was dissolved in ethanol at a temperature of from about 60 0C to about 80 0C, and the solution was then cooled to -5 0C and aged overnight. The product was isolated by filtration and vacuum dried at 400C for 1 hour to provide Form VII.A sample of Form VII was analyzed using a plurality of analytical techniques. Figures 25, 26, 27, and 28 respectively depict an experimental XRPD of Form VII, a TGA trace of Form VII, a DSC of Form VII, and a DVS of Form VII, each of which were obtained using the methods described above.

Reference： [1]Patent: WO2009/38683,2009,A2 .Location in patent: Page/Page column 48

10
[ 873054-44-5 ]
[ CAS Unavailable ]
[ CAS Unavailable ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
	In PVP at 85℃;	3.1 1. 510g PEG was heated to 75 0C, 30g of Potassium acetate was added and stirred to dissolution, and 12g of PVP slowly added and stirred to dissolution. 48g Compound 1 was added and stirred to dissolution with heating to 85 0C. The solution was then cooled to RT and 1 % w/w Compound 1 PEG/KOAc co-form added was as a seed. The mixture was aged overnight to provide Form III.
	In ethyl acetate; PVP at 20 - 80℃;	3.5 22.5g PEG, KOAc 1.36g, PVP 6g where heated until dissolution, approx 80 0C. 24g Compound 1 and 24Og EtOAc were then added and stirred until dissolution. The resulting solution was cooled to room temperature and aged overnight. 0.5g seed added at RT to provide form III.
	In ethyl acetate at 20 - 80℃;	3.2; 3.3; 3.4 2. PEG 22.91g and KOAc 8.70g were heated to +80C, 1Og of Compound 1 was added, 20.548g of EtOAc, and the system stirred at +85 0C. The system was then cooled to room temperature to provide Form III.3. PEG (3.10g), KOAc (0.6g), 2.5g Compound 1 and 9.25g EtOAc were slurried at 75 C for 4 hrs, then cooled to RT and aged overnight to provide Form III.4. 3.1g of PEG, 0.6g KOAc, 2.56g Compound 1 and 9.25g of EtOAc were slurried at ambient conditions overnight to provide Form III.

Reference： [1]Current Patent Assignee: VERTEX PHARMACEUTICALS (OLD) - WO2009/38683, 2009, A2 Location in patent: Page/Page column 47
[2]Current Patent Assignee: VERTEX PHARMACEUTICALS (OLD) - WO2009/38683, 2009, A2 Location in patent: Page/Page column 47
[3]Current Patent Assignee: VERTEX PHARMACEUTICALS (OLD) - WO2009/38683, 2009, A2 Location in patent: Page/Page column 47

11
[ 873054-44-5 ]
[ 849585-22-4 ]
[ 1134822-01-7 ]

Yield	Reaction Conditions	Operation in experiment
	In acetonitrile;	Compound 1, lOOmg, lactic acid 2ml, acetonitrile 120ml were heated to dissolve the mixture, slow evaporation of the solvent provided solids of Form IV.A sample of Form V was analyzed using a plurality of analytical techniques. Figures 13, 14, 15, and 16 respectively depict an experimental XRPD of Form IV, a TGA trace of Form IV, a DSC of Form IV, and a DVS of Form IV, each of which were obtained using the methods described above.

Reference： [1]Patent: WO2009/38683,2009,A2 .Location in patent: Page/Page column 47; 48

12
[ 873054-44-5 ]
[ 802294-64-0 ]
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide.propionic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	at -5 - 65℃;	4Og of Compound 1 was dissolved in 4000 ml of propionic acid at 65 0C, the resulting solution was cooled to -5 0C and aged overnight. The resulting solid was vacuum filtered to dryness to provide Form VI.A sample of Form VI was analyzed using a plurality of analytical techniques. Figures 21, 22, 23, and 24 respectively depict an experimental XRPD of Form VI, a TGA trace of Form VI, a DSC of Form VI, and a DVS of Form VI, each of which were obtained using the methods described above.

Reference： [1]Patent: WO2009/38683,2009,A2 .Location in patent: Page/Page column 48

13
[ 873054-44-5 ]
[ 1134822-07-3 ]

Yield	Reaction Conditions	Operation in experiment
	With water; at 20℃; for 2h;	An excess of amorphous Compound 1 was added to water to form a suspension and the suspension was stirred for two hours at room temperature. The solid was separated from the liquid and dried at room temperature to provide Form IX.A sample of Form IX was analyzed using a plurality of analytical techniques. Figures 33, 34, and 35, respectively depict an experimental XRPD of Form IX, a TGA trace of Form IX, a DSC of form IX, each of which were obtained using the methods described above.

Reference： [1]Patent: WO2009/38683,2009,A2 .Location in patent: Page/Page column 49

14
[ 873054-44-5 ]
[ 98-11-3 ]
[ 1134822-09-5 ]

Yield	Reaction Conditions	Operation in experiment
	In Isopropyl acetate; at 20 - 32.5℃; for 23 - 24h;Product distribution / selectivity;	10.0 g of Compound 1 and 70 ml isopropyl acetate were charged into a reactor. 5.25 g anhydrous benzenesulfonic acid was dissolved into 30 ml of isopropyl acetate using a 2nd reactor. The solution of benzenesulfonic acid was charged into the slurry of Compound 1. The resulting slurry was stirred at room temperature for 23 hrs and isolated by filtration. The cake was washed with isopropyl acetate and dried in a vacuum oven at 45 C +/- 5 0C to provide Form X.A sample of Form X was analyzed using a plurality of analytical techniques. Figures 36 and 37 depict an experimental XRPD of Form X and a DSC of Form X. The XRPD was recorded on a Corundum calibrated Bruker D8 Advance diffractometer with a Vantac line detector. The 2 Theta range was approximately 2 degrees to 40 degrees, with a step size of 0.014 degrees. The time per step was approximately 105 milliseconds. Cu Ka seal tube radiation was used at 40 kV, 4OmA under ambient conditions.; Compound 1 was added to reactor A with 10 vol of isopropyl acetate. In a separate reactor, benzenesulfonic acid monohydrate (0.95 eq based on anhydrous Benzenesulfonic acid) was dissolved with 10 vol of isopropyl acetate. The benzenesulfonic acid solution was <n="52"/>then added to reactor A. The resulting slurry was heated to 30 0C +/- 2.5 0C and stirred for 24 h. The mixture was cooled to 20.0 0C +/- 50C, the solids filtered and washed with 5 vol isopropyl acetate. The washed solids were dried at 30 0C in a fluidized bed with N2 bleed to provide Form XIII.A sample of Form XIII was analyzed using a plurality of analytical techniques. Figures 43-45 depict an experimental XRPD of Form XIII, a DSC of Form XIII and a TGA of Form XIII, respectively. The XRPD was recorded on a Corundum calibrated Bruker D8 Advance diffractometer with Vantac line detector. The 2 Theta range was approximately 2 degrees to 40 degrees, with a step size of 0.014 degrees. The time per step was approximately 105 milliseconds. Cu Ka seal tube radiation was used at 40 kV, 4OmA under ambient conditions. The TGA was recorded as described above except that data was recorded out to 35O0C.; Form XV 4.94 g of Compound 1 and 24.7 ml isopropyl acetate were charged to reactor A. 1.195 g (0.6 eq) benzenesulfonic acid hydrate and 24.7 ml isopropyl acetate was charged to reactor B. Reactor B contents were charged to reactor A at ambient temperature. The resulting slurry was stirred at room temperature for 23 hrs followed by <n="53"/>filtration and a wash with isopropyl acetate. The cake was dried in a vacuum oven to provide Form XV.A sample of Form XV was analyzed using a plurality of analytical techniques. Figure 49 depicts an experimental XRPD of Form XV. The XRPD was recorded on a Corundum calibrated Bruker D8 Advance diffractometer with Vantac line detector. The 2 Theta range was approximately 2 degrees to 40 degrees, with a step size of 0.014 degrees. The time per step was approximately 105 milliseconds. Cu Ka seal tube radiation was used at 40 kV, 4OmA under ambient conditions.
	In toluene; at 82.5 - 87.5℃; for 18h;Product distribution / selectivity;	43.6 g of Benzenesulfonic acid monohydrate was charged into reactor A. 2.00 L of Toluene (20.0 vol) was added to reactor A. The resulting mixture was heated to reflux, and concentrated to '/z volume (1.00 L). The concentrated mixture was cooled to 75C +/- 2.5 0C, followed by the addition of 1.00 L Toluene (10.0 vol). This mixture was cooled to 40C +/- 2.5 C. 100 g of Compound 1 (1.0 eq) was added to reactor B followed by the addition of the Benzenesulfonic acid / Toluene solution from reactor A. The resulting slurry was heated to 85C +/- 2.5C and stirred for a total of 18 hours at 85C +/- 2.5C. The slurry was cooled to 20.0 0C +/- 5 0C, solids were filtered, and washed with Toluene (1.00 L, 10 vol). The material was dried in a vacuum oven at 45 C +/- 5 0C to provide Form XII.A sample of Form XII was analyzed using a plurality of analytical techniques. Figures 40-42 depict an experimental XRPD of Form XII, a DSC of Form XII and a TGA of Form XII, respectively. The XRPD was recorded on a Corundum calibrated Bruker D8 Advance diffractometer with Vantac line detector. The 2 Theta range was approximately 2 degrees to 40 degrees, with a step size of 0.014 degrees. The time per step was approximately 105 milliseconds. Cu Ka seal tube radiation was used at 40 kV, 4OmA under ambient conditions. The TGA was recorded as described above except that data was recorded out to 35O0C.
	In acetonitrile; at 60℃; for 3h;Product distribution / selectivity;	12.1 g of anhydrous Benzenesulfonic acid and 24.92 g Compound 1 was charged into reactor. 250 ml Acetonitrile was added. The resulting slurry was heated to 60C for 3 hrs. This mixture was cooled to room temperature. The slurry was filtered, and washed with <n="51"/>acetonitrile. The material was re-suspended in the filtrate, and heated to 85C for 2 hrs, then cooled to room temperature and isolated by filtration. The wet cake was again re-suspended in 250 ml acetonitrile this time, and 12.0 g anhydrous benzenesulfonic acid was charged into the reactor. The resulting slurry was heated to 60C for 4 hrs followed by cooling to 40C for 2 hrs and then cooling to room temperature, and isolated by filtration. The cake was washed with acetonitrile and dried in a vacuum oven at 45 0C +/- 5 0C to provide Form XI.A sample of Form XI was analyzed using a plurality of analytical techniques. Figures 38 and 39 depict an experimental XRPD of Form XI and a DSC of Form XI, respectively. The XRPD was recorded on a Corundum calibrated Bruker D8 Advance diffractometer with Vantac line detector. The 2 Theta range was approximately 2 degrees to 40 degrees, with a step size of 0.014 degrees. The time per step was approximately 105 milliseconds. Cu Ka seal tube radiation was used at 40 kV, 4OmA under ambient conditions.

In 2-methyltetrahydrofuran; Isopropyl acetate;Heating / reflux;Product distribution / selectivity;

15.0 g of Compound 1 and 120 ml 2-methyltetrahydrofuran were charged to reactorA. 7.25 g benzenesulfonic acid hydrate and 180 ml isopropyl acetate was charged to reactorB. Reactor B contents were dried via azeotrope (solvent swap with fresh isopropyl acetate) twice to provide a dry solution of benzenesulfonic acid in isopropyl actete. Reactor B contents were charged into reactor A at ambient temperature. The resulting slurry was heated to reflux (homogeneous solution attained), and then cooled immediately to ambient temperature to afford a slurry. The slurry was concentrated under reduced pressure to Vi volume, followed by addition of isopropyl acetate to achieve the original volume. The concentration and suspension in isopropyl acetate was repeated followed by concentration to Vi volume, filtration, and a washed with isopropyl acetate. The cake was dried in a vacuum oven at 50 C to provide Form XIV.A sample of Form XIV was analyzed using a plurality of analytical techniques. Figures 47 and 48 depict an experimental XRPD of Form XIV and a DSC of Form XIV, respectively. The XRPD was recorded on a Corundum calibrated Bruker D8 Advance diffractometer with Vantac line detector. The 2 Theta range was approximately 2 degrees to 40 degrees, with a step size of 0.014 degrees. The time per step was approximately 105 milliseconds. Cu Ka seal tube radiation was used at 40 kV, 4OmA under ambient conditions.

Reference： [1]Patent: WO2009/38683,2009,A2 .Location in patent: Page/Page column 49; 50; 51; 52
[2]Patent: WO2009/38683,2009,A2 .Location in patent: Page/Page column 50
[3]Patent: WO2009/38683,2009,A2 .Location in patent: Page/Page column 49; 50
[4]Patent: WO2009/38683,2009,A2 .Location in patent: Page/Page column 51

15
[ 873054-44-5 ]
[ 98-11-3 ]
N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide.besylate.H₂O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With water; In Isopropyl acetate; at 20℃; for 18h;Product distribution / selectivity;	Form XVI 13.15 g of Compound l«besylate and 98.6 ml ethyl acetate were charged to reactor A. 21.04 g benzenesulfonic acid hydrate and 98.6 ml isopropyl acetate was charged to reactor B. Reactor B contents were charged to reactor A at ambient temperature. The resulting slurry was stirred at room temperature for 18 hrs followed by filtration and a wash with isopropyl acetate. The cake was dried in a vacuum oven at 35 0C to provide Form XVI.A sample of Form XVI was analyzed using a plurality of analytical techniques. Figures 50-52 respectively depict an experimental XRPD of Form XVI, a TGA trace of Form XVI, a DSC of Form XVI, and a DVS of Form XVI, each of which were obtained using the methods described above. The XRPD was recorded on a Corundum calibrated Bruker D8 Advance diffractometer with Vantac line detector. The 2 Theta range was approximately 3 degrees to 41 degrees, with a step size of 0.014 degrees. The time per step was approximately 105 milliseconds. Cu Ka seal tube radiation was used at 40 kV, 35mA under ambient conditions. The TGA was recorded as described above except that data was recorded out to 35O0C.

Reference： [1]Patent: WO2009/38683,2009,A2 .Location in patent: Page/Page column 52

16
[ 873054-44-5 ]
[ 1246213-23-9 ]
[ 1246213-24-0 ]

Yield	Reaction Conditions	Operation in experiment
	With Streptomyces rimosus (DSM 40260); In N,N-dimethyl-formamide; at 30℃; for 24h;pH 7.0;potassium phosphate buffer; Enzymatic reaction;	Streptomyces rimosus (DSM 40260) was purchased from DSMZ as frozen culture. This culture was used to inoculate agar slants, which were maintained and stored at 4 0C. Yeast extract-malt extract-peptone (YMP) media containing yeast extract (4 g/L), malt extract (10 g/L) and soya flour (5 g/L) was prepared and sterilized at 130 0C for 60 minutes. Five flasks containing 1 L of YMP media were directly inoculated with S. rimosus from the agar slants. The culture was allowed to grow for 2 - 3 days at 30 0C with gentle agitation of approximately 100 rpm. Under these conditions, two growth types have been observed, either a cloudy solution or spherical particulates which aggregate at the bottom of the flask. The latter growth type has been shown to result in higher conversions to Compound 27. The cells were then spun down, harvested and resuspended in two flasks containing 1 L of 0.1 M potassium phosphate buffer, pH 7.0. 5.0 g of Compound 34 in 50 mL N1N- dimethylformamide (DMF) were added to the flasks. The reactions proceeded for 24 hours at 30 0C with gentle agitation of about 100 rpm at which point conversions of 7.59% Compound 27 and 1.17% Compound 28 were indicated by HPLC.[0232] Both flasks were combined, centrifuged at 3500 rpm for 10 minutes, and re- suspended in 500 mL of methanol. This suspension was stirred vigorously for 30 minutes and then spun down again at 6000 rpm for 10 minutes. The organic layer was collected and the process was repeated two times. The methanol extracts were concentrated in vacuo to yield 2.50 g, 1.57 g and 1.11 g of solid material, respectively. The solids from these extracts were shown to contain 74.78 - 91.96% Compound 34, 7.66 - 19.73% Compound 27 and 0.39 - 5.49% Compound 28. In an effort to cull off a portion of Compound 34 from the bio- oxidation products, the solids from the first two extractions were combined, suspended in 250 mL methanol, agitated vigorously for 1 hour and vacuum filtered. While Compounds 27 and 28 were enriched in the filtrate (22.09 and 6.14%, respectively), the solids still also contained Compound 27 (8.96%) and Compound 28 (0.50%).[0233] The methanol filtrate containing approximately 2.2 g of dissolved solids was adsorbed onto 4.5 g of silica and purified by flash chromatography using a gradient of 100% dichloromethane to 88:12 dichloromethane/methanol. Fractions containing Compound 27 were concentrated in vacuo and further dried via freeze-drying to obtain 130 mg of Compound 27 (98.5% purity by HPLC). A fraction containing impure Compound 28 was also concentrated in vacuo to yield less than 10 mg of solid.[0234] The cell pellet was re-suspended in 500 mL methanol and homogenized in a BeadBeater to break apart the cells and recover any remaining product. The organic layer was obtained by centrifuging the homogenized suspension at 6000 rpm for 10 minutes. This was added to the solid obtained from the third extraction and the filtered solids from the slurry enrichment of the first two extractions and slurried at reflux overnight. The slurry was then cooled and suction filtered to obtain 1.99 g of solid. The solid was re-dissolved in 300 mL methanol which was then adsorbed onto approximately 5 g of silica and purified by flash chromatography using a gradient of 100% dichloromethane to 94:6 dichloromethane/methanol to provide 820 mg of solid containing Compound 34 and Compound 27 as well as other impurities. This was re-columned using a more gradual solvent gradient (100% DCM up to a mixture of 6% MeOH/94% DCM) to obtain an additional 89 mg of Compound 27. The 1H-NMR spectrum was consistent with that reported above.
	With Streptomyces rimosus (DSM 40260); In N,N-dimethyl-formamide; at 30℃; for 24h;pH 7.0;Enzymatic reaction; Aqueous phosphate buffer;	Streptomyces rimosus (DSM 40260) was purchased from DSMZ as frozen culture. This culture was used to inoculate agar slants, which were maintained and stored at 4 0C. Yeast extract-malt extract-peptone (YMP) media containing yeast extract (4 g/L), malt extract (10 g/L) and soya flour (5 g/L) was prepared and sterilized at 130 0C for 60 minutes. Five flasks containing 1 L of YMP media were directly inoculated with S. rimosus from the agar slants. The culture was allowed to grow for 2 - 3 days at 30 C with gentle agitation of approximately 100 rpm. Under these conditions, two growth types have been observed, either a cloudy solution or spherical particulates which aggregate at the bottom of the flask. The latter growth type has been shown to result in higher conversions to Compound 27. The cells were then spun down, harvested and resuspended in two flasks containing 1 L of 0.1 M potassium phosphate buffer, pH 7.0. 5.0 g of Compound 34 in 50 mL N,N- dimethylformamide (DMF) were added to the flasks. The reactions proceeded for 24 hours at 30 0C with gentle agitation of about 100 rpm at which point conversions of 7.59% Compound 27 and 1.17% Compound 28 were indicated by HPLC.[00369] Both flasks were combined, centrifuged at 3500 rpm for 10 minutes, and re- suspended in 500 mL of methanol. This suspension was stirred vigorously for 30 minutes and then spun down again at 6000 rpm for 10 minutes. The organic layer was collected and the process was repeated two times. The methanol extracts were concentrated in vacuo to yield 2.50 g, 1.57 g and 1.11 g of solid material, respectively. The solids from these extracts were shown to contain 74.78 - 91.96% Compound 34, 7.66 - 19.73% Compound 27 and 0.39 - 5.49% Compound 28. In an effort to cull off a portion of Compound 34 from the bio- oxidation products, the solids from the first two extractions were combined, suspended in 250 mL methanol, agitated vigorously for 1 hour and vacuum filtered. While Compounds 27 and 28 were enriched in the filtrate (22.09 and 6.14%, respectively), the solids still also contained Compound 27 (8.96%) and Compound 28 (0.50%).[00370] The methanol filtrate containing approximately 2.2 g of dissolved solids was adsorbent onto 4.5 g of silica and purified by flash chromatography using a gradient of 100% dichloromethane to 88:12 dichloromethane/methanol. Fractions containing Compound 27 were concentrated in vacuo and further dried via freeze-drying to obtain 130 mg of Compound 27 (98.5% purity by HPLC). A fraction containing impure Compound 28 was also concentrated in vacuo to yield less than 10 mg of solid.[00371] The cell pellet was re-suspended in 500 mL methanol and homogenized in a BeadBeater to break apart the cells and recover any remaining product. The organic layer was obtained by centrifuging the homogenized suspension at 6000 rpm for 10 minutes. This was added to the solid obtained from the third extraction and the filtered solids from the slurry enrichment of the first two extractions and slurried at reflux overnight. The slurry was then cooled and suction filtered to obtain 1.99 g of solid. The solid was re-dissolved in 300 mL methanol which was then adsorbed onto approximately 5 g of silica and purified by flash chromatography using a gradient of 100% dichloromethane to 94:6 dichloromethane/methanol to provide 820 mg of solid containing Compound 34 and Compound 27 as well as other impurities. This was re-columned using a more gradual solvent gradient (100% DCM up to a mixture of 6% MeOH/94% DCM) to obtain an additional 89 mg of Compound 27. The 1H-NMR spectrum was consistent with that reported above.

Reference： [1]Patent: WO2010/108155,2010,A1 .Location in patent: Page/Page column 56-57
[2]Patent: WO2010/108162,2010,A1 .Location in patent: Page/Page column 91-93

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In 2-methyltetrahydrofuran; Isopropyl acetate; water; at 0℃;Reflux;Purification / work up;	Compound 34 (1.0 eq) was charged to a reactor. 2-MeTHF (20.0 vol) was added followed by 0.1N HCl (5.0 vol). The biphasic solution was stirred and separated and the top organic phase was washed twice more with 0.1 N HCl (5.0 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 0C (jacket temperature) and no more than 8.0 C (internal reaction temperature) under reduced pressure to 10 vol. Isopropyl acetate (IPAc) (10 vol) was added and the solution concentrated at no more than 350C (jacket temperature) and no more than 8.00C (internal reaction temperature) to 10 vol. The addition of IPAc and concentration was repeated 2 more times for a total of 3 additions of IPAc and 4 concentrations to 10 vol. After the final concentration, 10 vol of IPAc was charged and the slurry was heated to reflux and maintained at this temperature for 5 hours. The slurry was cooled to 0.00C +/- 50C over 5 hours and filtered. The cake was washed with IPAc (5 vol) once. The resulting solid was dried in a vacuum oven at 50.0 0C +/- 5.0 0C.
	With hydrogenchloride; In 2-methyltetrahydrofuran; water;Purification / work up;	Example 3Procedure for the recrystallization of <strong>[873054-44-5]N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide</strong> (1) Compound 1 (1.0 eq) was charged to a reactor. 2-MeTHF (20.0 vol) was added followed by 0.1 N HCl (5.0 vol). The biphasic solution was stirred and separated and the top organic phase was washed twice more with 0.1 N HCl (5.0 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 more than 8.0 C. (internal reaction temperature) under reduced pressure to 10 vol. Isopropyl acetate (IPAc) (10 vol) was added and the solution concentrated at no more than 35 C. (jacket temperature) and no more than 8.0 C. (internal reaction temperature) to 10 vol. The addition of IPAc and concentration was repeated 2 more times for a total of 3 additions of IPAc and 4 concentrations to 10 vol. After the final concentration, 10 vol of IPAc was charged and the slurry was heated to reflux and maintained at this temperature for 5 hours. The slurry was cooled to 0.0 C.+/-5 C. over 5 hours and filtered. The cake was washed with IPAc (5 vol) once. The resulting solid was dried in a vacuum oven at 50.0 C.+/-5.0 C.

18
[ 1246213-45-5 ]
[ 873054-44-5 ]

Yield	Reaction Conditions	Operation in experiment
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%)

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[16]Journal of Organic Chemistry,2020

19
[ 134271-94-6 ]
[ 1182822-31-6 ]
T₃P [ No CAS ]
[ 13721-01-2 ]
[ 873054-44-5 ]

Yield	Reaction Conditions	Operation 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).

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20
[ 62-53-3 ]
[ 873054-44-5 ]

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[3]Patent: WO2013/185112,2013,A1
[4]Patent: WO2014/71122,2014,A1
[5]Patent: WO2014/118805,2014,A1
[6]Patent: WO2015/73231,2015,A1
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21
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[ 873054-44-5 ]

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[3]Patent: WO2013/185112,2013,A1
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[25]Journal of Organic Chemistry,2020

22
[ 54535-22-7 ]
[ 873054-44-5 ]

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[2]Patent: WO2013/67410,2013,A1
[3]Patent: WO2014/71122,2014,A1
[4]Patent: WO2014/118805,2014,A1
[5]Patent: WO2015/73231,2015,A1
[6]Patent: US2015/231142,2015,A1
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23
[ 52980-28-6 ]
[ 873054-44-5 ]

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24
[ 873055-55-1 ]
[ 873054-44-5 ]

Reference： [1]Patent: US2011/230519,2011,A1
[2]Patent: WO2013/67410,2013,A1
[3]Patent: WO2014/71122,2014,A1
[4]Patent: WO2014/118805,2014,A1
[5]Journal of Medicinal Chemistry,2014,vol. 57,p. 9776 - 9795
[6]Patent: WO2015/73231,2015,A1
[7]Patent: US2015/231142,2015,A1
[8]Patent: WO2007/79139,2007,A2
[9]Patent: WO2017/37672,2017,A1
[10]Patent: WO2017/37672,2017,A1
[11]Patent: US2011/98311,2011,A1
[12]Journal of Organic Chemistry,2020

25
[ 873055-54-0 ]
[ 873054-44-5 ]

Reference： [1]Patent: US2011/230519,2011,A1
[2]Patent: WO2013/67410,2013,A1
[3]Patent: WO2013/185112,2013,A1
[4]Patent: WO2014/71122,2014,A1
[5]Patent: US2014/221424,2014,A1
[6]Journal of Medicinal Chemistry,2014,vol. 57,p. 9776 - 9795
[7]Patent: WO2015/73231,2015,A1
[8]Patent: US2015/231142,2015,A1
[9]Patent: US2011/98311,2011,A1
[10]Patent: US2011/98311,2011,A1
[11]Patent: WO2018/64632,2018,A1
[12]Patent: WO2018/107100,2018,A1
[13]Patent: US2018/280349,2018,A1
[14]Patent: WO2019/10092,2019,A1
[15]Patent: WO2019/18395,2019,A1
[16]Patent: WO2019/18353,2019,A1
[17]Patent: US2019/119253,2019,A1
[18]Patent: WO2019/113089,2019,A1
[19]Patent: WO2018/227049,2018,A1
[20]Patent: US2019/240197,2019,A1
[21]Patent: WO2019/191620,2019,A1
[22]Journal of Organic Chemistry,2020

26
[ 1182822-31-6 ]
[ 13721-01-2 ]
[ 873054-44-5 ]

Yield	Reaction Conditions	Operation 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.

Reference： [1]Patent: WO2013/185112,2013,A1 .Location in patent: Paragraph 00545; 00546
[2]Patent: WO2014/71122,2014,A1
[3]Patent: US2014/221424,2014,A1 .Location in patent: Paragraph 0086
[4]Patent: EP2815749,2014,A1
[5]Patent: WO2015/73231,2015,A1
[6]Patent: US2015/231142,2015,A1
[7]Patent: US2017/96397,2017,A1 .Location in patent: Paragraph 0095

27
[ 610-14-0 ]
[ 873054-44-5 ]

Reference： [1]Heterocycles,2014,vol. 89,p. 1035 - 1040

28
[ 106718-56-3 ]
[ 873054-44-5 ]

Reference： [1]Heterocycles,2014,vol. 89,p. 1035 - 1040

29
[ 52119-39-8 ]
[ 873054-44-5 ]

Reference： [1]Heterocycles,2014,vol. 89,p. 1035 - 1040
[2]Journal of Heterocyclic Chemistry,2017,vol. 54,p. 3169 - 3173

30
2,4-di-tert-butyl-5-(3-(2-nitrophenyl)-3-oxopropanamido)phenyl methyl carbonate [ No CAS ]
[ 873054-44-5 ]

Reference： [1]Heterocycles,2014,vol. 89,p. 1035 - 1040

31
[ 873055-57-3 ]
[ 873054-44-5 ]

Reference： [1]Patent: WO2014/118805,2014,A1
[2]Journal of Medicinal Chemistry,2014,vol. 57,p. 9776 - 9795
[3]Patent: WO2007/79139,2007,A2
[4]Patent: CN103787968,2016,B
[5]Patent: WO2017/37672,2017,A1
[6]Patent: WO2017/37672,2017,A1
[7]Patent: WO2018/64632,2018,A1
[8]Patent: US2017/96397,2017,A1
[9]Patent: WO2018/107100,2018,A1
[10]Patent: US2018/280349,2018,A1
[11]Patent: WO2019/18353,2019,A1
[12]Patent: US2019/119253,2019,A1
[13]Patent: WO2019/113089,2019,A1
[14]Patent: WO2018/227049,2018,A1
[15]Patent: US2019/240197,2019,A1
[16]Patent: WO2019/191620,2019,A1

32
[ 873055-58-4 ]
[ 13721-01-2 ]
[ 873054-44-5 ]

Yield	Reaction Conditions	Operation in experiment
52%		[0231] To a suspension of 4-oxo-l,4-dihydroquinolin-3-carboxylic acid (35.5 g, 188 mmol) and HBTU (85.7 g, 226 mmol) in DMF (280 mL) was added Et3N (63.0 mL, 451 mmol) at ambient temperature. The mixture became homogeneous and was allowed to stir for 10 min before 5-amino-2,4-di-fert-butyl-phenol (50.0 g, 226 mmol) was added in small portions. The mixture was allowed to stir overnight at ambient temperature. The mixture became heterogeneous over the course of the reaction. After all of the acid was consumed (LC-MS analysis, MH+ 190, 1.71 min), the solvent was removed in vacuo. EtOH was added to the orange solid material to produce a slurry. The mixture was stirred on a rotovap (bath temperature 65 0C) for 15 min without placing the system under vacuum. The mixture was filtered and the captured solid was washed with hexanes to provide a white solid that was the EtOH crystalate. Et2theta was added to the material obtained above until a slurry was formed. The mixture was stirred on a rotovapor (bath temperature 25 0C) for 15 min without placing the system under vacuum. The mixture was filtered and the solid captured. This procedure was performed a total of five times. The solid obtained after the fifth precipitation was placed under vacuum overnight to provide 8 N-[2,4-bis(l,l-dimethylethyl)-5-hydroxyphenyl]-l,4- dihydro-4-oxoquinoline-3-carboxamide as a white powdery solid (38 g, 52%).[0232] HPLC ret. time 3.45 min, 10-99% CH3CN, 5 min run; 1H NMR (400 MHz, DMSO-4) delta 12.88 (s, IH), 11.83 (s, IH), 9.20 (s, IH), 8.87 (s, IH), 8.33 (dd, J = 8.2, 1.0 Hz, <n="52"/>IH), 7.83-7.79 (m, IH), 7.76 (d, J = 7.7 Hz, IH), 7.54-7.50 (m, IH), 7.17 (s, IH), 7.10 (s, IH), 1.38 (s, 9H), 1.37 (s, 9H); ESI-MS 393.3 m/z [M+H]+.
52%		To a suspension of 4-oxo-l,4-dihydroquinolin-3-carboxylic acid (35.5 g, 188 mmol) and HBTU (85.7 g, 226 mmol) in DMF (280 mL) was added Et3N (63.0 mL, 451 mmol) at ambient temperature. The mixture became homogeneous and was allowed to stir for 10 min before 5-amino-2,4-di-tert-butyl-phenol (50.0 g, 226 mmol) was added in small portions. The mixture was allowed to stir overnight at ambient temperature. The mixture became heterogeneous over the course of the reaction. After all of the acid was consumed (LC-MS analysis, MH+ 190, 1.71 min), the solvent was removed in vacuo. EtOH (ethyl alcohol) was added to the orange solid material to produce a slurry. The mixture was stirred on a rotovap (bath temperature 65 C) for 15 min without placing the system under vacuum. The mixture was filtered and the captured solid was washed with hexanes to provide a white solid that was the EtOH crystalate. Et20 (diethyl ether) was added to the solid obtained above until a slurry was formed. The mixture was stirred on a rotovapor (bath temperature 25 C) for 15 min without placing the system under vacuum. The mixture was filtered and the solid captured. This procedure was performed a total of five times. The solid obtained after the fifth precipitation was placed under vacuum overnight to provide N-(5-hydroxy-2,4-di-tert-butyl-phenyl)-4-oxo-lH-quinoline-3-carboxamide (38 g, 52%). HPLC ret. time 3.45 min, 10-99% CH3CN, 5 min run; 1H NMR (400 MHz, DMSO-d6) delta 12.88 (s, 1H), 11.83 (s, 1H), 9.20 (s, 1H), 8.87 (s, 1H), 8.33 (dd, J = 8.2, 1.0 Hz, 1H), 7.83-7.79 (m, 1H), 7.76 (d, J = 7.7 Hz, 1H), 7.54-7.50 (m, 1H), 7.17 (s, 1H), 7.10 (s, 1H), 1.38 (s, 9H), 1.37 (s, 9H); ESI-MS m/z calc'd 392.21; found 393.3 [M+H]+.
52%		To a suspension of 4-oxo-1,4-dihydroquinolin-3-carboxylic acid (35.5 g, 188 mmol) and HBTU (85.7 g, 226 mmol) in DMF (280 mL) was added Et3N (63.0 mL, 451 mmol) at ambient temperature. The mixture became homogeneous and was allowed to stir for 10 min before 5-amino-2,4-di-tert-butyl-phenol (50.0 g, 226 mmol) was added in small portions. The mixture was allowed to stir overnight at ambient temperature. The mixture became heterogeneous over the course of the reaction. After all of the acid was consumed (LC-MS analysis, MH+ 190, 1.71 min), the solvent was removed in vacuo. EtOH (ethyl alcohol) was added to the orange solid material to produce a slurry. The mixture was stirred on a rotovap (bath temperature 65 C) for 15 min without placing the system under vacuum. The mixture was filtered and the captured solid was washed with hexanes to provide a white solid that was the EtOH crystalate. Et2O (diethyl ether) was added to the solid obtained above until a slurry was formed. The mixture was stirred on a rotovapor (bath temperature 25 C) for 15 min without placing the system under vacuum. The mixture was filtered and the solid captured. This procedure was performed a total of five times. The solid obtained after the fifth precipitation was placed under vacuum overnight to provide N-(5-hydroxy-2,4-di-tert- butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (38 g, 52%). HPLC ret. time 3.45 min, 10-99% CH3CN, 5 min run;1H NMR (400 MHz, DMSO-d6) delta 12.88 (s, 1H), 11.83 (s, 1H), 9.20 (s, 1H), 8.87 (s, 1H), 8.33 (dd, J = 8.2, 1.0 Hz, 1H), 7.83-7.79 (m, 1H), 7.76 (d, J = 7.7 Hz, 1H), 7.54-7.50 (m, 1H), 7.17 (s, 1H), 7.10 (s, 1H), 1.38 (s, 9H), 1.37 (s, 9H); ESI-MS m/z calc?d 392.21; found 393.3 [M+H]+.

52%		Step E: N-(5-hydroxy-2,4-di-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide To a suspension of 4-oxo-1,4-dihydroquinolin-3-carboxylic acid (35.5 g, 188 mmol) and HBTU (85.7 g, 226 mmol) in DMF (2.80 mL) was added Et3N (63.0 mL, 451 mmol) at ambient temperature. The mixture became homogeneous and was allowed to stir for 10 min before 5-amino-2,4-di-tert-butyl-phenol (50.0 g, 226 mmol) was added in small portions. The mixture was allowed to stir overnight at ambient temperature. The mixture became heterogeneous over the course of the reaction. After all of the acid was consumed (LC-MS analysis, MH+ 190, 1.71 min), the solvent was removed in vacuo. EtOH was added to the orange solid material to produce a slurry. The mixture was stirred on a rotovap (bath temperature 65 C.) for 15 min without placing the system under vacuum. The mixture was filtered and the captured solid was washed with hexanes to provide a white solid that was the EtOH crystalate. Et2O was added to the solid obtained above until a slurry was formed. The mixture was stirred on a rotovapor (bath temperature 25 C.) for 15 min without placing the system under vacuum. The mixture was filtered and the solid captured. This procedure was performed a total of five times. The solid obtained after the fifth precipitation was placed under vacuum overnight to provide 1-(5-hydroxy-2,4-di-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide as a white powdery solid (38 g, 52%). HPLC ret. time 3.45 min, 10-99% CH3CN, 5 min run; 1H NMR (400 MHz, DMSO-d6) delta 12.88 (s, 1H), 11.83 (s, 1H), 9.20 (s, 1H), 8.87 (s, 1H), 8.33 (dd, J=8.2, 1.0 Hz, 1H), 7.83-7.79 (m. 1H), 7.76 (d, J=7.7 Hz, 1H), 7.54-7.50 (m, 1H), 7.17 (s, 1H), 7.10 (s, 1H), 1.38 (s, 9H), 1.37 (s, 9H) ppm; ESI-MS m/z calc'd 392.21; toured 393.3 [M+H]+.
52%		1003431 To a suspension of 4-oxo-1,4-dihydroquinolin-3-carboxylic acid (35.5 g, 188 mmol) and HBTU (85.7 g, 226 mmol) in DMF (280 mL) was added Et3N (63.0 mL, 451 mmol) at ambient temperature. The mixture became homogeneous and was allowed to stir for 10 mm before 5-amino-2,4-di-tert-butyl-phenol (50.0 g, 226 mmol) was added in small portions. The mixture was allowed to stir overnight at ambient temperature. The mixture became heterogeneous over the course of the reaction. After all of the acid was consumed (LC-MS analysis, MH+ 190, 1.71 mm), the solvent was removed in vacuo. EtOH was added to the orange solid material to produce a slurry. The mixture was stirred on a rotovap (bath temperature 65 C) for 15 mm without placing the system under vacuum. The mixture was filtered and the captured solid was washed with hexanes to provide a white solid that was the EtOH crystalate. Et20 was added to the solid obtained above until a slurry was formed. The mixture was stirred on a rotovapor (bath temperature 25 C) for 15 mm without placing the system under vacuum. The mixture was filtered and the solid captured. This procedure was performed a total of five times. The solid obtained after the fifth precipitation was placed under vacuum overnight to provide N-(5-hydroxy-2,4-di- tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide as a white powdery solid (38 g, 52%). HPLC ret. time 3.45 mm, 10-99% CH3CN, 5 mm run; ?H NIVIR (400 IVIHz, DMSO-d6) 12.88 (s, 1H), 11.83 (s, 1H), 9.20 (s, 1H), 8.87 (s, 1H), 8.33 (dd, J 8.2, 1.0 Hz, 1H), 7.83-7.79 (m, 1H), 7.76 (d, J = 7.7 Hz, 1H), 7.54-7.50 (m, 1H), 7.17 (s, 1H), 7.10 (s, 1H), 1.38 (s, 9H), 1.37 (s, 9H); ESI-MS m/z calc?d 392.21; found 393.3 [M+H]t
52%		To a suspension of 4-oxo-l,4-dihydroquinolin-3-carboxylic acid (35.5 g, 188 mmol) and HBTU (85.7 g, 226 mmol) in DMF (280 mL) was added Et3N (63.0 mL, 451 mmol) at ambient temperature. The mixture became homogeneous and was allowed to stir for 10 min before 5-amino-2,4-di-ie/ -butyl-phenol (50.0 g, 226 mmol) was added in small portions. The mixture was allowed to stir overnight at ambient temperature. The mixture became heterogeneous over the course of the reaction. After all of the acid was consumed (LC-MS analysis, MH+ 190, 1.71 min), the solvent was removed in vacuo. EtOH was added to the orange solid material to produce a slurry. The mixture was stirred on a rotovap (bath temperature 65 C) for 15 min without placing the system under vacuum. The mixture was filtered and the captured solid was washed with hexanes to provide a white solid that was the EtOH crystalate. Et20 was added to the solid obtained above until a slurry was formed. The mixture was stirred on a rotovap (bath temperature 25 C) for 15 min without placing the system under vacuum. The mixture was filtered and the solid captured. This procedure was performed a total of five times. The solid obtained after the fifth precipitation was placed under vacuum overnight to provide N-(5-hydroxy-2,4-di- ieri-butyl-phenyl)-4-oxo-lH-quinoline-3-carboxamide as a white powdery solid (38 g, 52%). HPLC ret. time 3.45 min, 10-99% CH3CN, 5 min run; lH NMR (400 MHz, DMSO-ifc) delta 12.88 (s, 1H), 11.83 (s, 1H), 9.20 (s, 1H), 8.87 (s, 1H), 8.33 (dd, J = 8.2, 1.0 Hz, 1H), 7.83-7.79 (m, 1H), 7.76 (d, J = 7.7 Hz, 1H), 7.54-7.50 (m, 1H), 7.17 (s, 1H), 7.10 (s, 1H), 1.38 (s, 9H), 1.37 (s, 9H); ESI-MS m z calc'd 392.21; found 393.3 [M+H]+.
52%		To a suspension of 4-oxo-l,4-dihydroquinolin-3-carboxylic acid (35.5 g, 188 mmol) and HBTU (85.7 g, 226 mmol) in DMF (280 mL) was added Et3N (63.0 mL, 451 mmol) at ambient temperature. The mixture became homogeneous and was allowed to stir for 10 min before 5-amino-2,4-di-ie/t-butyl-phenol (50.0 g, 226 mmol) was added in small portions. The mixture was allowed to stir overnight at ambient temperature. The mixture became heterogeneous over the course of the reaction. After all of the acid was consumed (LC-MS analysis, MH+ 190, 1.71 min), the solvent was removed in vacuo. EtOH was added to the orange solid material to produce a slurry. The mixture was stirred on a rotovap (bath temperature 65 C) for 15 min without placing the system under vacuum. The mixture was filtered and the captured solid was washed with hexanes to provide a white solid that was the EtOH crystallate. Et20 was added to the solid obtained above until a slurry was formed. The mixture was stirred on a rotovap (bath temperature 25 C) for 15 min without placing the system under vacuum. The mixture was filtered and the solid captured. This procedure was performed a total of five times. The solid obtained after the fifth precipitation was placed under vacuum overnight to provide N-(5-hydroxy-2,4-di-ieri-butyl-phenyl)-4-oxo-lH-quinoline-3- carboxamide as a white powdery solid (38 g, 52%). HPLC ret. time 3.45 min, 10-99% CH3CN, 5 min run; lH NMR (400 MHz, DMSO-d6) delta 12.88 (s, 1H), 11.83 (s, 1H), 9.20 (s, 1H), 8.87 (s, 1H), 8.33 (dd, J = 8.2, 1.0 Hz, 1H), 7.83-7.79 (m, 1H), 7.76 (d, J = 7.7 Hz, 1H), 7.54-7.50 (m, 1H), 7.17 (s, 1H), 7.10 (s, 1H), 1.38 (s, 9H), 1.37 (s, 9H); ESI- MS m/z calc'd 392.21 ; found 393.3 [M+H]+.
52%		To a suspension of 4-oxo-l,4-dihydroquinolin-3-carboxylic acid (35.5 g, 188 mmol) and HBTU (85.7 g, 226 mmol) in DMF (280 mL) was added Et3N (63.0 mL, 451 mmol) at ambient temperature. The mixture became homogeneous and was allowed to stir for 10 min before 5-amino-2,4-di-ie/ -butyl-phenol (50.0 g, 226 mmol) was added in small portions. The mixture was allowed to stir overnight at ambient temperature. The mixture became heterogeneous over the course of the reaction. After all of the acid was consumed (LC-MS analysis, MH+ 190, 1.71 min), the solvent was removed in vacuo. EtOH was added to the orange solid material to produce a slurry. The mixture was stirred on a rotovap (bath temperature 65 C) for 15 min without placing the system under vacuum. The mixture was filtered and the captured solid was washed with hexanes to provide a white solid that was the EtOH crystalate. Et20 was added to the solid obtained above until a slurry was formed. The mixture was stirred on a rotovapor (bath temperature 25 C) for 15 min without placing the system under vacuum. The mixture was filtered and the solid captured. This procedure was performed a total of five times. The solid obtained after the fifth precipitation was placed under vacuum overnight to provide N-(5-hydroxy-2,4-di- ieri-butyl-phenyl)-4-oxo-lH-quinoline-3-carboxamide as a white powdery solid (38 g, 52%). HPLC ret. time 3.45 min, 10-99% CH3CN, 5 min run; lH NMR (400 MHz, DMSO-ifc) delta 12.88 (s, 1H), 11.83 (s, 1H), 9.20 (s, 1H), 8.87 (s, 1H), 8.33 (dd, J = 8.2, 1.0 Hz, 1H), 7.83-7.79 (m, 1H), 7.76 (d, J = 7.7 Hz, 1H), 7.54-7.50 (m, 1H), 7.17 (s, 1H), 7.10 (s, 1H), 1.38 (s, 9H), 1.37 (s, 9H); ESI-MS m z calc'd 392.21; found 393.3 [M+H]+.
52%		To a suspension of 4-oxo-l,4-dihydroquinolin-3-carboxylic acid (35.5 g, 188 mmol) and HBTU (85.7 g, 226 mmol) in DMF (280 mL) was added Et3N (63.0 mL, 451 mmol) at ambient temperature. The mixture became homogeneous and was allowed to stir for 10 min before 5-amino-2,4-di-/
52%		To a suspension of 4-oxo-1,4-dihydroquinolin-3-carboxylic acid (35.5 g, 188 mmol) and HBTU (85.7 g, 226 mmol) in DMF (280 mL) was added Et3N (63.0 mL, 451 mmol) at ambient temperature. The mixture became homogeneous and was allowed to stir for 10 min before 5-amino-2,4-di-tert-butyl-phenol (50.0 g, 226 mmol) was added in small portions. The mixture was allowed to stir overnight at ambient temperature. The mixture became heterogeneous over the course of the reaction. After all of the acid was consumed (LC-MS analysis, MH+190, 1.71 min), the solvent was removed in vacuo. EtOH (ethyl alcohol) was added to the orange solid material to produce a slurry. The mixture was stirred on a rotovap (bath temperature 65 C.) for 15 min without placing the system under vacuum. The mixture was filtered and the captured solid was washed with hexanes to provide a white solid that was the EtOH crystalate. Et2O (diethyl ether) was added to the solid obtained above until a slurry was formed. The mixture was stirred on a rotovapor (bath temperature 25 C.) for 15 min without placing the system under vacuum. The mixture was filtered and the solid captured. This procedure was performed a total of five times. The solid obtained after the fifth precipitation was placed under vacuum overnight to provide N-(5-hydroxy-2,4-di-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (38 g, 52%). HPLC ret. time 3.45 min, 10-99% CH3CN, 5 min run; 1H NMR (400 MHz, DMSO-d6) delta 12.88 (s, 1H), 11.83 (s, 1H), 9.20 (s, 1H), 8.87 (s, 1H), 8.33 (dd, J=8.2, 1.0 Hz, 1H), 7.83-7.79 (m, 1H), 7.76 (d, J=7.7 Hz, 1H), 7.54-7.50 (m, 1H), 7.17 (s, 1H), 7.10 (s, 1H), 1.38 (s, 9H), 1.37 (s, 9H); ESI-MS m/z calc'd 392.21; found 393.3 [M+H]+.
52%		To a suspension of 4-oxo-1,4-dihydroquinolin-3-carboxylic acid (35.5 g, 188 mmol) and HBTU (85.7 g, 226 mmol) in DMF (280 mL) was added Et3N (63.0 mL, 451 mmol) at ambient temperature. The mixture became homogeneous and was allowed to stir for 10 min before 5 amino-2,4-di-tert-butyl-phenol (50.0 g, 226 mmol) was added in small portions. The mixture was allowed to stir overnight at ambient temperature. The mixture became heterogeneous over the course of the reaction. After all of the acid was consumed (LC-MS analysis, MH+ 190, 1.71 min), the solvent was removed in vacuo. EtOH (ethyl alcohol) was added to the orange solid material to produce a slurry. The mixture was stirred on a rotovap (bath temperature 65 C) for 15 min without placing the system under vacuum. The mixture was filtered and the captured solid was washed with hexanes to provide a white solid that was the EtOH crystalate. Et20 (diethyl ether) was added to the solid obtained above until a slurry was formed. The mixture was stirred on a rotovapor (bath temperature 25 C) for 15 min without placing the system under vacuum. The mixture was filtered and the solid captured. This procedure was performed a total of five times. The solid obtained after the fifth precipitation was placed under vacuum overnight to provide N-(5-hydroxy-2,4-di-ie - butyl-phenyl)-4-oxo-lH-quinoline-3-carboxamide (38 g, 52%). HPLC ret. time 3.45 min, 10-99% CH3CN, 5 min run; 1H NMR (400 MHz, DMSO-d6) d 12.88 (s, 1H), 11.83 (s, 1H), 9.20 (s, 1H), 8.87 (s, 1H), 8.33 (dd, J = 8.2, 1.0 Hz, 1H), 7.83-7.79 (m, 1H), 7.76 (d, J = 7.7 Hz, 1H), 7.54-7.50 (m, 1H), 7.17 (s, 1H), 7.10 (s, 1H), 1.38 (s, 9H), 1.37 (s, 9H); ESI-MS m/z calc'd 392.21; found 393.3 [M+H]+.
52%		To a suspension of 4-oxo-1,4-dihydroquinolin-3-carboxylic acid (35.5 g, 188 mmol) and HBTU (85.7 g, 226 mmol) in DMF (280 mL) was added Et3N (63.0 mL, 451 mmol) at ambient temperature. The mixture became homogeneous and was allowed to stir for 10 min before 5-amino-2,4-di-tert-butyl-phenol (50.0 g, 226 mmol) was added in small portions. The mixture was allowed to stir overnight at ambient temperature. The mixture became heterogeneous over the course of the reaction. After all of the acid was consumed (LC-MS analysis, MH+190, 1.71 min), the solvent was removed in vacuo. EtOH (ethyl alcohol) was added to the orange solid material to produce a slurry. The mixture was stirred on a rotovap (bath temperature 65 C.) for 15 min without placing the system under vacuum. The mixture was filtered and the captured solid was washed with hexanes to provide a white solid that was the EtOH crystalate. Et2O (diethyl ether) was added to the solid obtained above until a slurry was formed. The mixture was stirred on a rotovapor (bath temperature 25 C.) for 15 min without placing the system under vacuum. The mixture was filtered and the solid captured. This procedure was performed a total of five times. The solid obtained after the fifth precipitation was placed under vacuum overnight to provide N-(5-hydroxy-2,4-di-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (38 g, 52%). HPLC ret. time 3.45 min, 10-99% CH3CN, 5 min run; 1H NMR (400 MHz, DMSO-d6) delta 12.88 (s, 1H), 11.83 (s, 1H), 9.20 (s, 1H), 8.87 (s, 1H), 8.33 (dd, J=8.2, 1.0 Hz, 1H), 7.83-7.79 (m, 1H), 7.76 (d, J=7.7 Hz, 1H), 7.54-7.50 (m, 1H), 7.17 (s, 1H), 7.10 (s, 1H), 1.38 (s, 9H), 1.37 (s, 9H); ESI-MS m/z calc'd 392.21; found 393.3 [M+H]+.
46%		Examples: 3: Syn (0087) (0088) A mixture of 4-oxo-l,4-dihydroquinoline-3-carboxylic acid 3 (0.25 g, 1.32 mmol), N,N- diisopropylethylamine (0.97 mL, 5.38 mmol), and HATU (1.01 g, 2.64 mmol) in DMF (5 mL) was stirred at 25 C for 10 min and then 5-amino-2,4-di-tert-butylphenol 3a (0.58 g, 2.64 mmol) was added in one portion, allowed to stir forl2h. The reaction mass was extracted with EtOAc (2 X 10 mL). Combined organic layers were washed with H20 (5 mL), saturated NaHC03 solution (5 mL), H20 (5 mL), brine (5 mL), dried over anhydrous Na2S04 and evaporated to dryness, crude residue was purified by silica gel chromatography (2-3% MeOH-DCM) to give off-white solid, which on further crystallization in EtOH gave desired compound as white solid (0.23 g, 46%). (0089) 1H NMR (500MHz ,DMSO-d6) delta = 12.88 (brs, 1H), 11.82 (brs, 1H), 9.20 (brs, 1H), 8.87 (brs, 1H), 8.33 (d, J = 6.9 Hz, 1H), 7.88 - 7.68 (m, 2H), 7.52 (brs, 1H), 7.17 (brs, 1H), 7.11 (brs, 1H), 1.38 (d, J = 7.6 Hz, 18H).
		A mixture of 4-oxo-l,4-dihydroquinoline-3-carboxylic acid (lO.Ogm), HATU (24.12 gm), Di- isopropyl ethyl amine (20.56 ml) and DMF (60.0ml) was stirred for 30 minutes. 5-amino-2-4-di- tert-butyl-phenol (12.8 gm) was added to the reaction mass and stirred for a period of about 15.0 hr. Water was added to the reaction mass and product was extracted with ethyl acetate. Organic layer was washed with 10% sodium carbonate solution followed by brine. Organic layer was distilled under vacuum. 100ml of methanol was added to obtained residue and heated to 60-65C for 30min. The solid was filtered and dried at 50-55C for 12 hrs to obtain 15.1gm of title compound, (DSC) thermogram having endothermic peak at about 320.88, 192 .13±1C and exothermic peak at245.63±lC water content (by K.F): 0.34% , HPLC purity: 99.86%

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 9776 - 9795
[2]Journal of Medicinal Chemistry,2014,vol. 57,p. 9776 - 9795
[3]Journal of Heterocyclic Chemistry,2017,vol. 54,p. 3169 - 3173
[4]Patent: WO2007/79139,2007,A2 .Location in patent: Page/Page column 49; 50
[5]Patent: WO2018/64632,2018,A1 .Location in patent: Paragraph 00226; 00227
[6]Patent: WO2018/107100,2018,A1 .Location in patent: Paragraph 00245; 00246
[7]Patent: US2018/280349,2018,A1 .Location in patent: Paragraph 0103-0104
[8]Patent: WO2019/10092,2019,A1 .Location in patent: Paragraph 00324; 00325; 00333; 00342; 00343
[9]Patent: WO2019/18353,2019,A1 .Location in patent: Paragraph 00152
[10]Patent: WO2019/18395,2019,A1 .Location in patent: Paragraph 00183
[11]Patent: WO2018/227049,2018,A1 .Location in patent: Paragraph 00217; 00218
[12]Patent: WO2019/113089,2019,A1 .Location in patent: Paragraph 00250
[13]Patent: US2019/119253,2019,A1 .Location in patent: Paragraph 0521; 0522
[14]Patent: WO2019/191620,2019,A1 .Location in patent: Paragraph 00431
[15]Patent: US2019/240197,2019,A1 .Location in patent: Paragraph 0580; 0581
[16]Patent: WO2017/208253,2017,A2 .Location in patent: Page/Page column 14
[17]Patent: WO2014/118805,2014,A1 .Location in patent: Paragraph 0273

33
[ 53977-02-9 ]
[ 873054-44-5 ]

Reference： [1]Patent: WO2014/125506,2014,A2

34
[ 1622228-86-7 ]
[ 873054-44-5 ]

Yield	Reaction Conditions	Operation in experiment
8.45 g	With 20% palladium hydroxide-activated charcoal; ammonium formate; In N,N-dimethyl-formamide; at 70 - 80℃; for 3h;	EXAMPLE 6: Preparation of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-l,4- dihydroquinoline-3-carboxamide (Ivacaftor). To a flask was charged with N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l-benzyl-4-oxo- l,4-dihydroquinoline-3-carboxamide (13.0g, 0.0269mol) in dimethylformamide (195.0 mL, 15 vol), 20% palladium hydroxide (13.0 g, l.Owt) and ammonium formate (13. Og, l.Owt) was added at 25-30C. The reaction mass was heated to 70-80C and stirred for 3 hours. Then the reaction mass was cooled to 40C and filtered. The filtered mass was washed with ethyl acetate. Combined dimethylformamide and ethyl acetate layers were washed with water. The aqueous layer further extracted with ethyl acetate. Both organic layers were combined and washed with water. The organic layer was distilled off under vacuum to a minimum volume and methanol was added to it. The solid obtained was filtered and dried under vacuum at 45C to 50C. To the dried product, ethyl acetate (40 ml) was added and distilled off the solvent to a minimum volume under atmospheric pressure. n-heptane was added to above reaction mass and again distilled off the solvent to a minimum volume under atmospheric pressure. The solid obtained was filtered and dried at 45C to 50C under vacuum to yield the title compound (8.45 g). 1H NMR (DMSO-d6): delta 12.8 (s, 1H), delta 11.79 (s, 1H), delta 9.17 (s, 1H), delta 8.84 (s, 1H), delta 8.31 (dd, 1H), delta 7.7 (m, 2H), delta 7.4 (m, 1H), delta 7.20 (s, 1H), delta 7.10 (s, 1H), delta 1.36 (s, 9Eta), delta 1.34 (s, 9H); HPLC Purity: 99.3% area
2 g	With ammonium formate; palladium(II) hydroxide; In N,N-dimethyl-formamide; at 25 - 80℃; for 3h;	Example-3: Preparation of Ivacaftor. N-(2,4-di-teri-butyl-5-hydroxyphenyl)- 1 -benzyl-4-oxo- 1 ,4-dihydroquinoline-3-carboxamide (3g; obtained from Ex-2) and dimethylformamide (45ml), 20% palladium hydroxide (3g) and ammonium formate (3g) were charged into a round bottom flask at 25-30C. The reaction mass was heated to 70-80C and stirred for 3 hours. Then the reaction mass was cooled to 40C and filtered. To the filtered mass water (180ml) was added at 5-10C, then the reaction mass was stirred for 30 min at 25-30C and filtered the precipitated solid and solid bed washed with water (15ml). The obtained wet cake was dissolved in ethyl acetate (90ml) and filtered through celite bed and bed washed with ethyl acetate (10ml). Filtrate was distilled completely u/v at below 50C and crude product co-distilled with ethanol (10ml), charged ethanol (15ml) to crude product and stir for 30 min at 25-35 C. Filtered the obtained solids and washed with ethanol (6ml). Dry the material at 60-65C for 18 to 24 hrs to obtain Ivacaftor. Yield: 2.0 g.

Reference： [1]Patent: WO2014/125506,2014,A2 .Location in patent: Page/Page column 23
[2]Patent: WO2017/37672,2017,A1 .Location in patent: Page/Page column 47

35
ethyl 3-(dimethylamino)-2-(2-fluorobenzoyl)-2-propenoate [ No CAS ]
[ 873054-44-5 ]

Reference： [1]Patent: WO2014/125506,2014,A2

36
[ 445-29-4 ]
[ 873054-44-5 ]

Reference： [1]Patent: WO2014/125506,2014,A2
[2]Patent: WO2017/37672,2017,A1
[3]Patent: WO2017/37672,2017,A1
[4]Patent: WO2017/37672,2017,A1
[5]Patent: WO2017/37672,2017,A1
[6]Patent: WO2017/37672,2017,A1

37
[ 393-52-2 ]
[ 873054-44-5 ]

Reference： [1]Patent: WO2014/125506,2014,A2
[2]Patent: WO2017/37672,2017,A1

38
[ 1207748-75-1 ]
[ 873054-44-5 ]

Reference： [1]Patent: WO2014/125506,2014,A2

39
[ 108-88-3 ]
[ 873054-44-5 ]

Reference： [1]Patent: US2014/221424,2014,A1

40
5-amino-2,4-di-tert-butylphenol hydrochloride [ No CAS ]
[ 13721-01-2 ]
[ 873054-44-5 ]

Yield	Reaction Conditions	Operation in experiment
57.5 g		4-oxo-1 ,4-dihydroquinoline-3-carboxylic acid (44.4 g) in dimethyl formamide (275 mL) was added to a round bottomed flask fitted with a temperature inlet. N, N, N?, N?-tetramethyl-O-(l H-benzotriazol- 1 -yl)uronium hexafluorophosphate (101 .1 g) was added to the reaction flask and the reaction mixture was stirred for 15 minutes at25°C. 5-amino-2,4-di-tert-butylphenol hydrochloride (55.0 g) was added to the reaction mixture followed by the addition of diisopropylethylamine (82.7 g). The reaction mass was stirred for 2.5 hours at 45 - 50°C. After the completion of the reaction, methyl isobutyl ketone (550 mL) and 10percent aqueous hydrochloric acid (275 mL) were added to the reaction mixture and stirred for 15 minutes at 25 - 30°C. The resulting layers wereseparated. The organic layer was washed with 15percent aqueous hydrochloric acid (3 X 275 mL) and further washed with 10percent aqueous sodium carbonate solution (2 X 275 mL), followed by washing with water (275 mL). The organic layer was distilled under vacuum up to the volume of 275 mL and the suspension was allowed to cool to a temperature of 25°C. The suspension was further cooled to 0 ? 5°C and stirred for 2 hours. Theprecipitated material was filtered and dried under vacuum at 45°C for 8 hours. Yield: 95.1 g. Methyl isobutyl ketone solvate of Ivacaftor (90 g) prepared above was added to a mixture of methanol (247.5 mL) and toluene (247.5 mL) in a round bottom flaskequipped with mechanical stirrer, thermo pocket, guard tube and stopper. The reactionmixture was maintained under stirring at 25 - 30 °C for 2 hours. The material was filtered and washed with a mixture of methanol (90 mL) and toluene (90 mL). The material was dried at 70°C under vacuum.Yield: 57.5 g.Purity: 100percent (by HPLC).
5 g		Example- 1: Preparation of Ivacaftor. 4-oxo-l,4-dihydroquinoline-3-carboxylic acid (5g), methylene chloride (100ml) and triethylamine (5.35g) were charged into a round bottom flask at 25-35°C stirred at for lOmin at same temperature. Reactions mass was cooled to 0-5 °C, slowly add thionyl chloride (6.30g) over a period of 15min, then the reaction mass was heated to reflux and maintained for 2 to 3 hrs. After completion of the reaction, reaction mass was distilled completely under vacuum at below 40°C and co-distilled with methylene chloride (2x50ml). Reaction mass was cooled to room temperature and diluted with methylene chloride (50ml) further cooled to 0-5°C. To the reaction mass was charged solution of 5-amino-2,4-di-teri-butyl phenol hydrochloride (8.2g) in methylene chloride (50ml) and triethylamine (5.35g) at 0-5 °C. Reaction mass was heated to 25-35°C and stirred for 4 to 6 hrs. After completion of the reaction, reaction mass was distilled completely under vacuum at below 40°C and to the resultant reaction ethyl acetate (100ml) was charged and washed with 5percentsodium carbonate(2x50ml), water (50ml), lpercentaq.HCl solution (50ml) and water (50ml) and the resultant organic layer was distilled completely u/v and co-distilled with ethanol to obtain crude. The obtaine crude was dissolved in ethanol (450ml) at reflux temperature and then distilled the resultant reaction mass upto ~20vol at 40°C. Reaction mass was cooled to 25- 35°C then filtered the solid and washed with ethanol (10ml). The resulting wet cake was dried under vacuum at 60-65 °C to obtain Ivacaftor. Yield: 5.0g.

Reference： [1]Patent: WO2015/70336,2015,A1 .Location in patent: Page/Page column 20; 21
[2]Patent: WO2017/37672,2017,A1 .Location in patent: Page/Page column 46

41
[ 26892-90-0 ]
[ 873054-44-5 ]

Reference： [1]Patent: US2015/231142,2015,A1
[2]Patent: WO2007/79139,2007,A2
[3]Patent: US2011/98311,2011,A1
[4]Patent: WO2018/64632,2018,A1
[5]Patent: WO2018/107100,2018,A1
[6]Patent: US2018/280349,2018,A1
[7]Patent: WO2018/227049,2018,A1
[8]Patent: WO2019/18353,2019,A1
[9]Patent: US2019/119253,2019,A1
[10]Patent: US2019/240197,2019,A1
[11]Patent: WO2019/191620,2019,A1

42
C₂₆H₃₂N₂O₆ [ No CAS ]
[ 873054-44-5 ]

Reference： [1]European Journal of Organic Chemistry,2015,vol. 2015,p. 7433 - 7437

43
[ 87-51-4 ]
[ 873054-44-5 ]

Reference： [1]European Journal of Organic Chemistry,2015,vol. 2015,p. 7433 - 7437

44
5-(2-(1H-indol-3-yl)acetamido)-2,4-di-tert-butylphenyl methyl carbonate [ No CAS ]
[ 873054-44-5 ]

Reference： [1]European Journal of Organic Chemistry,2015,vol. 2015,p. 7433 - 7437
[2]Patent: WO2017/208253,2017,A2

45
[ 1182822-31-6 ]
[ 873054-44-5 ]

Reference： [1]European Journal of Organic Chemistry,2015,vol. 2015,p. 7433 - 7437
[2]Patent: US2016/96807,2016,A1
[3]Patent: WO2017/37672,2017,A1
[4]Patent: WO2017/37672,2017,A1

46
[ 873054-44-5 ]
[ 538-23-8 ]
3C₂₄H₂₈N₂O₃*C₂₇H₅₀O₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	at 80℃; for 1.0h;	General procedure: Approximately 50 mg neat amorphous Compound 1 was added to approximately 1 g triglyceride, heated to 80 C. and kept at this temperature for at least 1 hour. The solution was then cooled to a temperature above the melting point of the triglyceride to crystallize the Compound 1 co-crystal. In order to improve crystal quality and size the system was heated again to 80 C. and cooled down. The temperature cycling was repeated until crystals of suitable size for analysis were obtained. All Compound 1 co-crystals were isolated by centrifugal filtration at temperatures above the melting point of the triglyceride.

Reference： [1]Patent: US2016/96807,2016,A1 .Location in patent: Paragraph 0453-0454

47
[ 13721-01-2 ]
[ 873054-44-5 ]

Reference： [1]Patent: US2016/96807,2016,A1
[2]Patent: CN105130891,2018,B
[3]Patent: CN105130891,2018,B
[4]Patent: CN105130891,2018,B
[5]Patent: CN105130891,2018,B
[6]Patent: CN105130891,2018,B
[7]Patent: CN105130891,2018,B
[8]Patent: CN105130891,2018,B

48
C₃₁H₃₄N₂O₃ [ No CAS ]
[ 873054-44-5 ]

Yield	Reaction Conditions	Operation in experiment
80%	With 5%-palladium/activated carbon; hydrogen; In methanol; at 35℃; under 1520.1 Torr; for 5h;	Compound 7 (24.1 g, 0.05 mol) was added, Add 300 mL of anhydrous methanol to mix, Followed by the addition of 5% palladium on carbon, 2.4 g, The mixture is filled with H2 and sealed. The mixture was warmed to 35 C and stirred for 5 h, The pressure is maintained at 2 atmospheres. Reaction completed, cooling, The Pd / C was removed by filtration and the filtrate was concentrated to dry crude product. The crude product was dissolved in 50 mL of isopropanol, And 100 mL of a mixed solvent of acetone/tetrahydrofuran (V/V=1:1) Stirring 6h recrystallization, precipitation of solid, filtration, solid by vacuum drying, To give Ivacaftor as a white solid, 15.8 g (0.040 mol) yield 80.0%, purity 99.7% (high performance liquid phase).

Reference： [1]Patent: CN103787968,2016,B .Location in patent: Paragraph 0039; 0086; 0087

49
C₂₁H₂₇NO₃ [ No CAS ]
[ 873054-44-5 ]

Reference： [1]Patent: CN103787968,2016,B

50
[ 223679-79-6 ]
[ 873054-44-5 ]

Reference： [1]Patent: WO2017/37672,2017,A1
[2]Patent: WO2017/37672,2017,A1
[3]Patent: WO2017/37672,2017,A1

51
C₂₃H₂₈FNO₃ [ No CAS ]
[ 873054-44-5 ]

Reference： [1]Patent: WO2017/37672,2017,A1

52
C₂₆H₃₃FN₂O₃ [ No CAS ]
[ 873054-44-5 ]

Yield	Reaction Conditions	Operation in experiment
0.55 g		Example-9: Preparation of Ivacaftor. Compound of Formula Vila (lg; obtained from Ex-5), ethanol (10ml) and ammonium hydroxide (5ml) were charged into a round bottom flask at 25-35C and stirred for lhr at same temperature. After completion of the reaction, reaction mass was distilled completely under vacuum at below 50C and co-distilled with ethanol (10ml) to obtain residue. The obtained residue was dissolved in dimethylformamide (5ml) and charged potassium carbonate (0.67g) at 25-30C. Reactions mass was heated to 85-95C and stirred for 2hr at same temperature. After completion of the reaction, cooled the reaction mass to 25-30C and slowly added water (25ml) over a period of lhr and stirred for lhr at same temperature. Filtered the obtained solids and washed with water (2x10ml) and dryed under vacuum. The obtained solids were dissolved in ethyl acetate (10ml) and washed with water (5ml). Organic layer was distilled completely under vacuum and co-distilled with ethanol (10ml) to obtain residue. The obtained residue was added ethanol (5ml) at room temperature and the reaction mass was heated to 75-80C and stirred for lhr. Reaction mass was cooled to 25-35 C and filtered the solids obtained and washed with ethanol (2ml). Dry the material at 45-50C to obtain title compound. Yield: 0.55 g.

Reference： [1]Patent: WO2017/37672,2017,A1 .Location in patent: Page/Page column 48; 49

53
[ 1479-24-9 ]
[ 873054-44-5 ]

Reference： [1]Patent: WO2017/37672,2017,A1

54
C₂₆H₃₃N₃O₅ [ No CAS ]
[ 873054-44-5 ]

Yield	Reaction Conditions	Operation in experiment
0.7 g	With iron; ammonium chloride; In ethanol; water; at 25 - 75℃;	Example-11: Preparation of Ivacaftor. Compound Vllb (l.Og), iron powder (0.48g) and ethanol (10.0ml) were charged into a round bottom flask at 25-35C and heated to 65 to 75C. To the reaction mass was added ammonium chloride solution (1.14g dissolved in water 5ml) at 65 to 75 C for 60 to 90 min and stirred for 2 to 3 hr at same temperature. After the completion of the reaction, reaction mass was cooled to 25-35C and distilled reaction mass under vacuum at 50C to obtain a residue. To the obtained residue was added ethylacetate (10.0ml) and water (10ml) and stirred for 10 min and separated the organic layer, washed the organic layer with water (10ml) and distilled the reaction mass at 45 to 50C and co-distilled with ethanol (10ml) to obtain a residue. The obtained residue was added ethanol (5ml) at room temperature and the reaction mass was heated to 75-80C and stirred for lhr. Reaction mass was cooled to 25- 35C and filtered the solids obtained and washed with ethanol (2ml). Dry the material at 45- 50C to obtain title compound. Yield: 0.7 g.

Reference： [1]Patent: WO2017/37672,2017,A1 .Location in patent: Page/Page column 49

55
5-([(E)-3-ethoxyprop-2-enoyl]amino)-2,4-di-tert-butylphenyl methyl carbonate [ No CAS ]
[ 393-52-2 ]
[ 873054-44-5 ]

Reference： [1]Patent: WO2017/37672,2017,A1

56
2,4-di-tert-butyl-5-(3-(2-fluorophenyl)-3-oxopropanamido)phenyl methyl carbonate [ No CAS ]
[ 873054-44-5 ]

Reference： [1]Patent: WO2017/37672,2017,A1

57
2,4-di-tert-butyl-5-(3-ethoxy-2-(2-fluorobenzoyl)acrylamido)phenyl methyl carbonate [ No CAS ]
[ 873054-44-5 ]

Yield	Reaction Conditions	Operation in experiment
5 g		Example-15: Preparation of Ivacaftor. Compound of Formula XIIIp (6.75g), ethanol (70mL) and ammonium hydroxide (35mL) were charged in to round bottom flask at 25-35C. Reaction mass was heated to reflux and stirred for 10 to 12 hrs at same temperature. After completion of reaction, reaction mass was distilled at 45-50C under vacuum and co-distilled with ethanol (lOmL) to obtain a residue. The obtained residue was dissolved in dimethylformamide (54mL) and charged potassium carbonate (5.94g) at 25-30C. Reactions mass was heated to 100-105C and stirred for 12hrs at same temperature. After completion of the reaction, cooled the reaction mass to 25-30C and slowly added water (270mL) and pH of the reaction mass was adjusted to 2.0 with aq hydrochloric acid. Filtered the precipitated solids and was charged ethanol (200mL) and heated to 75-80C and stirred for a period of 60min at same temperature. Reaction mass was cooled to 25-35C and distilled reaction mass to 60mL. Filtered the solids obtained and washed with ethanol (12ml). Dry the material at 45-50C to obtain title compound. Yield: 5.0g.

Reference： [1]Patent: WO2017/37672,2017,A1 .Location in patent: Page/Page column 50; 51

58
5-amino-2,4-di-tert-butylphenol hydrochloride [ No CAS ]
[ 35975-86-1 ]
[ 873054-44-5 ]

Reference： [1]Patent: WO2017/37672,2017,A1

59
2,4-di-tert-butylphenyl ethyl carbonate [ No CAS ]
[ 873054-44-5 ]

Reference： [1]Patent: US2017/96397,2017,A1

60
[ 552-16-9 ]
[ 873054-44-5 ]