[ CAS No. 1346242-81-6 ] {[proInfo.proName]}

Name: 1346242-81-6|N1-(3,5-Dimethoxyphenyl)-N2-isopropyl-N1-(3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl)ethane-1,2-diamine|98%
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Quality Control of [ 1346242-81-6 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 1346242-81-6 ]

CAS No. :	1346242-81-6	MDL No. :	MFCD28502040
Formula :	C₂₅H₃₀N₆O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	OLAHOMJCDNXHFI-UHFFFAOYSA-N
M.W :	446.54	Pubchem ID :	67462786
Synonyms :	JNJ-42756493	Chemical Name :	N1-(3,5-Dimethoxyphenyl)-N2-isopropyl-N1-(3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl)ethane-1,2-diamine

Safety of [ 1346242-81-6 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 1346242-81-6 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Upstream synthesis route of [ 1346242-81-6 ]
Downstream synthetic route of [ 1346242-81-6 ]

[ 1346242-81-6 ] Synthesis Path-Upstream 1~14

1
[ 1346245-10-0 ]
[ 75-31-0 ]
[ 1346242-81-6 ]

Yield	Reaction Conditions	Operation in experiment
86.5%	at 100℃; for 18 h; sealed vessel	A mixture of intermediate 10 (322g; 666mmol) and 2-propanamine (196.8g; 3.3mol) in acetonitrile (2.66L) was heated at 100°C in a sealed vessel for 18 hours. The reaction mixture was cooled to room temperature and concentrated to -30percent of its initial volume. Water (1 .5L), 2-methyltetrahydrofurane (2.5L) and NaHC0₃ (50g) were added. The layers were separated, the organic layer was washed with a solution made of 50g of NaHC0₃ in water (1 L), dried (MgS0₄), filtered over silica gel and evaporated till dryness. The residue was crystallized from 2-propanol. The precipitate was filtered off, dried in vacuum to provide 257.2g (86.5percent) of compound 4.

Reference： [1] Patent: WO2011/135376, 2011, A1, . Location in patent: Page/Page column 253

2
[ 1346133-39-8 ]
[ 6306-61-2 ]
[ 1346242-81-6 ]

Reference： [1] Patent: WO2011/135376, 2011, A1, . Location in patent: Page/Page column 254

3
[ 82031-32-1 ]
[ 1346242-81-6 ]

Reference： [1] Patent: WO2011/135376, 2011, A1,
[2] Patent: WO2011/135376, 2011, A1,
[3] Patent: WO2011/135376, 2011, A1,
[4] Patent: WO2011/135376, 2011, A1,

4
[ 89891-65-6 ]
[ 1346242-81-6 ]

Reference： [1] Patent: WO2011/135376, 2011, A1,
[2] Patent: WO2011/135376, 2011, A1,
[3] Patent: WO2011/135376, 2011, A1,
[4] Patent: WO2011/135376, 2011, A1,

5
[ 1083325-87-4 ]
[ 1346242-81-6 ]

Reference： [1] Patent: WO2011/135376, 2011, A1,
[2] Patent: WO2011/135376, 2011, A1,
[3] Patent: WO2011/135376, 2011, A1,
[4] Patent: WO2011/135376, 2011, A1,

6
[ 1346245-03-1 ]
[ 1346242-81-6 ]

Reference： [1] Patent: WO2011/135376, 2011, A1,
[2] Patent: WO2011/135376, 2011, A1,
[3] Patent: WO2011/135376, 2011, A1,

7
[ 55686-94-7 ]
[ 1346242-81-6 ]

Reference： [1] Patent: WO2011/135376, 2011, A1,
[2] Patent: WO2011/135376, 2011, A1,
[3] Patent: WO2011/135376, 2011, A1,

8
[ 1346245-04-2 ]
[ 1346242-81-6 ]

Reference： [1] Patent: WO2011/135376, 2011, A1,
[2] Patent: WO2011/135376, 2011, A1,
[3] Patent: WO2011/135376, 2011, A1,

9
[ 10272-07-8 ]
[ 1346242-81-6 ]

Reference： [1] Patent: WO2011/135376, 2011, A1,

10
[ 1021002-43-6 ]
[ 1346242-81-6 ]

Reference： [1] Patent: WO2011/135376, 2011, A1,

11
[ 1346245-09-7 ]
[ 1346242-81-6 ]

Reference： [1] Patent: WO2011/135376, 2011, A1,

12
[ 1346133-39-8 ]
[ 1346242-81-6 ]

Reference： [1] Patent: WO2011/135376, 2011, A1,
[2] Patent: WO2011/135376, 2011, A1,

13
[ 1346245-08-6 ]
[ 1346242-81-6 ]

Reference： [1] Patent: WO2011/135376, 2011, A1,

14
[ 1346242-78-1 ]
[ 1346242-81-6 ]

Reference： [1] Patent: WO2011/135376, 2011, A1,

[ 1346242-81-6 ] Synthesis Path-Downstream 1~50

1
[ 5460-29-7 ]
[ 1346242-81-6 ]
[ 1346245-63-3 ]

Yield	Reaction Conditions	Operation in experiment
34%	With potassium carbonate; In acetonitrile; at 80℃; for 48.0h;	A mixture of compound 4 (1 .3 g; 2.9 mmol), N-(3-bromopropyl) phtalimide (1.56 g; 5.8 mmol) and K2C03 (0.805 g; 5.8 mmol) in CH3CN (100 mL) was stirred at 80C for 48 hours. The reaction mixture was cooled to room temperature, poured out into ice water and EtOAc was added. The organic layer was separated, washed with brine, dried (MgS04), filtered and the solvent was evaporated until dryness. The residue (0.566 g) was purified by chromatography over silica gel (SiOH, 15-40mueta-iota, 50g; mobile phase 0.1 % NH4OH, 96% DCM, 4% MeOH ). The product fractions were collected and the solvent was evaporated to give 1 .26 g (34%) of intermediate 87.

Reference： [1]Patent: WO2011/135376,2011,A1 .Location in patent: Page/Page column 228

2
[ 10272-07-8 ]
[ 1346242-81-6 ]

Reference： [1]Patent: WO2011/135376,2011,A1

3
[ 1346242-81-6 ]
[ 100-11-8 ]
[ 1346253-27-7 ]

Yield	Reaction Conditions	Operation in experiment
52%	With potassium carbonate; In acetonitrile; at 20℃; for 48.0h;	A mixture of compound 4 (0.5 g; 1.2 mmol), 4-nitrobenzyl bromide (0.29 g; 1.35 mmol) and K2C03 (0.24 g; 51 .8 mmol) in CH3CN (20 mL) was stirred at room temperature for 48 hours. The reaction mixture was cooled to room temperature, poured out into ice water and EtOAc was added. The organic layer was separated, washed with brine, dried (MgS04), filtered and the solvent was evaporated until dryness. The residue (0.8 g) was purified by chromatography over silica gel (Stability SiOH, deltamuetaeta, 150*30mm; mobile phase gradient from 71 %Heptane,1 %MeOH, 28%EtOAc to 20%MeOH, 80%EtOAc). The product fractions were collected and the solvent was evaporated to give 0.34 g (52%) of intermediate 1 10.

Reference： [1]Patent: WO2011/135376,2011,A1 .Location in patent: Page/Page column 241; 242

4
[ 82031-32-1 ]
[ 1346242-81-6 ]

Reference： [1]Patent: WO2011/135376,2011,A1
[2]Patent: WO2011/135376,2011,A1
[3]Patent: WO2011/135376,2011,A1
[4]Patent: WO2011/135376,2011,A1

5
[ 1346245-10-0 ]
[ 75-31-0 ]
[ 1346242-81-6 ]

Yield	Reaction Conditions	Operation in experiment
86.5%	In acetonitrile; at 100℃; for 18.0h;sealed vessel;Product distribution / selectivity;	A mixture of intermediate 10 (322g; 666mmol) and 2-propanamine (196.8g; 3.3mol) in acetonitrile (2.66L) was heated at 100C in a sealed vessel for 18 hours. The reaction mixture was cooled to room temperature and concentrated to -30% of its initial volume. Water (1 .5L), 2-methyltetrahydrofurane (2.5L) and NaHC03 (50g) were added. The layers were separated, the organic layer was washed with a solution made of 50g of NaHC03 in water (1 L), dried (MgS04), filtered over silica gel and evaporated till dryness. The residue was crystallized from 2-propanol. The precipitate was filtered off, dried in vacuum to provide 257.2g (86.5%) of compound 4.

Reference： [1]Patent: WO2011/135376,2011,A1 .Location in patent: Page/Page column 253

6
[ 89891-65-6 ]
[ 1346242-81-6 ]

Reference： [1]Patent: WO2011/135376,2011,A1
[2]Patent: WO2011/135376,2011,A1
[3]Patent: WO2011/135376,2011,A1
[4]Patent: WO2011/135376,2011,A1

7
[ 1346133-39-8 ]
[ 6306-61-2 ]
[ 1346242-81-6 ]

Yield	Reaction Conditions	Operation in experiment
		Intermediate 3 (20. Og; 55.3mmol), then tetra-N-butylammonium bromide (9.06g;27.7mmol) were added at 2C under inert atmosphere to a solution of potassium hydroxide (46.6g; 830mmol) in THF (387ml_) and water (6ml_). The reaction was stirred at room temperature for 2 hours before portionwise addition of N-(2-chloroethyl)-2- propanamine HCI (CAS[6306-61 -2]), and then at 50C upon complete conversion. Water was added, layers were separated and the organic layer concentrated, taken up in DCM/water, neutralized with HCI to neutral pH. Organic layer was washed with water, dried (MgS04), filtered and evaporated till dryness to give 26.6g of compound 4.

Reference： [1]Patent: WO2011/135376,2011,A1 .Location in patent: Page/Page column 254

8
[ 1083325-87-4 ]
[ 1346242-81-6 ]

Reference： [1]Patent: WO2011/135376,2011,A1
[2]Patent: WO2011/135376,2011,A1
[3]Patent: WO2011/135376,2011,A1
[4]Patent: WO2011/135376,2011,A1

9
[ 1346133-39-8 ]
[ 1346242-81-6 ]

Reference： [1]Patent: WO2011/135376,2011,A1
[2]Patent: WO2011/135376,2011,A1

10
[ 1346242-81-6 ]
C₂₈H₃₇N₇O₂*(x)ClH [ No CAS ]

Reference： [1]Patent: WO2011/135376,2011,A1

11
[ 1346242-81-6 ]
[ 1346411-44-6 ]

Reference： [1]Patent: WO2011/135376,2011,A1

12
[ 1346242-81-6 ]
[ 1346243-60-4 ]

Reference： [1]Patent: WO2011/135376,2011,A1

13
C₂₅H₃₀N₆O₂*(x)ClH [ No CAS ]
[ 1346242-81-6 ]

Yield	Reaction Conditions	Operation in experiment
91%	With ammonium hydroxide; In dichloromethane; water;pH 9.5;Product distribution / selectivity;	To 51.69g (107mmol) of the HCI salt from the previous step was added water (258ml_) and DCM (258ml_). The pH of the reaction mixture was adjusted using ammonium hydroxide (17.25ml_) until pH = 9.5. The layers were separated and the organic layer was concentrated. The residue was crystallized from 2-propanol (258ml_). After drying at 50C under vacuum compound 4 was obtained in 91 % yield (43.4g).

Reference： [1]Patent: WO2011/135376,2011,A1 .Location in patent: Page/Page column 254

14
[ 1346245-03-1 ]
[ 1346242-81-6 ]

Reference： [1]Patent: WO2011/135376,2011,A1
[2]Patent: WO2011/135376,2011,A1
[3]Patent: WO2011/135376,2011,A1

15
[ 55686-94-7 ]
[ 1346242-81-6 ]

Reference： [1]Patent: WO2011/135376,2011,A1
[2]Patent: WO2011/135376,2011,A1
[3]Patent: WO2011/135376,2011,A1

16
[ 1346245-04-2 ]
[ 1346242-81-6 ]

Reference： [1]Patent: WO2011/135376,2011,A1
[2]Patent: WO2011/135376,2011,A1
[3]Patent: WO2011/135376,2011,A1

17
[ 1346245-08-6 ]
[ 1346242-81-6 ]

Reference： [1]Patent: WO2011/135376,2011,A1

18
[ 1021002-43-6 ]
[ 1346242-81-6 ]

Reference： [1]Patent: WO2011/135376,2011,A1

19
[ 1346245-09-7 ]
[ 1346242-81-6 ]

Reference： [1]Patent: WO2011/135376,2011,A1

20
[ 1346242-78-1 ]
[ 1346242-81-6 ]

Reference： [1]Patent: WO2011/135376,2011,A1

21
[ 50-00-0 ]
[ 1346242-81-6 ]
C₂₆H₃₀N₆O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64%	In 1,4-dioxane; water; at 20℃; for 72.0h;	A solution of N-(3 ,5 -dimethoxyphenyl)-N'-( 1 -methylethyl)-N- [3 -( 1 -methyl- 1 H-pyrazol-4- yl)quinoxalin-6-yl]ethane-l,2-diamine (intermediate 1) (0.42g; 0.9mmol), formaldehyde (37% solution in water; 0.2 lmL; 2.8mmol) in dioxane (8mL) was stirred at room temperature for 3 days. Water and EtOAc were added. The organic layer was decanted, washed with water, dried over MgS04 and evaporated to dryness. The residue (0.52 g) was purified by chromatography over silica gel (Stationary phase: Spherical bare silica 5muiotaeta 150x30.0mm, Mobile phase: (0479) Gradient from 0.2% NH4OH, 98% DCM, 2% MeOH to 1.2% NH4OH, 88% DCM, 12% MeOH). The fractions containing the desired product were collected and evaporated to dryness. The residue (0.37 g) was crystallized from a mixture of MeOH and Et20. The precipitate was filtered off and dried, yielding 0.27 g (64 %) of compound 1 (MP: 190 C (DSC)).

Reference： [1]Patent: WO2015/144803,2015,A1 .Location in patent: Page/Page column 57

22
[ 1346242-81-6 ]
[ 104-15-4 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
90%	In acetonitrile at 25 - 55℃; for 15h;	10 Preparation of Erdafitinib PTSA salt Impure Erdafitinib (500 mg) obtained from example 9 and acetonitrile (6 mL) were added into a flask and the mixture was heated to 50-55 °C to get a solution. A solution of i-toluene sulfonic acid (190 mg) in acetonitrile (3 mL) was added drop wise at 50-55°C to the above solution and stirred for 3 h. The slurry containing precipitated solid was stirred for 12 h at 25-30°C. The solid, obtained by filtration, was washed with THF (15 mL) and dried under reduced pressure below 45°C to obtain the PTSA salt as a yellow solid. Yield: 0.625 g (90%) HPLC purity: 99.98%; Impurity A: 0.02% NMR (400 MHz, DMSO-76) S 9.01 (s, 1H), 8.53 (s, 1H), 8.31 (brs, 2H), 8.20 (d, 7 = 0.4 Hz, 1H), 7.82 (d, 7= 9.1 Hz, 1H), 7.47 (d, 7= 8.1 Hz, 2H), 7.28 (d, 7 = 2.6 Hz, 1H), 7.24 (dd, 7 = 9.1, 2.7 Hz, 1H), 7.10 (d, 7 = 7.8 Hz, 2H), 6.50 (d, 7 = 2.2 Hz, 2H), 6.47 (t, 7 = 2.1 Hz, 1H), 4.09 (t, 7 = 7.5 Hz, 2H), 3.94 (s, 3H), 3.76 (s, 6H), 3.46 - 3.33 (m, 1H), 3.25 - 3.10 (m, 2H), 2.28 (s, 3H), 1.22 (d, 7 = 6.5 Hz, 6H)

Reference： [1]Current Patent Assignee: DR REDDY'S LABORATORIES LIMITED - WO2020/208592, 2020, A1 Location in patent: Page/Page column 24

23
[ CAS Unavailable ]
[ 1346242-81-6 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate In water at 25 - 30℃; for 0.5h;	11 Preparation of Erdafitinib from Erdafitinib PTSA salt. Erdafitinib PTSA salt (600 mg) obtained from example 10 and water (14 mL) were added into a flask at 25-30°C. The pH was adjusted to 7-8 by adding 10 % aqueous sodium bicarbonate solution to the reaction mixture which was then stirred for 30 min at 25-35 °C. The reaction mass was extracted with ethyl acetate (2 x 18 mL) and washed with brine solution. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain Erdafitinib. HPLC purity: 99.98 % Impurity A: 0.02%

Reference： [1]Current Patent Assignee: DR REDDY'S LABORATORIES LIMITED - WO2020/208592, 2020, A1 Location in patent: Page/Page column 24-25

24
[ 1346242-81-6 ]
[ 65-85-0 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
85%	In acetonitrile at 25 - 55℃; for 16h;	12 Preparation of Erdafitinib benzoate salt Impure Erdafitinib (500 mg) obtained from example 9 and acetonitrile (7 mL) were added into a flask and the mixture was heated to 50-55 °C to get a solution. Benzoic acid (136 mg) was added at 50-55°C to the above solution and stirred for 4 h. The slurry containing precipitated solid was stirred for 12 h at 25-30°C. The solid, obtained by filtration, washed with THF. The solid was stirred in THF (10 mL) for 16 h, filtered and dried under reduced pressure below 45°C to obtain the benzoate salt as yellow solid. Yield: 85 % HPLC purity: 99.97% Impurity A: 0.03% NMR (400 MHz, DMSO) d 8.96 (s, 1H), 8.53 (s, 1H), 8.19 (s, 1H), 8.02 - 7.87 (m, 2H), 7.76 (d, J= 9.2 Hz, 1H), 7.61 - 7.50 (m, 1H), 7.49 - 7.39 (m, 2H), 7.29 (d, J = 9.2 Hz, 1H), 7.18 (s, 1H), 6.47 (d, J = 2.2 Hz, 2H), 6.44 - 6.36 (m, 1H), 4.06 - 3.85 (m, 5H), 3.74 (s, 6H), 3.00 - 2.75 (m, 3H), 1.04 (d, J= 5.9 Hz, 6H).

Reference： [1]Current Patent Assignee: DR REDDY'S LABORATORIES LIMITED - WO2020/208592, 2020, A1 Location in patent: Page/Page column 25

25
[ 2895-21-8 ]
[ 1346242-81-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: potassium carbonate; potassium iodide / N,N-dimethyl-formamide / 17 h / 20 - 85 °C / Inert atmosphere 2.1: lithium aluminium tetrahydride / tetrahydrofuran / 17.5 h / 0 - 75 °C / Inert atmosphere 3.1: caesium carbonate / toluene / 0.25 h / Inert atmosphere; Reflux 3.2: 17 h / 110 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: DR REDDY'S LABORATORIES LIMITED - WO2020/208592, 2020, A1

26
[ 110-15-6 ]
[ 1346242-81-6 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
89%	In acetonitrile at 25 - 55℃; for 16h;	13 Preparation of Erdafitinib succinate salt Impure Erdafitinib (500 mg) obtained from example 9 and acetonitrile (7 mL) were added into a flask and the mixture was heated to 50-55 °C to get a solution. Succinic acid (132 mg) was added at 50-55°C to the above solution and stirred for 4 h. The slurry containing precipitated solid was stirred for 12 h at 25-30°C. The solid, obtained by filtration, was washed with THF. The solid was stirred in THF (10 mL) for 16 h, filtered and dried under reduced pressure below 45°C to obtain the benzoate salt as a yellow solid. Yield: 89 % HPLC purity: 99.98% Impurity A: 0.02% NMR (400 MHz, D20) d 8.62 (s, 1H), 8.15 (s, 1H), 8.03 (s, 1H), 7.57 (d, J = 9.2 Hz, 1H), 7.11 (d, J= 9.6 Hz, 1H), 7.02 (s, 1H), 6.49 (s, 1H), 6.45 (s, 2H), 4.16 (t, J= 7.1 Hz, 2H), 3.96 (s, 3H), 3.78 (s, 6H), 3.50 - 3.41 (m, 1H), 3.33 (t, J= 6.8 Hz, 2H), 2.44 (s, 2H), 1.32 (d, J= 6.5 Hz, 6H).

Reference： [1]Current Patent Assignee: DR REDDY'S LABORATORIES LIMITED - WO2020/208592, 2020, A1 Location in patent: Page/Page column 25-26

27
[ 1020931-81-0 ]
[ 1346242-81-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: lithium aluminium tetrahydride / tetrahydrofuran / 17.5 h / 0 - 75 °C / Inert atmosphere 2.1: caesium carbonate / toluene / 0.25 h / Inert atmosphere; Reflux 2.2: 17 h / 110 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: DR REDDY'S LABORATORIES LIMITED - WO2020/208592, 2020, A1

28
[ 1083325-87-4 ]
[ 2504933-33-7 ]
[ 1346242-81-6 ]

Yield	Reaction Conditions	Operation in experiment
89%	With palladium diacetate; Cs₂CO₃; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In toluene at 100℃; for 12h; Inert atmosphere;
85%	Stage #1: 7-bromo-2-(1-methyl-1H-pyrazol-4-yl)-quinoxaline; N<SUP>1</SUP>-(3,5-dimethoxyphenyl)-N<SUP>2</SUP>-isopropylethane-1,2-diamine With Cs₂CO₃ In toluene for 0.25h; Inert atmosphere; Reflux; Stage #2: With tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In toluene at 110℃; for 17h; Inert atmosphere;	4 Preparation of Erdafitinib Compound of Formula III (1.0 g, 4.20 mmoles) obtained from example-3 and toluene (20 mL) were added at room temperature into a 100 mL flask equipped with a magnetic stir bar and reflux condenser. Compound of Formula IV (1.82 g) and CS2CO3 (4.0 g) were added into the reaction flask under N2 atmosphere. The reaction mass was purged with argon gas for 15 minutes. Pd2(dba)3 (0.384 g) and Xantphos (0.239 g) were added into the reaction mixture under N2 atmosphere. The reaction mass was again purged with argon gas for 15 minutes. The reaction mixture was refluxed at 110 °C for 17 h. The progress of the reaction was monitored by TLC. The reaction mixture was cooled to room temperature after completion of the reaction and filtered through a pad of Celite. The Celite pad was washed with ethyl acetate (25 mL). The combined organic layers were dried over sodium sulphate and evaporated under reduced pressure below 40 °C to obtain crude product. The crude product was purified by column chromatography using silica gel (100-200 mesh) and 10% MeOH in ethyl acetate as eluent to obtain Erdafitinib as a yellow solid. Yield: 1.6 g, Yield (%): 85%The PXRD pattern of the isolated material is represented as Figure- 1.

Reference： [1]Xu, Zhiyong; Wang, Han; Jiang, Shun; Lu, Sheng; Mao, Yongjun [Journal of Heterocyclic Chemistry, 2022, vol. 59, # 12, p. 2093 - 2097]
[2]Current Patent Assignee: DR REDDY'S LABORATORIES LIMITED - WO2020/208592, 2020, A1 Location in patent: Page/Page column 22

29
[ 1346242-81-6 ]
[ 1346242-82-7 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride In isopropyl alcohol at 60℃;	14 Preparation of Erdafitinib HC1 salt Impure Erdafitinib (500 mg) obtained from example 9 and IPA (2 mL) were added into a flask and the mixture was heated to 60 °C to get a solution. Isopropanolic hydrochloride (IPA.HC1) was added slowly to the reaction mixture at 60 °C to adjust pH to 2. The precipitated product slurry was cooled to 25-30°C. Erdafitinib hydrochloride salt was obtained by filtration as a solid. The solid was stirred in THF (2.5 mL) for 18 h and filtered under vacuum. Yield: HPLC purity: 99.73% Impurity A: 0.27% 1H NMR (400 MHz, DMSO-i) S 9.10 (s, 2H), 9.02 (s, 1H), 8.57 (s, 1H), 8.22 (s, 1H), 7.83 (d, J = 9.2 Hz, 1H), 7.38 (d, J = 9.2 Hz, 1H), 7.26 (d, J = 2.7 Hz, 1H), 6.94 (brs, 2H), 6.51 (d, J = 2.2 Hz, 2H), 6.45 (t, J = 2.1 Hz, 1H), 4.21 (t, J = 7.3 Hz, 2H), 3.94 (s, 3H), 3.76 (s, 6H), 3.42 - 3.27 (m, 1H), 3.24 - 3.03 (m, 2H), 1.25 (d, J = 6.5 Hz, 6H).

Reference： [1]Current Patent Assignee: DR REDDY'S LABORATORIES LIMITED - WO2020/208592, 2020, A1 Location in patent: Page/Page column 26

30
[ 706819-66-1 ]
[ 1346242-81-6 ]

Reference： [1]Patent: CN112047929,2020,A
[2]Patent: CN112079816,2020,A

31
[ 97-02-9 ]
[ 1346242-81-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: water / 100 - 110 °C 2.1: indium; hydrogenchloride / water / 100 - 110 °C 3.1: potassium <i>tert</i>-butylate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; palladium diacetate / 1,2-dimethoxyethane / 1 h / 135 °C / Inert atmosphere; Microwave irradiation 4.1: tetrabutylammomium bromide; potassium hydroxide / water; tetrahydrofuran / 2 h / 0 - 20 °C / Inert atmosphere 4.2: 6 h / 55 °C
	Multi-step reaction with 4 steps 1.1: magnesium sulfate / ethanol / 50 - 60 °C 2.1: sodium dithionite / water / 45 - 55 °C 3.1: potassium <i>tert</i>-butylate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / 1,2-dimethoxyethane / 0.5 h / 20 °C / Inert atmosphere 3.2: 1 h / 135 °C / Microwave irradiation 4.1: tert-butylamine hydrobromide; potassium hydroxide / water; tetrahydrofuran / 2 h / 0 - 5 °C / Inert atmosphere 4.2: 6 h / 55 °C / Inert atmosphere
	Multi-step reaction with 6 steps 1.1: water / 100 - 110 °C 2.1: water; sodium dithionite / 45 - 90 °C 3.1: trichlorophosphate / N,N-dimethyl-formamide / 1 h / 0 °C 3.2: 16 h / 20 - 100 °C 4.1: ethanol / 80 - 85 °C 5.1: potassium <i>tert</i>-butylate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / 1,2-dimethoxyethane / 0.5 h / 20 °C / Inert atmosphere 5.2: 1 h / 135 °C / Microwave irradiation; Inert atmosphere 6.1: tert-butylamine hydrobromide; potassium hydroxide / tetrahydrofuran; water / 2 h / 0 - 20 °C / Inert atmosphere 6.2: 6 h / 55 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: SUZHOU MIRACPHARMA TECHNOLOGY CO LTD - CN112047929, 2020, A
[2]Current Patent Assignee: SUZHOU MIRACPHARMA TECHNOLOGY CO LTD - CN112079818, 2020, A
[3]Current Patent Assignee: SUZHOU MIRACPHARMA TECHNOLOGY CO LTD - CN112125888, 2020, A

32
[ 2566668-60-6 ]
[ 1346242-81-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: indium; hydrogenchloride / water / 100 - 110 °C 2.1: potassium <i>tert</i>-butylate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; palladium diacetate / 1,2-dimethoxyethane / 1 h / 135 °C / Inert atmosphere; Microwave irradiation 3.1: tetrabutylammomium bromide; potassium hydroxide / water; tetrahydrofuran / 2 h / 0 - 20 °C / Inert atmosphere 3.2: 6 h / 55 °C

Reference： [1]Current Patent Assignee: SUZHOU MIRACPHARMA TECHNOLOGY CO LTD - CN112047929, 2020, A

33
[ 1346245-08-6 ]
[ 75-31-0 ]
[ 1346242-81-6 ]

Yield	Reaction Conditions	Operation in experiment
89.7%	Stage #1: N-(3,5-dimethoxyphenyl)-N-[2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]ethyl]-3 -(1-methyl-1H-pyrazol-4-yl)-6-quinoxalinamine With methanesulfonyl chloride; triethylamine In dichloromethane at 20℃; for 4h; Inert atmosphere; Stage #2: isopropylamine In acetonitrile at 100℃; for 18h;	3 Under nitrogen protection, add N-(3,5-dimethoxyphenyl)-N-[2-[[(1,1-dimethylethyl)dimethylsilyl]oxy to the reaction flask ]Ethyl)-3-(1-methyl-1H-pyrazol-4-yl)-6-quinoxalinamine (V) (2.6g, 5mmol), methylsulfonyl chloride (1.15g, 10mmol), Triethylamine (1.26 g, 12.5 mmol) and 50 mL of dichloromethane were stirred at room temperature for 4 hours. The reaction was quenched with water, and the organic phase was washed successively with saturated sodium bicarbonate solution and water, dried, and concentrated to dryness. The above concentrate was dissolved in 25 mL of acetonitrile, 2-propylamine (1.2 g, 20 mmol) was added at room temperature, and the temperature was raised to 100° C. and the reaction was stirred for 18 hours. Cool to room temperature, add saturated sodium bicarbonate aqueous solution and 2-methyltetrahydrofuran, stir for 15 minutes, stand still and separate. Separate the organic phase, wash with saturated sodium bicarbonate aqueous solution and water successively, and dry with anhydrous magnesium sulfate. Concentrate to dryness under reduced pressure and recrystallize with isopropanol to obtain 2.0 g of white solid erdafitinib (VI) with a yield of 89.7%.
89.7%	Stage #1: N-(3,5-dimethoxyphenyl)-N-[2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]ethyl]-3 -(1-methyl-1H-pyrazol-4-yl)-6-quinoxalinamine With methanesulfonyl chloride; triethylamine In dichloromethane at 20℃; for 4h; Stage #2: isopropylamine In acetonitrile at 20 - 100℃; for 18h;	4 Under nitrogen protection,Add N-(3,5-dimethoxyphenyl)-N-[2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]ethyl] into the reaction flask -3-(1-methyl-1H-pyrazol-4-yl)-6-quinoxalinamine (V) (2.6g, 5mmol), methylsulfonyl chloride (1.15g, 10mmol), triethylamine ( 1.26g, 12.5mmol) and 50mL of dichloromethane,Stir at room temperature for 4 hours. The reaction was quenched with water, the organic phase was washed successively with saturated sodium bicarbonate solution and water, and dried,Concentrate to dryness. Dissolve the above concentrate with 25 mL of acetonitrile, add 2-propylamine (1.2 g, 20 mmol) at room temperature,The temperature was raised to 100°C and the reaction was stirred for 18 hours. Cool to room temperature,Add saturated aqueous sodium bicarbonate solution and 2-methyltetrahydrofuran,Stir for 15 minutes and let stand for layering. Separate the organic phase,Wash with saturated sodium bicarbonate aqueous solution and water successively,Dry with anhydrous magnesium sulfate. Concentrate to dryness under reduced pressure and recrystallize with isopropanol to obtain 2.0 g of erdafitinib (VI) as a white solid, with a yield of 89.7%.
89.7%	Stage #1: N-(3,5-dimethoxyphenyl)-N-[2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]ethyl]-3 -(1-methyl-1H-pyrazol-4-yl)-6-quinoxalinamine With methanesulfonyl chloride; triethylamine In dichloromethane at 20℃; for 4h; Inert atmosphere; Stage #2: isopropylamine In acetonitrile at 20 - 100℃; for 18h;	6 Embodiment 6: Under nitrogen protection, add to the reaction flask N-(3,5-Dimethoxyphenyl)-N-[2-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]ethyl]-3-(1 -Methyl-1H-pyrazol-4-yl)-6-quinoxalinamine (VI) (2.6g, 5mmol), Methanesulfonyl chloride (1.15g, 10mmol), Triethylamine (1.26 g, 12.5 mmol) and 50 mL of dichloromethane were stirred at room temperature for 4 hours. The reaction was quenched with water, and the organic phase was washed with saturated sodium bicarbonate solution and water successively, Dry and concentrate to dryness. The above-mentioned concentrate was dissolved in 25 mL of acetonitrile, 2-propylamine (1.2 g, 20 mmol) was added at room temperature, and the temperature was raised to 100° C. and the reaction was stirred for 18 hours. Cool to room temperature, add saturated sodium bicarbonate aqueous solution and 2-methyltetrahydrofuran, stir for 15 minutes, and stand to separate layers. Separate the organic phase, wash with saturated sodium bicarbonate aqueous solution and water successively, Dry with anhydrous magnesium sulfate. Concentrate to dryness under reduced pressure and recrystallize with isopropanol to obtain 2.0 g of erdatinib (VII) as a white solid. The yield was 89.7%,

Reference： [1]Current Patent Assignee: SUZHOU MIRACPHARMA TECHNOLOGY CO LTD - CN112079816, 2020, A Location in patent: Paragraph 0024; 0033-0034
[2]Current Patent Assignee: SUZHOU MIRACPHARMA TECHNOLOGY CO LTD - CN112079817, 2020, A Location in patent: Paragraph 0025; 0034-0035
[3]Current Patent Assignee: SUZHOU MIRACPHARMA TECHNOLOGY CO LTD - CN112125889, 2020, A Location in patent: Paragraph 0042-0043

34
[ 2567730-28-1 ]
[ 1346242-81-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: hydrogenchloride; indium / water / 100 - 110 °C 2.1: palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; caesium carbonate / 1,2-dimethoxyethane / 2 h / 80 °C / Inert atmosphere 3.1: methanesulfonyl chloride; triethylamine / dichloromethane / 4 h / 20 °C / Inert atmosphere 3.2: 18 h / 100 °C

Reference： [1]Current Patent Assignee: SUZHOU MIRACPHARMA TECHNOLOGY CO LTD - CN112079816, 2020, A

35
[ 875-51-4 ]
[ 1346242-81-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: water / 100 - 110 °C 2.1: hydrogenchloride; indium / water / 100 - 110 °C 3.1: palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; caesium carbonate / 1,2-dimethoxyethane / 2 h / 80 °C / Inert atmosphere 4.1: methanesulfonyl chloride; triethylamine / dichloromethane / 4 h / 20 °C / Inert atmosphere 4.2: 18 h / 100 °C
	Multi-step reaction with 4 steps 1.1: magnesium sulfate / 50 - 60 °C 2.1: sodium dithionite / water / 45 - 90 °C 3.1: caesium carbonate; palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / 1,2-dimethoxyethane / 2.5 h / 20 - 80 °C / Inert atmosphere 4.1: methanesulfonyl chloride; triethylamine / dichloromethane / 4 h / 20 °C 4.2: 18 h / 20 - 100 °C
	Multi-step reaction with 6 steps 1.1: water / 100 - 110 °C 2.1: sodium dithionite / water / 4 h / 44 - 55 °C 3.1: trichlorophosphate / 1 h / 0 °C 3.2: 16 h / 20 - 100 °C 4.1: ethanol / 80 - 85 °C 5.1: (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene" to "2,2′-bis(diphenylphosphino)-1,1′-binaphthalene; palladium diacetate; caesium carbonate / 1,2-dimethoxyethane / 2 h / 20 - 80 °C / Inert atmosphere 6.1: methanesulfonyl chloride; triethylamine / dichloromethane / 4 h / 20 °C / Inert atmosphere 6.2: 18 h / 20 - 100 °C

Reference： [1]Current Patent Assignee: SUZHOU MIRACPHARMA TECHNOLOGY CO LTD - CN112079816, 2020, A
[2]Current Patent Assignee: SUZHOU MIRACPHARMA TECHNOLOGY CO LTD - CN112079817, 2020, A
[3]Current Patent Assignee: SUZHOU MIRACPHARMA TECHNOLOGY CO LTD - CN112125889, 2020, A

36
[ 1380345-34-5 ]
[ 1346242-81-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: magnesium sulfate / 50 - 60 °C 2.1: sodium dithionite / water / 45 - 90 °C 3.1: caesium carbonate; palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / 1,2-dimethoxyethane / 2.5 h / 20 - 80 °C / Inert atmosphere 4.1: methanesulfonyl chloride; triethylamine / dichloromethane / 4 h / 20 °C 4.2: 18 h / 20 - 100 °C
	Multi-step reaction with 4 steps 1.1: magnesium sulfate / ethanol / 50 - 60 °C 2.1: sodium dithionite / water / 45 - 55 °C 3.1: potassium <i>tert</i>-butylate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / 1,2-dimethoxyethane / 0.5 h / 20 °C / Inert atmosphere 3.2: 1 h / 135 °C / Microwave irradiation 4.1: tert-butylamine hydrobromide; potassium hydroxide / water; tetrahydrofuran / 2 h / 0 - 5 °C / Inert atmosphere 4.2: 6 h / 55 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: SUZHOU MIRACPHARMA TECHNOLOGY CO LTD - CN112079817, 2020, A
[2]Current Patent Assignee: SUZHOU MIRACPHARMA TECHNOLOGY CO LTD - CN112079818, 2020, A

37
[ 2567559-54-8 ]
[ 1346242-81-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: sodium dithionite / water / 45 - 90 °C 2.1: caesium carbonate; palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / 1,2-dimethoxyethane / 2.5 h / 20 - 80 °C / Inert atmosphere 3.1: methanesulfonyl chloride; triethylamine / dichloromethane / 4 h / 20 °C 3.2: 18 h / 20 - 100 °C

Reference： [1]Current Patent Assignee: SUZHOU MIRACPHARMA TECHNOLOGY CO LTD - CN112079817, 2020, A

38
[ 2567609-29-2 ]
[ 1346242-81-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: sodium dithionite / water / 45 - 55 °C 2.1: potassium <i>tert</i>-butylate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / 1,2-dimethoxyethane / 0.5 h / 20 °C / Inert atmosphere 2.2: 1 h / 135 °C / Microwave irradiation 3.1: tert-butylamine hydrobromide; potassium hydroxide / water; tetrahydrofuran / 2 h / 0 - 5 °C / Inert atmosphere 3.2: 6 h / 55 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: SUZHOU MIRACPHARMA TECHNOLOGY CO LTD - CN112079818, 2020, A

39
[ 2577306-95-5 ]
[ 1346242-81-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: sodium dithionite / water / 4 h / 44 - 55 °C 2.1: trichlorophosphate / 1 h / 0 °C 2.2: 16 h / 20 - 100 °C 3.1: ethanol / 80 - 85 °C 4.1: (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene" to "2,2′-bis(diphenylphosphino)-1,1′-binaphthalene; palladium diacetate; caesium carbonate / 1,2-dimethoxyethane / 2 h / 20 - 80 °C / Inert atmosphere 5.1: methanesulfonyl chloride; triethylamine / dichloromethane / 4 h / 20 °C / Inert atmosphere 5.2: 18 h / 20 - 100 °C

Reference： [1]Current Patent Assignee: SUZHOU MIRACPHARMA TECHNOLOGY CO LTD - CN112125889, 2020, A

40
[ 2577306-96-6 ]
[ 1346242-81-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: trichlorophosphate / 1 h / 0 °C 1.2: 16 h / 20 - 100 °C 2.1: ethanol / 80 - 85 °C 3.1: (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene" to "2,2′-bis(diphenylphosphino)-1,1′-binaphthalene; palladium diacetate; caesium carbonate / 1,2-dimethoxyethane / 2 h / 20 - 80 °C / Inert atmosphere 4.1: methanesulfonyl chloride; triethylamine / dichloromethane / 4 h / 20 °C / Inert atmosphere 4.2: 18 h / 20 - 100 °C

Reference： [1]Current Patent Assignee: SUZHOU MIRACPHARMA TECHNOLOGY CO LTD - CN112125889, 2020, A

41
[ 2577306-97-7 ]
[ 1346242-81-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: ethanol / 80 - 85 °C 2.1: (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene" to "2,2′-bis(diphenylphosphino)-1,1′-binaphthalene; palladium diacetate; caesium carbonate / 1,2-dimethoxyethane / 2 h / 20 - 80 °C / Inert atmosphere 3.1: methanesulfonyl chloride; triethylamine / dichloromethane / 4 h / 20 °C / Inert atmosphere 3.2: 18 h / 20 - 100 °C

Reference： [1]Current Patent Assignee: SUZHOU MIRACPHARMA TECHNOLOGY CO LTD - CN112125889, 2020, A

42
[ 1346133-39-8 ]
[ 58203-30-8 ]
[ 1346242-81-6 ]

Yield	Reaction Conditions	Operation in experiment
81.5%	Stage #1: N‐(3,5‐dimethoxyphenyl)‐3‐(1‐methyl‐1H‐pyrazol‐4‐yl)quinoxalin‐6‐amine With tert-butylamine hydrobromide; potassium hydroxide In tetrahydrofuran; water at 0 - 20℃; for 2h; Inert atmosphere; Stage #2: N-(2-chloroethyl)-N-propylamine hydrochloride In tetrahydrofuran; water at 55℃; for 6h; Inert atmosphere;	6 Nitrogen protection and 05, Add N-(3,5-Dimethoxyphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-6-quinoxalinamine (VI) (1.8g) to the reaction flask ,5mmol), Tert-butylammonium bromide (1.15g, 2.5mmol), Potassium hydroxide (4.2g, 75mmol), 100 mL of tetrahydrofuran and 5 mL of water. To room temperature, The reaction was stirred for 2 hours. Add N-(2-chloroethyl)-2-propylamine hydrochloride (1.6g, 10mmol), Warm up to 55°C, The reaction was stirred for 6 hours. Cool to room temperature, Add dilute hydrochloric acid to adjust the pH to neutral, Dichloromethane extraction three times, Separate the organic phase, Wash with saturated brine and water successively, Dry with anhydrous magnesium sulfate. Concentrate under reduced pressure to dryness and recrystallize with isopropanol to obtain 1.9 g of erdatinib (VII) as a white solid. The yield was 81.5%,

Reference： [1]Current Patent Assignee: SUZHOU MIRACPHARMA TECHNOLOGY CO LTD - CN112125888, 2020, A Location in patent: Paragraph 0029; 0042-0043

43
[ 2570470-47-0 ]
[ 1346242-81-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: water; sodium dithionite / 45 - 90 °C 2.1: trichlorophosphate / N,N-dimethyl-formamide / 1 h / 0 °C 2.2: 16 h / 20 - 100 °C 3.1: ethanol / 80 - 85 °C 4.1: potassium <i>tert</i>-butylate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / 1,2-dimethoxyethane / 0.5 h / 20 °C / Inert atmosphere 4.2: 1 h / 135 °C / Microwave irradiation; Inert atmosphere 5.1: tert-butylamine hydrobromide; potassium hydroxide / tetrahydrofuran; water / 2 h / 0 - 20 °C / Inert atmosphere 5.2: 6 h / 55 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: SUZHOU MIRACPHARMA TECHNOLOGY CO LTD - CN112125888, 2020, A

44
[ 1522127-31-6 ]
[ 1346242-81-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: trichlorophosphate / N,N-dimethyl-formamide / 1 h / 0 °C 1.2: 16 h / 20 - 100 °C 2.1: ethanol / 80 - 85 °C 3.1: potassium <i>tert</i>-butylate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / 1,2-dimethoxyethane / 0.5 h / 20 °C / Inert atmosphere 3.2: 1 h / 135 °C / Microwave irradiation; Inert atmosphere 4.1: tert-butylamine hydrobromide; potassium hydroxide / tetrahydrofuran; water / 2 h / 0 - 20 °C / Inert atmosphere 4.2: 6 h / 55 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: SUZHOU MIRACPHARMA TECHNOLOGY CO LTD - CN112125888, 2020, A

45
[ 2657666-24-3 ]
[ 75-31-0 ]
[ 1346242-81-6 ]

Yield	Reaction Conditions	Operation in experiment
76.6%	With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 14h;	10-12 Example 10 Synthesis of compound represented by formula I At room temperature, compound 8 (7.1 g, 0.12 mol) was added to a stirred THF solution (400 mL) of compound 7 (42.4 g, 0.1 mol) and DIPEA (16.2 g, 0.125 mol), and stirred for 14 hours until the reaction was completed. The reaction solution was concentrated by half the volume, washed with saturated NaHCO3 solution (50mL), extracted with ethyl acetate (60mL*3 times) for 3 times, dried and concentrated the organic phase, and purified by column chromatography (using a 1:1 volume ratio of petroleum ether and A mixed solvent of ethyl acetate) to obtain the compound of formula I erdatinib as a white solid, the yield is 33.1 g, the yield is 76.6%, and the HPLC purity is 99.6%.
89.18 %	With potassium iodide at 100℃; Sealed tube;	8 Example 8 N1-(3,5-dimethoxyphenyl)-N2-(1-methylethyl)-N1-[3-(1-methyl-1H-pyrazol-4-yl)quinoxaline- 6-yl]-1,2-ethylenediamine(Compound 1) Preparation Compound 15 (2.00g, 4.27mmol), KI (0.71g, 4.27mmol),Isopropylamine (10mL) was stirred and dissolved in a closed tetrafluoro tube, and reacted at 100°C for 18h,The reaction solution was placed at room temperature, and TLC detected that the reaction was complete; EA (30mL*3) was added to the reaction solution, extracted with water (30mL), dried over anhydrous Na2SO4,Concentration under reduced pressure gave a yellow solid (2.72 g) which was air-dried at 60°C,Add isopropanol and recrystallize to obtain crystal N1-(3,5-dimethoxyphenyl)-N2-(1-methylethyl)-N1-[3-(1-methyl-1H-pyrazole- 4-yl)quinoxalin-6-yl]-1,2-ethylenediamine 1 (1.70 g, 89.18%).

Reference： [1]Current Patent Assignee: WUHAN JIUZHOU YUMIN PHARMACEUTICAL TECH - CN113024517, 2021, A Location in patent: Paragraph 0068-0074
[2]Current Patent Assignee: SHANGHAI UNIVERSITY OF ENGINEERING SCIENCES - CN115108926, 2022, A Location in patent: Paragraph 0048; 0071-0073

46
[ 1346242-81-6 ]
[ 64-19-7 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
59%	In acetone at 20℃;	1 Procedure A 1.9 grams of Erdafitinib (HPLC purity 88.7%) was dissolved in refluxing acetone (16 mL). Acetic acid (1 mol. eq., 0.249 ml) was added. Mixture was left spontaneously to cool to room temperature while stirred overnight. After 20 hours, thick suspension was filtered and product was washed with acetone (2 ml) yielding 1.296 g (59 %) of yellow Erdafitinib acetate. The obtained solid was analyzed by XRPD and the XRPD pattern is presented in Figure 1. HPLC purity 97.81 %.

Reference： [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2022/40111, 2022, A2 Location in patent: Paragraph 00144

47
[ CAS Unavailable ]
[ 1346242-81-6 ]
[ 2762064-63-9 ]

Yield	Reaction Conditions	Operation in experiment
88%	In 2-methyltetrahydrofuran at -5 - 65℃; for 2.5h;	2-3; 9 Example 3: Preparation of Form D of Erdafitinib Formate Erdafitinib (HPLC purity 97.80%, 1.0 grams) was suspended in 2-methyl tetrahydrofurane (59 mL). The solid phase was dissolved by heating to 65°C in 100 mL glass reactor with PBT impeller (300 rpm). Formic acid (103 mg - 1 eq) was then added at 65°C. The solution was left to cool down until it reached a temperature of 58°C. At this point the solution was seeded (with about 4 mg of Form B Erdafitinib formic acid salt, prepared according to Example 2). Further cooled down according to linear cooling ramp from 58°Cto (- 5°C) over 150 minutes. The product gradually crystallized from the moment of seeding. The refrigerated suspension was left to stand in (at 0°C in multireactor station) until the next day without stirring. In the morning the crystalline phase was blended, separated by filtration and washed with 10 mL of 2-Me-THF. The cake was dried up on the filter at room temperature during 3 hours. Yield 0.96 grams (88%), HPLC purity was 99.96%. The obtained solid was analyzed by XRPD and the XRPD pattern is presented in Figure 3.

Reference： [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2022/40111, 2022, A2 Location in patent: Paragraph 00145-00146; 00153

48
[ 75-75-2 ]
[ 1346242-81-6 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
	In acetone at 5 - 20℃; for 1.25h;	4 Example 4: Preparation of Form F of Erdafitinib Mesylate 500 mg of Erdafitinib (purity: 98.47% by HPLC) was suspended in 6.2 ml acetone at RT, during 30 min heated up to 50 °C, clear solution was cooled down to 20 °C during 30 minutes. At 20 °C 75 pl (1 eq.) methanesulfonic acid was added. After 15 minutes at 20 °C, suspension was cooled down to 5 °C and stirred for 1 hour. The suspension was filtered and dried at RT under vacuum during 10 minutes. The obtained solid (purity: 99.15% by HPLC) was analyzed by XRPD and the XRPD pattern is presented in Figure 4.

Reference： [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2022/40111, 2022, A2 Location in patent: Paragraph 00147

49
[ 2762064-63-9 ]
[ 1346242-81-6 ]

Yield	Reaction Conditions	Operation in experiment
85%	With ammonium hydroxide In Isopropyl acetate; water monomer at -5 - 80℃; for 3h; Inert atmosphere;	10 Example 10: Conversion of Erdafitinib formate Erdafitinib (pure) Erdafitinib formate (441 grams, 0.89 mol) was suspended in purified water (5.52L, 12.5 ml/g). Isopropyl acetate (5.52L, 12.5 ml/g) was added and the system was properly inertized. The mixture was heated at 30-35°C and stirred until all material was dissolved. An aqueous ammonia solution 25% (154 ml, 2.30 eq) was added (pH > 8). The mixture was extracted with isopropylacetate/water and the organic layer was distilled under reduced pressure to about 3.9L (8.7 - 9.0 V/SM) while heating at 60-70°C. The mixture was then heated at 75-80°C under atmospheric pressure, and stirred until the solids were dissolved. The solution was cooled to -5°C over about 3 hours. During cooling, when the mixture reached a temperature of 65°C, it was seeded with Erdafitinib crystals (3.3 grams, 0.005 g/g) (the seeding with Erdafitinib crystals is optional). The mixture was stirred at -5°C for 1 hour, and the product was separated by filtration, washed with cooled isopropyl acetate (670ml; 1.5 V) and dried, (yield 85 %). Purity 99.95% by HPLC.

Reference： [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2022/40111, 2022, A2 Location in patent: Paragraph 00154

50
[ 1196-57-2 ]
[ 1346242-81-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: acetic acid; bromine / 6.5 h / 20 °C 2: trichlorophosphate / 2 h / 100 °C 3: palladium diacetate; sodium carbonate; triphenylphosphine / 1,4-dioxane; water / 20 h / 100 °C / Inert atmosphere 4: palladium diacetate; Xantphos; caesium carbonate / toluene / 12 h / 100 °C / Inert atmosphere
	Multi-step reaction with 5 steps 1: acetic acid; bromine / 20 °C 2: trichlorophosphate / 100 °C 3: palladium diacetate; sodium carbonate; triphenylphosphine / 1,4-dioxane / 100 °C / Inert atmosphere 4: palladium diacetate; Xantphos; caesium carbonate / toluene / Inert atmosphere; Reflux 5: potassium iodide / 18 h / 100 °C / Sealed tube

Reference： [1]Xu, Zhiyong; Wang, Han; Jiang, Shun; Lu, Sheng; Mao, Yongjun [Journal of Heterocyclic Chemistry, 2022, vol. 59, # 12, p. 2093 - 2097]
[2]Current Patent Assignee: SHANGHAI UNIVERSITY OF ENGINEERING SCIENCES - CN115108926, 2022, A

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Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 1346242-81-6 ] {[proInfo.proName]}

Quality Control of [ 1346242-81-6 ]

Related Doc. of [ 1346242-81-6 ]

Product Details of [ 1346242-81-6 ]

Safety of [ 1346242-81-6 ]

Application In Synthesis of [ 1346242-81-6 ]

[ 1346242-81-6 ] Synthesis Path-Upstream 1~14

[ 1346242-81-6 ] Synthesis Path-Downstream 1~50

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry