6973-09-7|5-Amino-2-methylbenzenesulfonamide| Ambeed

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Quality Control of [ 6973-09-7 ] Purity: 95% SDS Specification

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Product Details of [ 6973-09-7 ]

CAS No. :	6973-09-7
Formula :	C₇H₁₀N₂O₂S
M.W :	186.23
SMILES Code :	O=S(C1=CC(N)=CC=C1C)(N)=O
MDL No. :	MFCD06681071
InChI Key :	KTPBKMYOIFHJMI-UHFFFAOYSA-N
Pubchem ID :	235511

Safety of [ 6973-09-7 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H315-H319
Precautionary Statements:	P264-P280-P302+P352-P337+P313-P305+P351+P338-P362+P364-P332+P313

Computational Chemistry of [ 6973-09-7 ] Show Less

Physicochemical Properties

Num. heavy atoms	12
Num. arom. heavy atoms	6
Fraction Csp3	0.14
Num. rotatable bonds	1
Num. H-bond acceptors	3.0
Num. H-bond donors	2.0
Molar Refractivity	46.81
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	94.56 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	0.37
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	0.17
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.31
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	0.05
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-0.3
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	0.32

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.41
Solubility	7.32 mg/ml ; 0.0393 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-1.71
Solubility	3.6 mg/ml ; 0.0193 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-1.99
Solubility	1.89 mg/ml ; 0.0102 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	No
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	No
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-7.32 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	1.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	1.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	1.75

Application In Synthesis of [ 6973-09-7 ]

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

Downstream synthetic route of [ 6973-09-7 ]

[ 6973-09-7 ] Synthesis Path-Downstream 1~35

1
[ 200266-64-4 ]
[ 6973-09-7 ]

References: [1]Organic Preparations and Procedures International,1997,vol. 29,p. 671 - 677.
[2]Zhurnal Prikladnoi Khimii,1938,vol. 11,p. 316,318, 323.
Chemisches Zentralblatt,1939,vol. 110,p. 4934.

2
[ 98-01-1 ]
[ 6973-09-7 ]
5-(2'-Furfurylideneamino)-2-toluenesulfonamide [ No CAS ]

References: [1]Organic Preparations and Procedures International,1997,vol. 29,p. 671 - 677.

3
[ 527-69-5 ]
[ 6973-09-7 ]
Furan-2-carboxylic acid (4-methyl-3-sulfamoyl-phenyl)-amide [ No CAS ]

References: [1]Organic Preparations and Procedures International,1997,vol. 29,p. 671 - 677.

4
[ 26726-16-9 ]
[ 6973-09-7 ]
5-Bromo-furan-2-carboxylic acid (4-methyl-3-sulfamoyl-phenyl)-amide [ No CAS ]

References: [1]Organic Preparations and Procedures International,1997,vol. 29,p. 671 - 677.

5
[ 698-63-5 ]
[ 6973-09-7 ]
5-(5'-Nitro-2'-furfurylideneamino)-2-toluenesulfonamide [ No CAS ]

References: [1]Organic Preparations and Procedures International,1997,vol. 29,p. 671 - 677.

6
[ 4521-33-9 ]
[ 6973-09-7 ]
5-(5'-Nitro-2'-thienylmethylideneamino)-2-toluenesulfonamide [ No CAS ]

References: [1]Organic Preparations and Procedures International,1997,vol. 29,p. 671 - 677.

7
[ 25084-14-4 ]
[ 6973-09-7 ]
5-Nitro-furan-2-carboxylic acid (4-methyl-3-sulfamoyl-phenyl)-amide [ No CAS ]

References: [1]Organic Preparations and Procedures International,1997,vol. 29,p. 671 - 677.

8
[ 7147-77-5 ]
[ 6973-09-7 ]
5-[5'-(p-Nitrophenyl)-2'-furfurylideneamino]-2-toluenesulfonamide [ No CAS ]

References: [1]Organic Preparations and Procedures International,1997,vol. 29,p. 671 - 677.

9
[ 6973-09-7 ]
[ 89-98-5 ]
5-(o-Chlorobenzylideneamino)-2-toluenesulfonamide [ No CAS ]

References: [1]Organic Preparations and Procedures International,1997,vol. 29,p. 671 - 677.

10
[ 6973-09-7 ]
[ 555-16-8 ]
5-(p-Nitrobenzylideneamino)-2-toluenesulfonamide [ No CAS ]

References: [1]Organic Preparations and Procedures International,1997,vol. 29,p. 671 - 677.

11
[ 6973-09-7 ]
[ 122-01-0 ]
5-(p-Chlorobenzoylamino)-2-toluenesulfonamide [ No CAS ]

References: [1]Organic Preparations and Procedures International,1997,vol. 29,p. 671 - 677.

12
[ 6973-09-7 ]
[ 122-04-3 ]
5-(p-Nitrobenzoylamino)-2-toluenesulfonamide [ No CAS ]

References: [1]Organic Preparations and Procedures International,1997,vol. 29,p. 671 - 677.

13
[ 64-17-5 ]
[ 6973-09-7 ]
mixture of gaseous nitrogen oxides [ No CAS ]
[ 88-19-7 ]

References: [1]Justus Liebigs Annalen der Chemie,1883,vol. 221,p. 208.

Yield	Reaction Conditions	Operation in experiment
95.1%	With ethanol; tin(ll) chloride; at 70℃; for 6h;	General procedure: Take 8a (558mg, 3mmol) was dissolved in absolute ethanol (30.0 mL of), the The addition of stannous chloride (5.0 equiv.) Was carried out at 70 °C for 6 h, TLC was monitored until the reaction was complete, cooled to room temperature, With 5percent sodium bicarbonate solution to adjust the pH to 9-10, A large amount of yellow floc appears in the system, extracted with ethyl acetate, The organic phase was washed with saturated brine, the organic phase was separated, Dried over anhydrous sodium sulfate, filtered to obtain a filtrate, the organic reagent was distilled off, A yellow oil was added thereto, ethyl acetate was added thereto, The petroleum ether regulates the polarity of the system, and a large amount of solid appears. The yellow powder is filtered 9a (210mg, 41.7percent).

15
4-nitro-toluene-sulfonic acid-⁽²⁾-amide [ No CAS ]
[ 6973-09-7 ]

References: [1]Justus Liebigs Annalen der Chemie,1883,vol. 221,p. 208.

16
[ 103-89-9 ]
[ 6973-09-7 ]

References: [1]Organic Preparations and Procedures International,1997,vol. 29,p. 671 - 677.

17
[ 6269-91-6 ]
[ 6973-09-7 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; tin(ll) chloride; In diethylene glycol dimethyl ether; water; for 0.75h;	To a stirred solution of 2-methyl-5-nitrobenzenesulfonamide (4.6 g, 0.021 mol) in 2-methoxyethyl ether (43 mL), at [0] C, was added a solution of 16.1 g [OF TIN (II)] chloride in 32 mL of concentrated HCI dropwise over 15 min. After the addition was complete, the ice bath was removed and the solution was allowed to stir for an additional 30 min. Approximately 130 mL of diethyl ether was added to reaction. The mixture was stirred vigorously for 1 h. The mixture was basified with a solution of [NAOH] and [NAHCO3,] and extracted with ethyl acetate (x 3). The combined ethyl acetate layers were dried over anhydrous [MGS04,] filtered and concentrated to give crude product. Trituation of the crude product with methanol provided 2.4 g of pure [5-AMINO-2-METHYLBENZENESULFONAMIDE] as light brown [SOLID.APOS;H] NMR (300 MHz, DMSO-d6) [# 7.11-7. ] 10 (m, 3H), 6.95 (d, J = 8. 1 Hz, [1 H),] 6.60 (dd, J = 8.1 [# 2.4 HZ, 1H),] 5.24 (s, 2H), 2.36 (s, 3H). MS [(ES+,] m/z) 187 (M+H).
	With hydrogen;palladium 10% on activated carbon; In methanol; dichloromethane; under 2585.81 Torr; for 0.25h;	To a solution of 3-aminosulfonyl-4-methylnitrobenzene in dichloromethane and methanol was added 10percent Pd/C and the mixture shaken under a hydrogen atmosphere at 50 psi for 15 minutes. The mixture was filtered through diatomaceous earth and the filter cake was washed with methanol. The combined organic solvents were concentrated under reduced pressure to give crude product, which was further purified by flash column chromatography (ethyl acetate:hexanes 1:1) to give 3-aminosulfonyl-4-methylaniline, LCMS: purity: 87percent; MS (m/e): 187 (MH+).
	palladium-carbon; In methanol; dichloromethane;	To a solution of 3-aminosulfonyl-4-methylnitrobenzene in dichloromethane and methanol was added 10percent Pd/C and the mixture shaken under a hydrogen atmosphere at 50 psi for 15 minutes.The mixture was filtered through diatomaceous earth and the filter cake was washed with methanol.The combined organic solvents were concentrated under reduced pressure to give crude product, which was further purified by flash column chromatography (ethyl acetate:hexanes 1:1) to give 3-aminosulfonyl-4-methylaniline, LCMS: purity: 87percent; MS (m/e): 187 (MH+).

	With palladium 10% on activated carbon; hydrogen; In methanol; dichloromethane; under 2585.81 Torr; for 0.25h;	To a solution of 3-aminosulfonyl-4-methylnitrobenzene in dichloromethane and methanol was added 10percent Pd/C and the mixture shaken under a hydrogen atmosphere at 50 psi for 15 minutes. The mixture was filtered through diatomaceous earth and the filter cake was washed with methanol. The combined organic solvents were concentrated under reduced pressure to give crude product, which was further purified by flash column chromatography (ethyl acetate:hexanes 1:1) to give 3-aminosulfonyl-4-methylaniline, LCMS: purity: 87percent; MS (m/e): 187 (MH+).
	With palladium 10% on activated carbon; hydrogen; In methanol; dichloromethane; under 2585.81 Torr; for 0.25h;	To a solution of 3-aminosulfonyl-4-methylnitrobenzene in dichloromethane and methanol was added 10percent Pd/C and the mixture shaken under a hydrogen atmosphere at 50 psi for 15 minutes. The mixture was filtered through diatomaceous earth and the filter cake was washed with methanol. The combined organic solvents were concentrated under reduced pressure to give crude product, which was further purified by flash column chromatography (ethyl acetate:hexanes 1:1) to give 3-aminosulfonyl-4-methylaniline, LCMS: purity: 87percent; MS (m/e): 187 (M+).
	With palladium 10% on activated carbon; hydrogen; In methanol; dichloromethane; under 2585.81 Torr; for 0.25h;	To a solution of 3-aminosulfonyl-4-methylnitrobenzene in dichloromethane and methanol was added 10 percentPd/C and the mixture shaken under a hydrogen atmosphere at 50 psi for 15 minutes. The mixture was filtered throughdiatomaceous earth and the filter cake was washed with methanol. The combined organic solvents were concentratedunder reduced pressure to give crude product, which was further purified by flash column chromatography (ethyl acetate:hexanes 1:1) to give 3-aminosulfonyl-4-methylaniline, LCMS: purity: 87percent; MS (m/e): 187 (MH+).
		To a stirred solution of 2-methyl-5-nitrobenzenesulfonamide (4.6 g, 0.021 mol) in 2-methoxyethyl ether (43 mL), at 0° C., was added a solution of 16.1 g of tin(II) chloride in 32 mL of concentrated HCl dropwise over 15 min. After the addition was complete, the ice bath was removed and the solution was allowed to stir for an additional 30 min. Approximately 130 mL of diethyl ether was added to reaction. The mixture was stirred vigorously for 1 h. The mixture was basified with a solution of NaOH and NaHCO3, and extracted with ethyl acetate (*3). The combined ethyl acetate layers were dried over anhydrous MgSO4, filtered and concentrated to give crude product. Trituation of the crude product with methanol provided 2.4 g of pure 5-amino-2-methylbenzenesulfonamide as light brown solid. 1H NMR (300 MHz, DMSO-d6) delta 7.11-7.10 (m, 3H), 6.95 (d, J=8.1 Hz, 1H), 6.60 (dd, J=8.1 and 2.4 Hz, 1H), 5.24 (s, 2H), 2.36 (s, 3H). MS (ES+, m/z) 187 (M+H).
	With hydrogenchloride; tin(ll) chloride; In diethyl ether; diethylene glycol dimethyl ether; water; at 0℃; for 1.75h;	Intermediate Example 5 Preparation of 5-amino-2-methylbenzenesulfonamide Procedure 1 To a stirred solution of 2-methyl-5-nitrobenzenesulfonamide (4.6 g, 0.021 mol) in 2-methoxyethyl ether (43 mL), at 0 °C, was added a solution of 16.1 g of tin(II) chloride in 32 mL of concentrated HCI dropwise over 15 min. After the addition was complete, the ice bath was removed and the solution was allowed to stir for an additional 30 min. Approximately 130 mL of diethyl ether was added to reaction. The mixture was stirred vigorously for 1 h. The mixture was basified with a solution of NaOH and NaHC03, and extracted with ethyl acetate (x 3). The combined ethyl acetate layers were dried over anhydrous MgS04, filtered and concentrated to give crude product. Trituation of the crude product with methanol provided 2.4 g of pure 5-amino-2- methylbenzenesulfonamide as light brown solid.

References: [1]Patent: WO2003/106416,2003,A2 .Location in patent: Page 46.
[2]Patent: US2011/28503,2011,A1 .Location in patent: Page/Page column 11.
[3]Patent: US2012/232106,2012,A1 .
[4]Patent: US2014/73659,2014,A1 .Location in patent: Paragraph 0117.
[5]Patent: US2014/206708,2014,A1 .Location in patent: Paragraph 0088.
[6]Patent: EP2683385,2018,B1 .Location in patent: Paragraph 0106; 0108.
[7]Patent: US2008/293691,2008,A1 .Location in patent: Page/Page column 10.
[8]Patent: WO2005/105094,2005,A2 .Location in patent: Page/Page column 33-34.

18
[ 444731-75-3 ]
[ 6973-09-7 ]
pazopanib hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97%	With hydrogenchloride; In isopropyl alcohol;Reflux;	Example 4b: Synthesis of Pazopanib Hydrochloride (0040) To a suspension of <strong>[444731-75-3]N-(2-chloropyrimidin-4-yl)-N-2,3-trimethyl-2H-indazol-6-amine</strong> (90 g, 0.312 mol) and 5-amino-2-methyl benzene sulfonamide (64.07 g, 0.344 mol) in isopropyl alcohol (900 mL) was added 4M hydrochloric acid solution in isopropyl alcohol (1.56 mL, 6.25 mol). The reaction mixture was heated to reflux temperature for 10 hours to 12 hours. The reaction mixture was cooled to 25 C. The reaction mixture was further stirred at 25 C. to 30 C. for 30 minutes, then the solid was filtered. The wet solid was washed with isopropyl alcohol (180 mL×2), and then dried under vacuum at 45 C. to 50 C. for 12 hours to afford the hydrochloride salt of 5-({4-[(2,3-dimethyl-21-I-indazol-6-yl)(methyl) amino] pyrimidin-2-yl} amino-Z-methylbenzene sulfonamide as a light brown solid. Yield: 97% w/w.
96.4%		A 250-mL 3-necked flask equipped with a magnetic stir bar, thermometer, reflux condenser, and nitrogen inlet/outlet was charged with ethanol (60 ml_, 10 volumes), the product of Intermediate Example 4 (6.00 g, 20.85 mmol, 1.0 equiv) and 5-amino-2-rnethylbenzenesulfonamide (4.00 g, 21.48 mmol, 1.03 equiv) with stirring. The reaction mixture was heated to 70 0C. After stirring the reaction mixture at 68 - 72 0C for 3 hrs, 4M HCI in dioxane (0.11 mL, 0.44 mmol, 0.02 equiv) was charged over ca. 2 min. The reaction mixture was stirred at 68 - 72 0C until < 1.5% by area of the starting product of Intermediate Example 4 was remaining by HPLC analysis (Typically, this reaction is complete in > 8 hrs). The reaction mixture was cooled to 20 <n="33"/>0C over ca. 30 min and stirred at 20 - 22 0C for 40 min. The product was then isolated by filtration and the filter cake washed with ethanol (20 mL, 3.3 volumes). The wet cake was dried under vacuum at 45 - 50 0C. The monohydrochloride salt of 5-({4- [(2,3-dimethyl-2H-indazol-6-yl)(methyl)amino]-pyrimidin-2-yl}amino)-2- methylbenzenesulfonamide (9.52 g, 96.4%) was isolated as a white solid. 1H NMR (400 MHz, d6DMSO+NaHCO3) delta 9.50 (br s, 1 H), 8.55 (br s, 1 H), 7.81 (d, J = 6.2 Hz, 1 H), 7.75 (d, J = 8.7 Hz, 1 H), 7.69 (m, 1 H), 7.43 (s, 1 H), 7.23 (s, 2H), 7.15 (d, J = 8.4 Hz, 1 H), 6.86 (m, 1 H), 5.74 (d, J = 6.1 Hz, 1 H), 4.04 (s, 3H), 3.48 (s, 3H), 2.61 (s, 3H), 2.48 (s, 3H). MS (ES+, m/z) 438 (M+H).
96.4%		A 250-mL 3-necked flask equipped with a magnetic stir bar, thermometer, reflux condenser, and nitrogen inlet/outlet was charged with ethanol (60 mL, 10 volumes), the product of Intermediate Example 4 (6.00 g, 20.85 mmol, 1.0 equiv) and 5-amino-2-methylbenzenesulfonamide (4.00 g, 21.48 mmol, 1.03 equiv) with stirring. The reaction mixture was heated to [70 C.] After stirring the reaction mixture at 68- [72 C] for 3 hrs, 4M HCI in dioxane (0.11 mL, 0.44 mmol, 0.02 equiv) was charged over ca. 2 min. The reaction mixture was stirred at [68-72 C UNTIL] < 1. [5%] by area of the starting product of Intermediate Example 4 was remaining by HPLC analysis (Typically, this reaction is complete in > 8 hrs). The reaction mixture was cooled to [20 C] over ca. 30 min and stirred at [20-22 C] for 40 min. The product was then isolated by filtration and the filter cake washed with ethanol (20 mL, 3.3 volumes). The wet cake was dried under vacuum at [45-50 C.] The [MONOHYDROCHLORIDE] salt of [5- ( {4- [ (2,] 3- [DIMETHYL-2H-INDAZOL-6-YL) (METHYL) AMINO]-PYRIMIDIN-2-YL} AMINO)-2-] [METHYLBENZENESULFONAMIDE] (9.52 g, 96. [40/0)] was isolated as a white [SOLID.'H] NMR (400 MHz, [D6DMSO+NAHCO3)] 8 9.50 (br s, [1] [H),] 8.55 (br s, 1 H), 7.81 (d, J = 6.2 Hz, 1 H), 7.75 (d, J = 8.7 Hz, 1H), 7.69 (m, 1H), 7.43 (s, [1 H),] 7. [23 (S, 2H),] 7.15 [(D, J =] 8.4 Hz, 1H), 6. [86] (m, [1 H),] 5.74 (d, J = 6.1 Hz, 1H), 4.04 (s, 3H), 3.48 (s, 3H), 2.61 (s, 3H), 2.48 (s, 3H). MS (ES+, m/z) 438 (M+H).

96.4%	With hydrogenchloride; In 1,4-dioxane; ethanol; at 68 - 72℃; for 11.0333h;Product distribution / selectivity;	A 250-mL 3-necked flask equipped with a magnetic stir bar, thermometer, reflux condenser, and nitrogen inlet/outlet was charged with ethanol (60 mL, 10 volumes), the product of Intermediate Example 4 (6.00 g, 20.85 mmol, 1.0 equiv) and 5-amino-2- methylbenzenesulfonamide (4.00 g, 21.48 mmol, 1.03 equiv) with stirring. The reaction mixture was heated to 70 0C. After stirring the reaction mixture at 68 - 72 0C for 3 hrs, 4M HCI in dioxane (0.11 mL, 0.44 mmol, 0.02 equiv) was charged over ca. 2 min. The reaction mixture was stirred at 68 - 72 0C until < 1.5% by area of the starting product of Intermediate Example 4 was remaining by HPLC analysis (Typically, this reaction is complete in > 8 hrs). The reaction mixture was cooled to 20 0C over ca. 30 min and stirred at 20 - 22 0C for 40 min. The product was then isolated by filtration and the filter cake washed with ethanol (20 mL, 3.3 volumes). The wet cake was dried under vacuum at 45 - 50 0C. The monohydrochloride salt of 5-({4-[(2,3-dimethyl-2/-/-indazol- 6-yl)(methyl)amino]-pyrimidin-2-yl}amino)-2-methylbenzenesulfonamide (9.52 g, 96.4%) was isolated as a white solid. 1H NMR (400 MHz, d6DMSO+NaHCO3) delta 9.50 (br s, 1 H), 8.55 (br s, 1 H), 7.81 (d, J = 6.2 Hz, 1 H), 7.75 (d, J = 8.7 Hz, 1 H), 7.69 (m, 1 H), 7.43 (s, 1 H), 7.23 (s, 2H), 7.15 (d, J = 8.4 Hz1 1 H), 6.86 (m, 1 H)1 5.74 (d, J = 6.1 Hz, 1 H), 4.04 (s, 3H), 3.48 (s, 3H), 2.61 (s, 3H)1 2.48 (s, 3H). MS (ES+, m/z) 438 (M+H).
96.4%		A 250-mL 3-necked flask equipped with a magnetic stir bar, thermometer, reflux condenser, and nitrogen inlet/outlet was charged with ethanol (60 mL, 10 volumes), the product of Intermediate Example 4 (6.00 g, 20.85 mmol, 1.0 equiv) and 5-amino-2-methylbenzenesulfonamide (4.00 g, 21.48 mmol, 1.03 equiv) with stirring. The reaction mixture was heated to 70 C. After stirring the reaction mixture at 68-72 C. for 3 hrs, 4M HCl in dioxane (0.11 mL, 0.44 mmol, 0.02 equiv) was charged over ca. 2 min. The reaction mixture was stirred at 68-72 C. until <1.5% by area of the starting product of Intermediate Example 4 was remaining by HPLC analysis (Typically, this reaction is complete in >8 hrs). The reaction mixture was cooled to 20 C. over ca. 30 min and stirred at 20-22 C. for 40 min. The product was then isolated by filtration and the filter cake washed with ethanol (20 mL, 3.3 volumes). The wet cake was dried under vacuum at 45-50 C. The monohydrochloride salt of 5-({4-[(2,3-dimethyl-2H-indazol-6-yl)(methyl)amino]-pyrimidin-2-yl}amino)-2-methylbenzenesulfonamide (9.52 g, 96.4%) was isolated as a white solid. 1H NMR (400 MHz, d6DMSO+NaHCO3) delta 9.50 (br s, 1H), 8.55 (br s, 1H), 7.81 (d, J=6.2 Hz, 1H), 7.75 (d, J=8.7 Hz, 1H), 7.69 (m, 1H), 7.43 (s, 1H), 7.23 (s, 2H), 7.15 (d, J=8.4 Hz, 1H), 6.86 (m, 1H), 5.74 (d, J=6.1 Hz, 1H), 4.04 (s, 3H), 3.48 (s, 3H), 2.61 (s, 3H), 2.48 (s, 3H). MS (ES+, m/z) 438 (M+H).
96.4%		Procedure 2 A 250-mL 3-necked flask equipped with a magnetic stir bar, thermometer, reflux condenser, and nitrogen inlet/outlet was charged with ethanol (60 mL, 10 volumes), the product of Intermediate Example 4 (6.00 g, 20.85 mmol, 1.0 equiv) and 5-amino-2-methylbenzenesulfonamide (4.00 g, 21.48 mmol, 1.03 equiv) with stirring. The reaction mixture was heated to 70 C. After stirring the reaction mixture at 68 - 72 C for 3 hrs, 4M HCI in dioxane (0.11 mL, 0.44 mmol, 0.02 equiv) was charged over ca. 2 min. The reaction mixture was stirred at 68 - 72 C until < 1.5% by area of the starting product of Intermediate Example 4 was remaining by HPLC analysis (Typically, this reaction is complete in > 8 hrs). The reaction mixture was cooled to 20 C over ca. 30 min and stirred at 20 - 22 C for 40 min. The product was then isolated by filtration and the filter cake washed with ethanol (20 mL, 3.3 volumes). The wet cake was dried under vacuum at 45 - 50 C. The monohydrochloride salt of 5-({4-[(2,3-dimethyl-2H-indazol-6- yl)(methyl)amino]-pyrimidin-2-yl)amino)-2-methylbenzenesulfonamide (9.52 g, 96.4%) was isolated as a white solid.
96.4%		A 250-mL 3-necked flask equipped with a magnetic stir bar, thermometer, reflux condenser, and nitrogen inlet/outlet was charged with ethanol (60 ml_, 10 volumes), Intermediate Example 4 (6.00 g, 20.85 mmol, 1.0 equiv) and 5-amino-2- methylbenzenesulfonamide (4.00 g, 21.48 mmol, 1.03 equiv) with stirring. The reaction mixture was heated to 70 0C. After stirring the reaction mixture at 68 - 72 0C for 3 hrs, 4M HCI in dioxane (0.1 1 ml_, 0.44 mmol, 0.02 equiv) was charged over ca. 2 min. The reaction mixture was stirred at 68 - 72 0C until < 1.5% by area of the starting product of Intermediate Example 4 was remaining by HPLC analysis (Typically, this reaction is <n="36"/>complete in > 8 hrs). The reaction mixture was cooled to 20 0C over ca. 30 min and stirred at 20 - 22 0C for 40 min. The product was then isolated by filtration and the filter cake washed with ethanol (20 ml_, 3.3 volumes). The wet cake was dried under vacuum at 45 - 50 0C. The monohydrochloride salt of 5-({4-[(2,3-dimethyl-2H-indazol-6- yl)(methyl)amino]-pyhmidin-2-yl}amino)-2-methylbenzenesulfonamide (9.52 g, 96.4%) was isolated as a white solid. 1H NMR (400 MHz, d6DMSO+NaHCO3) delta 9.50 (br s, 1 H), 8.55 (br s, 1 H), 7.81 (d, J = 6.2 Hz, 1 H), 7.75 (d, J = 8.7 Hz, 1 H), 7.69 (m, 1 H), 7.43 (s, 1 H), 7.23 (s, 2H), 7.15 (d, J = 8.4 Hz, 1 H), 6.86 (m, 1 H), 5.74 (d, J = 6.1 Hz, 1 H), 4.04 (s, 3H), 3.48 (s, 3H), 2.61 (s, 3H), 2.48 (s, 3H). MS (ES+, m/z) 438 (M+H).
92%		To a stirred suspension of the product of Intermediate Example 4 (1.1 g, 3.7 mmol) in 10 mL of THF, was added 5-amino-2-methylbenzenesulfonamide (0.70 g, 3.8 mmol, 1.0 equiv) at room temperature. The reaction mixture was heated at reflux for 3 h, then 4 M HCI in 1 ,4-dioxane (18 muL, 0.072 mmol) was added in one portion. After 5 h, the suspension was cooled to room temperature, and filtered. The resulting solid was washed with 16 mL of THF and dried in the air to yield 1.6 g (92%) of 5-({4- [(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl}amino)-2-methylbenzene sulfonamide monohydrochloride as a light yellow solid.
92%		To a stirred suspension of the product of Intermediate Example 4 (1.1 g, 3.7 [MMOL)] in 10 mL of THF, was added 5-amino-2-methylbenzenesulfonamide (0.70 g, 3.8 mmol, 1.0 equiv) at room temperature. The reaction mixture was heated at reflux for 3 h, then 4 M HCI in 1,4-dioxane (18 l, 0.072 [MMOL)] was added in one portion. After 5 h, the suspension was cooled to room temperature, and filtered. The resulting solid was washed with 16 [ML OF THF AND] dried in the air to yield 1. [6 G (92%) OF 5-({4-[(2,] 3- dimethyl-2H-indazol-6-yl) [METHYLAMINO]-2-PYRIMIDINYL} AMINO)-2-METHYLBENZENE] sulfonamide monohydrochloride as a light yellow solid.
92%	With hydrogenchloride; In tetrahydrofuran; 1,4-dioxane; at 20℃; for 8h;Heating / reflux;Product distribution / selectivity;	To a stirred suspension of the product of Intermediate Example 4 (1 .1 g, 3.7 mmol) in 10 mL of THF, was added 5-amino-2-methylbenzenesulfonamide (0.70 g, 3.8 mmol, 1 .0 equiv) at room temperature. The reaction mixture was heated at reflux for 3 h, then 4 M HCI in 1 ,4-dioxane (18 muL, 0.072 mmol) was added in one portion. After 5 h, the suspension was cooled to room temperature, and filtered. The resulting solid was washed with 16 mL of THF and dried in the air to yield 1 .6 g (92%) of 5-({4-[(2,3- dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl}amino)-2-methylbenzene sulfonamide monohydrochloride as a light yellow solid.
92%		To a stirred suspension of the product of Intermediate Example 4 (1.1 g, 3.7 mmol) in 10 mL of THF, was added 5-amino-2-methylbenzenesulfonamide (0.70 g, 3.8 mmol, 1.0 equiv) at room temperature. The reaction mixture was heated at reflux for 3 h, then 4 M HCl in 1,4-dioxane (18 muL, 0.072 mmol) was added in one portion. After 5 h, the suspension was cooled to room temperature, and filtered. The resulting solid was washed with 16 mL of THF and dried in the air to yield 1.6 g (92%) of 5-({4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl}amino)-2-methylbenzene sulfonamide monohydrochloride as a light yellow solid.
92%		Procedure 4 To a stirred suspension of the product of Intermediate Example 4 (1.1 g, 3.7 mmol) in 10 mL of THF, was added 5-amino-2- methylbenzenesulfonamide (0.70 g, 3.8 mmol, 1.0 equiv) at room temperature. The reaction mixture was heated at reflux for 3 h, then 4 M HCI in 1,4-dioxane (18 muL, 0.072 mmol) was added in one portion. After 5 h, the suspension was cooled to room temperature, and filtered. The resulting solid was washed with 16 mL of THF and dried in the air to yield 1.6 g (92%) of 5- ({4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl)amino)-2- methylbenzene sulfonamide monohydrochloride as a light yellow solid.
92%		To a stirred suspension of Intermediate Example 4 (1.1 g, 3.7 mmol) in 10 mL of THF, was added 5-amino-2-methylbenzenesulfonamide (0.70 g, 3.8 mmol, 1.0 equiv) at room temperature. The reaction mixture was heated at reflux for 3 h, then 4 M HCI in 1 ,4-dioxane (18 mul_, 0.072 mmol) was added in one portion. After 5 h, the suspension was cooled to room temperature, and filtered. The resulting solid was washed with 16 mL of THF and dried in the air to yield 1.6 g (92%) of 5-({4-[(2,3-dimethyl-2H-indazol-6- yl)methylamino]-2-pyrimidinyl}amino)-2-methylbenzene sulfonamide monohydrochloride as a light yellow solid
88.5%	In acetic acid; at 55 - 100℃; for 28.5h;Product distribution / selectivity;	Example 60: Process for the preparation of PZP.HCI[000177] A 250 mL reactor equipped with a mechanical stirrer was charged with CPM I (4.84 g, 16.82 mmol), AMBS (3.29 g, 17.66 mmol, 1 .05 eq) and 90% acetic acid (29 mL, 6V) and the reaction mixture was heated to 55 C with stirring, leading to dissolution. After 3.5 h precipitation commenced and the reaction was continue for 22 h in total. The resulting mixture was then heated to 65 C over 0.5 h and stirring was continued at the same temperature for an additional 5 h. The reaction mixture was then heated to 100 C over 1 h leading to complete dissolution. Stirring was continued at the same temperature for 0.5 h and then EtOH abs. (48 mL, 10V) was added drop-wise with concomitant cooling to 80 C over a period of 0.5 h. The mixture was then cooled to 0 C over a period of 4 h and stirring was continued at the same temperature for 16 h. The solids were filtered and the filter cake was washed with EtOH abs. (4x 14.5 mL, 4x3 V) at Patent ApplicationAtty Docket No. 14669.0172 WOU 1 room temperature and dried in a vacuum oven (35 mbar) at 60 C for 22 h to give pure PZP.HC1 (7.05 g, 88.5% yield, 99.4% assay, 99.9% purity, 7.32% CI, CPMI < 20 ppm) as a beige powder.
81%	With hydrogenchloride; In 1,4-dioxane; methanol; at 50 - 85℃; for 10h;Heating / reflux;Product distribution / selectivity;	To a 2 L jacketed reactor was charged with MeOH (1005 ml_), the product of Intermediate Example 4 (84 g, 0.292 mol, 1 equiv) and 5-amino-2- methylbenzenesulfonamide (60 g, 0.320 mol, 1.1 equiv). The solution was stirred and heated to 50 0C and 4M HCI in Dioxane (1.46 ml_, 2 mol%) was added. The solution was then stirred and heated to reflux with a jacket temperature of 85 0C for 10 hours. The resulting slurry was then cooled to 20-25 0C and filtered. The filtered solid was washed with acetonitrile (293 ml_ X 2) at room temperature. After drying at overnight, under vacuum at 60 0C afforded 116 g (81%) of 5-({4-[(2,3-dimethyl-2H-indazol-6- yl)methylamino]-2-pyrimidinyl}amino)-2-methyl benzenesulfonamide monohydrochloride.
81%	With hydrogenchloride; In 1,4-dioxane; methanol; at 50 - 85℃; for 10h;Heating / reflux;Product distribution / selectivity;	To a 2 L jacketed reactor was charged with MeOH (1005 mL), Intermediate Example 4 (84 g, 0.292 mol, 1 equiv) and 5-amino-2-methylbenzenesulfonamide (60 g, 0.320 mol, 1.1 equiv). The solution was stirred and heated to 50 0C and 4M HCI in Dioxane (1.46 mL, 2 mol%) was added. The solution was then stirred and heated to reflux with a jacket temperature of 85 0C for 10 hours. The resulting slurry was then cooled to 20-25 0C and filtered. The filtered solid was washed with acetonitrile (293 mL X 2) at room temperature. After drying at overnight, under vacuum at 60 0C afforded 1 16 g (81 %) of 5-({4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl}amino)- 2-methyl benzenesulfonamide monohydrochlohde.
73%		To a stirred suspension of the product of Intermediate Example 4 (1.0 g, 3.6 mmol) in 10 ml_ of CH3CN, was added 5-amino-2-methylbenzenesulfonamide (0.70 g, 3.8 mmol, 1.Oequiv) at room temperature. The reaction mixture was heated at reflux for 3 h, then 4 M HCI in 1 ,4-dioxane (18 mul_, 0.076 mmol) was added in one portion. After 20 h, the suspension was cooled to room temperature, and filtered. The resulting solid was washed with 10 ml_ of CH3CN and dried in the air to yield 1.3 g(73%) of 5-({4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl}amino)-2- methyl benzenesulfonamide monohydrochloride as an off-white solid.
73%		To a stirred suspension of the product of Intermediate Example 4 (1.0 g, 3.6 [MMOL)] in 10 mL of CH3CN, was added 5-amino-2-methylbenzenesulfonamide (0.70 g, 3.8 mmol, 1. [OEQUIV)] at room temperature. The reaction mixture was heated at reflux for 3 h, then 4 M HCI in 1,4-dioxane [(18] uL, 0.076 [MMOL)] was added in one portion. After 20 h, the suspension was cooled to room temperature, and filtered. The resulting solid was washed with 10 mL of CH3CN and dried in the air to yield 1.3 g [(73%)] of 5- [( {4- [ (2, 3-DIMETHYL-2H-INDAZOL-6-YL) METHYLAMINO]-2-PYRIMIDINYL} AMINO)-2-METHYL] [BENZENESULFONAMIDE] [MONOHYDROCHLORIDE] as an off-white solid.
73%	With hydrogenchloride; In 1,4-dioxane; acetonitrile; at 20℃; for 23h;Heating / reflux;Product distribution / selectivity;	To a stirred suspension of the product of Intermediate Example 4 (1 .0 g, 3.6 mmol) in 10 mL of CH3CN, was added 5-amino-2-methylbenzenesulfonamide (0.70 g, 3.8 mmol, 1 .Oequiv) at room temperature. The reaction mixture was heated at reflux for 3 h, then 4 M HCI in 1 ,4-dioxane (18 muL, 0.076 mmol) was added in one portion. After 20 h, the suspension was cooled to room temperature, and filtered. The resulting solid was washed with 10 mL of CH3CINI and dried in the air to yield 1.3 g (73%) of 5-({4- [(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl}amino)-2-methyl benzenesulfonamide monohydrochloride as an off-white solid.
73%		To a stirred suspension of the product of Intermediate Example 4 (1.0 g, 3.6 mmol) in 10 mL of CH3CN, was added 5-amino-2-methylbenzenesulfonamide (0.70 g, 3.8 mmol, 1.0 equiv) at room temperature. The reaction mixture was heated at reflux for 3 h, then 4 M HCl in 1,4-dioxane (18 muL, 0.076 mmol) was added in one portion. After 20 h, the suspension was cooled to room temperature, and filtered. The resulting solid was washed with 10 mL of CH3CN and dried in the air to yield 1.3 g (73%) of 5-({4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl}amino)-2-methyl benzenesulfonamide monohydrochloride as an off-white solid.
73%		Procedure 5 To a stirred suspension of the product of Intermediate Example 4 (1.0 g, 3.6 mmol) in 10 mL of CH3CN, was added 5-amino-2- methylbenzenesulfonamide (0.70 g, 3.8 mmol, I.Oequiv) at room temperature. The reaction mixture was heated at reflux for 3 h, then 4 M HCI in 1,4-dioxane (18 (at)L, 0.076 mmol) was added in one portion. After 20 h, the suspension was cooled to room temperature, and filtered. The resulting solid was washed with 10 mL of CH3CN and dried in the air to yield 1.3 g (73%) of 5-((at)4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl}amino)-2- methyl benzenesulfonamide monohydrochloride as an off-white solid.
73%		To a stirred suspension of Intermediate Example 4 (1.0 g, 3.6 mmol) in 10 mL of CH3CN, was added 5-amino-2-methylbenzenesulfonamide (0.70 g, 3.8 mmol, <n="37"/>1.Oequiv) at room temperature. The reaction mixture was heated at reflux for 3 h, then 4 M HCI in 1 ,4-dioxane (18 mul_, 0.076 mmol) was added in one portion. After 20 h, the suspension was cooled to room temperature, and filtered. The resulting solid was washed with 10 mL of CH3CN and dried in the air to yield 1.3 g (73%) of 5-({4-[(2,3- dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl}amino)-2-methyl benzenesulfonamide monohydrochlohde as an off-white solid.
72%		To a stirred suspension of the product of Intermediate Example 4 (1.1 g, 3.8 mmol) in 14 mL of MeOH, was added 5-amino-2-methylbenzenesulfonamide (0.78 g, 4.2 mmol, 1.1 equiv) at room temperature. The reaction mixture was heated at reflux for 3 h, then 4 M HCI in 1 ,4-dioxane (19 mul_, 0.076 mmol) was added in one portion. After 4 h, the suspension was cooled to room temperature, and filtered. The resulting solid was washed with 10 mL of MeOH and dried in vacuo to yield 1.3 g (72%) of 5- ({4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl}amino)-2-methyl benzenesulfonamide monohydrochloride as a white solid. 1 H NMR (DMSO-d6, 400 MHz) delta 10.95 (s, 1 H), 8.36 (s, 1 H), 7.86 (d, J= 8.8 Hz, 2H), 7.64-7.59 (m, 2H), 7.40 (m, 3H), 6.93 (dd, J = 8.8, 2.0 Hz, 1 H), 5.92 (s, 1 H), 4.08 (s, 3H), 3.57 (s, 3H), 2.65 (s, 3H), 2.56 (s, 3H).
72%		To a stirred suspension of the product of Intermediate Example 4 (1.1 g, 3.8 [MMOL)] in 14 mL of MeOH, was added [5-AMINO-2-METHYLBENZENESULFONAMIDE] (0.78 g, 4.2 mmol, 1.1 equiv) at room temperature. The reaction mixture was heated at reflux for 3 h, then 4 M HCI in 1,4-dioxane (19 L, 0.076 [MMOL)] was added in one portion. After 4 h, the suspension was cooled to room temperature, and filtered. The resulting solid was washed with 10 mL of MeOH and dried in vacuo to yield 1.3 g [(72%)] of 5- ({4-[(2,3-=dimethyl-2H-indazol-6-yl)metylamino]-2-pyrimidinyl}amino)-2-mnethyl [BENZENESULFONAMIDE] [MONOHYDROCHLORIDE] as a white [SOLID. 1H] NMR [(DMSO-D6,] 400 MHz) [5] 10.95 (s, 1H), 8.36 (s, [1 H),] 7.86 (d, J = 8.8 Hz, 2H), 7.64-7. 59 (m, 2H), 7.40 (m, [3H),] 6.93 [(DD,] [J =] 8. 8, 2.0 Hz, 1H), 5.92 (s, 1H), 4.08 (s, [3H),] 3.57 (s, [3H),] 2.65 (s, 3H), 2. [56 (S, 3H).]
72%	With hydrogenchloride; In 1,4-dioxane; methanol; at 20℃; for 7h;Heating / reflux;Product distribution / selectivity;	To a stirred suspension of the product of Intermediate Example 4 (1 .1 g, 3.8 mmol) in 14 mL of MeOH, was added 5-amino-2-methylbenzenesulfonamide (0.78 g, 4.2 mmol, 1.1 equiv) at room temperature. The reaction mixture was heated at reflux for 3 h, then 4 M HCI in 1 ,4-dioxane (19 mul_, 0.076 mmol) was added in one portion. After 4 h, the suspension was cooled to room temperature, and filtered. The resulting solid was washed with 10 mL of MeOH and dried in vacuo to yield 1 .3 g (72%) of 5-({4- [(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl}amino)-2-methyl benzenesulfonamide monohydrochloride as a white solid. 1 H NMR (DMSO-d6, 400 MHz) delta 10.95 (s, 1 H), 8.36 (s, 1 H), 7.86 (d, J = 8.8 Hz, 2H), 7.64-7.59 (m, 2H), 7.40 (m, 3H), 6.93 (dd, J = 8.8, 2.0 Hz, 1 H), 5.92 (s, 1 H), 4.08 (s, 3H), 3.57 (s, 3H), 2.65 (s, 3H), 2.56 (s, 3H).
72 - 81%		To a stirred suspension of the product of Intermediate Example 4 (1.1 g, 3.8 mmol) in 14 mL of MeOH, was added 5-amino-2-methylbenzenesulfonamide (0.78 g, 4.2 mmol, 1.1 equiv) at room temperature. The reaction mixture was heated at reflux for 3 h, then 4 M HCl in 1,4-dioxane (19 muL, 0.076 mmol) was added in one portion. After 4 h, the suspension was cooled to room temperature, and filtered. The resulting solid was washed with 10 mL of MeOH and dried in vacuo to yield 1.3 g (72%) of 5-({4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl}amino)-2-methyl benzenesulfonamide monohydrochloride as a white solid. 1H NMR (DMSO-d6, 400 MHz) delta 10.95 (s, 1H), 8.36 (s, 1H), 7.86 (d, J=8.8 Hz, 2H), 7.64-7.59 (m, 2H), 7.40 (m, 3H), 6.93 (dd, J=8.8, 2.0 Hz, 1H), 5.92 (s, 1H), 4.08 (s, 3H), 3.57 (s, 3H), 2.65 (s, 3H), 2.56 (s, 3H).; Procedure 6To a 2 L jacketed reactor was charged with MeOH (1005 mL), the product of Intermediate Example 4 (84 g, 0.292 mol, 1 equiv) and 5-amino-2-methylbenzenesulfonamide (60 g, 0.320 mol, 1.1 equiv). The solution was stirred and heated to 50 C. and 4M HCl in Dioxane (1.46 mL, 2 mol %) was added. The solution was then stirred and heated to reflux with a jacket temperature of 85 C. for 10 hours. The resulting slurry was then cooled to 20-25 C. and filtered. The filtered solid was washed with acetonitrile (293 mL×2) at room temperature. After drying at overnight, under vacuum at 60 C. afforded 116 g (81%) of 5-({4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl}amino)-2-methyl benzenesulfonamide monohydrochloride.
72%		Procedure 3: To a stirred suspension of the product of Intermediate Example 4 (1.1 g, 3.8 mmol) in 14 mL of MeOH, was added 5-amino-2- methylbenzenesulfonamide (0.78 g, 4.2 mmol, 1.1 equiv) at room temperature. The reaction mixture was heated at reflux for 3 h, then 4 M HCI in 1,4-dioxane (19 muL, 0.076 mmol) was added in one portion. After 4 h, the suspension was cooled to room temperature, and filtered. The resulting solid was washed with 10 mL of MeOH and dried in vacuo to yield 1.3 g (72%) of 5- ((at)4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl}amino)-2-methyl benzenesulfonamide monohydrochloride as a white solid.
72%		To a stirred suspension of Intermediate Example 4 (1.1 g, 3.8 mmol) in 14 ml. of MeOH, was added 5-amino-2-methylbenzenesulfonamide (0.78 g, 4.2 mmol, 1.1 equiv) at room temperature. The reaction mixture was heated at reflux for 3 h, then 4 M HCI in 1 ,4-dioxane (19 mul_, 0.076 mmol) was added in one portion. After 4 h, the suspension was cooled to room temperature, and filtered. The resulting solid was washed with 10 ml. of MeOH and dried in vacuo to yield 1.3 g (72%) of 5-({4-[(2,3-dimethyl-2H-indazol- 6-yl)methylamino]-2-pyrimidinyl}amino)-2-methyl benzenesulfonamide monohydrochloride as a white solid. 1 H NMR (DMSO-d6, 400 MHz) delta 10.95 (s, 1 H), 8.36 (s, 1 H), 7.86 (d, J = 8.8 Hz, 2H), 7.64-7.59 (m, 2H), 7.40 (m, 3H), 6.93 (dd, J = 8.8, 2.0 Hz, 1 H), 5.92 (s, 1 H), 4.08 (s, 3H), 3.57 (s, 3H), 2.65 (s, 3H), 2.56 (s, 3H).
45.2%	With hydrogenchloride; In isopropyl alcohol; for 2h;Reflux;	A mixture of ISO-IM2 (0.7g, 2.4 mmol) and SM3 (0.44 g, 2.4 mmol), conc HCl 0.5ml in isopropanol (50 mL) was stirred at reflux for 2 h. The mixture was cooled to room temperature and the resultant precipitate was collected by filtration and washed with isopropanol. The solid was dried to give impurity I (0.52 g, 45.2 %) as a off-white solid. 1H NMR (300 MHz, DMSO-d6) (delta, ppm): 11.84 (s, 1H), 7.84 (d, J= 7.2 Hz, 1H), 7.73 - 7.75 (m, 2H), 7.67 (s, 1H), 7.40 - 7.42 (m, 2H), 6.98 (d, J = 8.7Hz, 1H), 6.71 (d, J = 6.8 Hz, 1H), 4.10 (s, 3H), 3.58 (s, 3H), 2.67 (s, 3H), 2.53 (s, 3H). 13C NMR (600 MHz, DMSO-d6) (delta, ppm): 160.8, 153.7, 147.2, 143.1, 142.6, 136.4, 133.0, 131.9, 124.2, 123.3, 120.8, 119.9, 119.1, 115.7, 99.6, 38.0, 19.7, 9.88; HRMSm/z calcd for C21H24N7O2S [M+H]+ 438.1707, found 438.1705.
	With hydrogenchloride; In water; isopropyl alcohol;Heating / reflux;Product distribution / selectivity;	To a solution of Intermediate Example 4 (200 mg, 0.695 mmol) and 5-amino-2- methylbenzenesulfonamide (129.4 mg, 0.695 mmol) in isopropanol (6 ml) was added 4 drops of cone. HCI. The mixture was heated to reflux overnight. The mixture was cooled to rt and diluted with ether (6 ml). Precipitate was collected via filtration and washed with ether. The hydrochloride salt of 5-({4-[(2,3-dimethyl-2H-indazol~6- yl)(methyl)amino]-pyrimidin-2-yl}amino)-2-methylbenzenesulfonamide was isolated as an off-white solid. 1H NMR (400 MHz, d6DMSO+NaHCO3) delta 9.50 (br s, 1 H), 8.55 (br s, 1 H), 7.81 (d, J= 6.2 Hz, 1 H), 7.75 (d, J = 8.7 Hz1 1 H), 7.69 (m, 1 H), 7.43 (s, 1 H), 7.23 (S1 2H), 7.15 (d, J= 8.4 Hz1 1H), 6.86 (m, 1 H), 5.74 (d, J= 6.1 Hz, 1 H), 4.04 (s, 3H), 3.48 (S1 3H)1 2.61 (s, 3H)1 2.48 (s, 3H). MS (ES+, m/z) 438 (M+H).
	With hydrogenchloride; In water; isopropyl alcohol;Heating / reflux;	To a solution of Intermediate Example 4 (200 mg, 0.695 [MMOL)] and 5-amino- 2-methylbenzenesulfonamide (129.4 mg, 0.695 [MMOL)] in isopropanol (6 ml) was added 4 drops of conc. HCI. The mixture was heated to reflux overnight. The mixture was cooled to rt and diluted with ether (6 [ML).] Precipitate was collected via filtration and washed with ether. The hydrochloride salt of [5- ( {4- [ (2, 3-DIMETHYL-2H-INDAZOL-6-] yl) (methyl) [AMINO]-PYRIMIDIN-2-YL} AMINO)-2-METHYIBENZENESULFONAMIDE] was isolated as an off-white [SOLID.'H NMR (400 MHZ, D6DMSO+NAHC03)] 8 9.50 (br s, 1 H), 8.55 (br s, 1H), 7.81 (d, [J= 6.] 2 Hz, [1 H),] 7.75 (d, J = 8.7 Hz, 1H), 7.69 (m, 1H), 7.43 (s, [1 H),] 7.23 (s, 2H), 7.15 (d, [J= 8.] 4 Hz, [1 H),] 6.86 (m, 1H), 5.74 (d, J = 6.1 Hz, [1 H),] 4.04 (s, 3H), 3.48 (s, 3H), 2.61 (s, 3H), 2.48 (s, 3H). MS [(ES+,] [M/Z)] 438 (M+H).
	With hydrogenchloride; In water; isopropyl alcohol;Heating / reflux;Product distribution / selectivity;	To a solution of Intermediate Example 4 (200 mg, 0.695 mmol) and 5-amino-2- methylbenzenesulfonamide (129.4 mg, 0.695 mmol) in isopropanol (6 ml) was added 4 drops of cone. HCI. The mixture was heated to reflux overnight. The mixture was cooled to rt and diluted with ether (6 ml). Precipitate was collected via filtration and washed with ether. The hydrochloride salt of 5-({4-[(2,3-dimethyl-2H-indazol-6- yl)(methyl)amino]-pyrimidin-2-yl}amino)-2-methylbenzenesulfonamide was isolated as an off-white solid. 1H NMR (400 MHz, d6DMSO+NaHCO3) delta 9.50 (br s, 1 H), 8.55 (br s, 1 H), 7.81 (d, J = 6.2 Hz, 1 H), 7.75 (d, J = 8.7 Hz, 1 H), 7.69 (m, 1 H), 7.43 (s, 1 H), 7.23 (s, 2H), 7.15 (d, J = 8.4 Hz, 1 H), 6.86 (m, 1 H), 5.74 (d, J = 6.1 Hz, 1 H), 4.04 (s, 3H), 3.48 (s, 3H), 2.61 (s, 3H), 2.48 (s, 3H). MS (ES+, m/z) 438 (M+H).
		Intermediate 3; Synthesis of 5-({4-[(2,3-dimethyl-2H-indazol-6-yl)(methyl)amino]-2- pyrimidinyl}amino)-2-methylbenzenesulfonamide Hydrochloride (Intermediate 3); Intermediate 3; <strong>[444731-75-3]N-(2-chloro-4-pyrimidinyl)-N,2,3-trimethyl-2H-indazol-6-amine</strong> (Intermediate 2) (1.66 kg, 5.8 mol, 1.0 equiv) and 5-amino-2-methyl benzenesulfonamide (Starting Material 3 (SM3)) (commercially available from Asymchem Laboratories (Fuxin) Co., Ltd, PR China and from Sumitomo Seika Chemicals Co. Ltd, Japan) (1.19 kg, 6.4 mol, 1.1 equiv) is suspended in 19.9 L of methanol. The mixture is heated to reflux and stirred until complete dissolution is observed. At this stage, the mixture is charged with 4M HCl in 1, 4-dioxane (30.0 mL, 0.116 mol, 0.02 equiv) between 60-65 C. The mixture is stirred at reflux for 12 hours. The reaction is deemed complete when the amount IM2 is less than or equal to 0.05% w/w by HPLC. The mixture is cooled to 20-25 C and stirred for 1 hour. The product is isolated by filtration and the filter cake is washed with acetonitrile (2 X 5.8 L). The wet cake is dried under vacuum at 50-60 C to afford Intermediate 3.
	With hydrogenchloride; In water; isopropyl alcohol;Reflux; Inert atmosphere;	Example 69 5-({4-[(2,3-dimethyl-2H-indazol-6-yl)(methyl)amino]pyrimidin-2-yl}amino)-2-methylbenzenesulfonamide To a solution of Intermediate Example 13 (200 mg, 0.695 mmol) and 5-amino-2-methylbenzenesulfonamide (129.4 mg, 0.695 mmol) in isopropanol (6 ml) was added 4 drops of conc. HCl. The mixture was heated to reflux overnight. The mixture was cooled to rt and diluted with ether (6 ml). Precipitate was collected via filtration and washed with ether. HCl salt of 5-({4-[(2,3-dimethyl-2H-indazol-6-yl)(methyl)amino]-pyrimidin-2-yl}amino)-2-methylbenzenesulfonamide was isolated as an off-white solid. 1H NMR (400 MHz, d6DMSO+NaHCO3) delta 9.50 (br s, 1H), 8.55 (br s, 1H), 7.81 (d, J = 6.2 Hz, 1H), 7.75 (d, J = 8.7 Hz, 1H), 7.69 (m, 1H), 7.43 (s, 1H), 7.23 (s, 2H), 7.15 (d, J = 8.4 Hz, 1H), 6.86 (m, 1H), 5.74 (d, J = 6.1 Hz, 1H), 4.04 (s, 3H), 3.48 (s, 3H), 2.61 (s, 3H), 2.48 (s, 3H). MS (ES+, m/z) 438 (M+H).
	With hydrogenchloride; In isopropyl alcohol;Heating / reflux;Product distribution / selectivity;	To a solution of Intermediate Example 4 (200 mg, 0.695 mmol) and 5-amino-2-methylbenzenesulfonamide (129.4 mg, 0.695 mmol) in isopropanol (6 ml) was added 4 drops of conc. HCl. The mixture was heated to reflux overnight. The mixture was cooled to rt and diluted with ether (6 ml). Precipitate was collected via filtration and washed with ether. The hydrochloride salt of 5-({4-[(2,3-dimethyl-2H-indazol-6-yl)(methyl)amino]-pyrimidin-2-yl}amino)-2-methylbenzenesulfonamide was isolated as an off-white solid. 1H NMR (400 MHz, d6DMSO+NaHCO3) delta 9.50 (br s, 1H), 8.55 (br s, 1H), 7.81 (d, J=6.2 Hz, 1H), 7.75 (d, J=8.7 Hz, 1H), 7.69 (m, 1H), 7.43 (s, 1H), 7.23 (s, 2H), 7.15 (d, J=8.4 Hz, 1H), 6.86 (m, 1H), 5.74 (d, J=6.1 Hz, 1H), 4.04 (s, 3H), 3.48 (s, 3H), 2.61 (s, 3H), 2.48 (s, 3H). MS (ES+, m/z) 438 (M+H).
	With hydrogenchloride; In water; isopropyl alcohol;Heating / reflux;Product distribution / selectivity;	Example 1 5-((at)4-[(2, 3-dimeth yl-2H-indazol-6-yl) (meth yl) amino]p yrimidin-2-yl}a min o)-2- methylbenzenesulfonamide Procedure 1 To a solution of Intermediate Example 4 (200 mg, 0.695 mmol) and 5- amino-2-methylbenzenesulfonamide (129.4 mg, 0.695 mmol) in isopropanol (6 ml) was added 4 drops of conc. HCI. The mixture was heated to reflux overnight. The mixture was cooled to rt and diluted with ether (6 ml). Precipitate was collected via filtration and washed with ether. The hydrochloride salt of 5-({4-[(2,3-dimethyl-2H-indazol-6-yl)(methyl)amino]- pyrimidin-2-yl}amino)-2-methylbenzenesulfonamide was isolated as an off- white solid.
	With hydrogenchloride; In water; isopropyl alcohol;Heating / reflux;Product distribution / selectivity;	To a solution of Intermediate Example 4 (200 mg, 0.695 mmol) and 5-amino-2- methylbenzenesulfonamide (129.4 mg, 0.695 mmol) in isopropanol (6 ml) was added 4 drops of cone. HCI. The mixture was heated to reflux overnight. The mixture was cooled to rt and diluted with ether (6 ml). Precipitate was collected via filtration and washed with ether. The hydrochloride salt of 5-({4-[(2,3-dimethyl-2/-/-indazol-6- yl)(methyl)amino]-pyhmidin-2-yl}amino)-2-methylbenzenesulfonamide was isolated as an off-white solid. 1H NMR (400 MHz, d6DMSO+NaHCO3) delta 9.50 (br s, 1 H), 8.55 (br s, 1 H), 7.81 (d, J = 6.2 Hz, 1 H), 7.75 (d, J = 8.7 Hz, 1 H), 7.69 (m, 1 H), 7.43 (s, 1 H), 7.23 (s, 2H), 7.15 (d, J = 8.4 Hz, 1 H), 6.86 (m, 1 H), 5.74 (d, J = 6.1 Hz, 1 H), 4.04 (s, 3H), 3.48 (s, 3H), 2.61 (s, 3H), 2.48 (s, 3H). MS (ES+, m/z) 438 (M+H).

References: [1]Patent: US2015/329526,2015,A1 .Location in patent: Paragraph 0040.
[2]Patent: WO2007/64753,2007,A2 .Location in patent: Page/Page column 31-32.
[3]Patent: WO2003/106416,2003,A2 .Location in patent: Page 52-53.
[4]Patent: WO2006/20564,2006,A1 .Location in patent: Page/Page column 18-19.
[5]Patent: US2008/293691,2008,A1 .Location in patent: Page/Page column 12-13.
[6]Patent: WO2005/105094,2005,A2 .Location in patent: Page/Page column 40.
[7]Patent: WO2007/143483,2007,A2 .Location in patent: Page/Page column 34-35.
[8]Patent: WO2007/64753,2007,A2 .Location in patent: Page/Page column 32.
[9]Patent: WO2003/106416,2003,A2 .Location in patent: Page 53-54.
[10]Patent: WO2006/20564,2006,A1 .Location in patent: Page/Page column 19.
[11]Patent: US2008/293691,2008,A1 .Location in patent: Page/Page column 13.
[12]Patent: WO2005/105094,2005,A2 .Location in patent: Page/Page column 41.
[13]Patent: WO2007/143483,2007,A2 .Location in patent: Page/Page column 35.
[14]Patent: WO2011/69053,2011,A1 .Location in patent: Page/Page column 38-39.
[15]Patent: WO2007/64753,2007,A2 .Location in patent: Page/Page column 33.
[16]Journal of Medicinal Chemistry,2008,vol. 51,p. 4632 - 4640.
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19
[ 575473-00-6 ]
[ 6973-09-7 ]
N₂-(3-aminosulfonyl-4-methylphenyl)-5-fluoro-N₄-[4-(prop-2-ynyloxy)phenyl]-2,4-pyrimidinediamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With trifluoroacetic acid; In isopropyl alcohol; at 100℃; for 3h;	VI-53: N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(prop-2-ynyIoxy)phenyl]-2,4-pyrimidinediamine[0863] 2-Chloro-5-fluoro-N4-[4-(prop-2-ynyloxy)phenyl]-4-pyrimidineaniine (0.514 g, 1.85 mmol), <strong>[6973-09-7]3-(aminosulfonyl)-4-methylaniline</strong> (0.689 g, 3.70 mmol), and trifluoroacetic acid (0.186 mL, 2.41 mmol) were combined with iPrOH (6.0 niL) in a sealed vial and heated at 1OQ0C for 3h. The reaction mixture was cooled to room temperature and diluted with IN HCl (80 mL). N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(prop- 2-ynyloxy)phenyl]-2,4-pyrimidinediamine VI-53) was isolated as a white solid by suction filtration (0.703 g). 1H NMR (DMSO-^): delta 10.08 (bs, 2H), 8.19 (d, J= 4.5 Hz, 1H), 7.89 (s, 1H), 7.74 (dd, J= 2.4 and 8.4 Hz, 1H), 7.58 (d, J= 8.7 Hz, 2H), 7.32 (bs, 2H), 7.23 (d, J= 8.4 Hz, 1H), 6.97 (d, J= 8.4 Hz, 2H), 4.79 (d, J= 2.1 Hz, 2H), 3.59-3.55 (m, 1H), 2.53 (s, 3H); LCMS: purity: 97percent; MS (m/e): 428 (MH+).

References: [1]Patent: WO2006/133426,2006,A2 .Location in patent: Page/Page column 312.

20
N₄-[2-(tert-butylcarbonyl)amino-3-methoxypyrid-6-yl]-2-chloro-5-fluoro-4-pyrimidineamine [ No CAS ]
[ 6973-09-7 ]
N₂-(3-aminosulfonyl-4-fluoro)phenyl-N₄-[2-amino-3-methoxypyrid-6-yl]-5-fluoro-2,4-pyrimidinediamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; at 100℃; for 48h;	Example 28VII-9: N2-(3-Aminosulfonyl-4-methylphenyl)-N4-[2-amino-3-methoxypyrid-6-yl]-5- fluoro-2,4-pyrimidinediamine (66); [0680] A mixture of N4-[2-(tert-butylcarbonyl)amino-3-methoxypyrid-6-yl]-2- chloro-5-fluoro-4-pyrimidineamine (65) (25 mg, 0.07 mmol) and 3-aminosulfonyl-4- methylaniline (15 mg) in methanol (1 niL) was shaken in a sealed tube at 100 0C for 48 h. The reaction mixture was then chromatographed (silica gel, CH2Cl2 then 2-4percent 2N NH3MeOH in CH2Cl2) to obtain N2-(3 -aminosulfonyl-4-methylrhohenyl)-N4-(2-amino-3 - methoxypyrid-6-yl)-5-fluoro-2,4-pyrimidinediamine (66). (Note: The N- tert-butylcarbonyl group was cleaved during this reaction to give free amine function). LCMS: purity: 90percent; MS (m/z): 420 (MH+).

References: [1]Patent: WO2006/133426,2006,A2 .Location in patent: Page/Page column 266.

21
[ 916738-12-0 ]
[ 6973-09-7 ]
N₂-(3-aminosulfonyl-4-methylphenyl)-5-fluoro-N₄-[4-(prop-2-ynyloxy)phenyl]-2,4-pyrimidinediamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With trifluoroacetic acid; In isopropyl alcohol; at 100℃; for 3h;Sealed vial;	2-Chloro-5-fluoro-N4-[4-(prop-2-ynyloxy)phenyl]-4-pyrimidineamine (0.514 g, 1.85 mmol), <strong>[6973-09-7]3-(aminosulfonyl)-4-methylaniline</strong> (0.689 g, 3.70 mmol, made by reduction of commercially available 2-methyl-5-nitrobenzenesulfonamide or synthesized as described below), and trifluoroacetic acid (0.186 mL, 2.41 mmol) were combined with iPrOH (6.0 mL) in a sealed vial and heated at 100° C. for 3 h. The reaction mixture was cooled to room temperature and diluted with 1N HCl (80 mL). N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(prop-2-ynyloxy)phenyl]-2,4-pyrimidinediamine (I) was isolated as a white solid by suction filtration (0.703 g). 1H NMR (DMSO-d6): delta 10.08 (bs, 2H), 8.19 (d, J=4.5 Hz, 1H), 7.89 (s, 1H), 7.74 (dd, J=2.4 and 8.4 Hz, 1H), 7.58 (d, J=8.7 Hz, 2H), 7.32 (bs, 2H), 7.23 (d, J=8.4 Hz, 1H), 6.97 (d, J=8.4 Hz, 2H), 4.79 (d, J=2.1 Hz, 2H), 3.59-3.55 (m, 1H), 2.53 (s, 3H); LCMS: purity: 97percent; MS (m/e): 428 (MH+).
0.703 g	With trifluoroacetic acid; In isopropyl alcohol; at 100℃; for 3h;Sealed tube;	2-Chloro-5-fluoro-N4-[4-(prop-2-ynyloxy)phenyl]-4-pyrimidineamine (0.514 g, 1.85 mmol), <strong>[6973-09-7]3-(aminosulfonyl)-4-methylaniline</strong> (0.689 g, 3.70 mmol, made by reduction of commercially available 2-methyl-5-nitrobenzenesulfonamide or synthesized as described below), and trifluoroacetic acid (0.186 mL, 2.41 mmol) were combined with iPrOH (6.0 mL) in a sealed vial and heated at 100° C. for 3 h. The reaction mixture was cooled to room temperature and diluted with 1N HCl (80 mL). N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(prop-2-ynyloxy)phenyl]-2,4-pyrimidinediamine (I) was isolated as a white solid by suction filtration (0.703 g). 1H NMR (DMSO-d6): delta 10.08 (bs, 2H), 8.19 (d, J=4.5 Hz, 1H), 7.89 (s, 1H), 7.74 (dd, J=2.4 and 8.4 Hz, 1H), 7.58 (d, J=8.7 Hz, 2H), 7.32 (bs, 2H), 7.23 (d, J=8.4 Hz, 1H), 6.97 (d, J=8.4 Hz, 2H), 4.79 (d, J=2.1 Hz, 2H), 3.59-3.55 (m, 1H), 2.53 (s, 3H); LCMS: purity: 97percent; MS (m/e): 428 (MH+).
0.703 g	With trifluoroacetic acid; In isopropyl alcohol; at 100℃; for 3h;Sealed tube;	2-Chloro-5-fluoro-N4-[4-(prop-2-ynyloxy)phenyl]-4-pyrimidineamine (0.514 g, 1.85 mmol), <strong>[6973-09-7]3-(aminosulfonyl)-4-methylaniline</strong> (0.689 g, 3.70 mmol, made by reduction of commercially available 2-methyl-5-nitrobenzenesulfonamide or synthesized as described below), and trifluoroacetic acid (0.186 mL, 2.41 mmol) were combined with iPrOH (6.0 mL) in a sealed vial and heated at 100° C. for 3 hours. The reaction mixture was cooled to room temperature and diluted with 1N HCl (80 mL). N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(prop-2-ynyloxy)phenyl]-2,4-pyrimidinediamine (II) was isolated as a white solid by suction filtration (0.703 g). 1H NMR (DMSO-d6): delta 10.08 (bs, 2H), 8.19 (d, J=4.5 Hz, 1H), 7.89 (s, 1H), 7.74 (dd, J=2.4 and 8.4 Hz, 1H), 7.58 (d, J=8.7 Hz, 2H), 7.32 (bs, 2H), 7.23 (d, J=8.4 Hz, 1H), 6.97 (d, J=8.4 Hz, 2H), 4.79 (d, J=2.1 Hz, 2H), 3.59-3.55 (m, 1H), 2.53 (s, 3H); LCMS: purity: 97percent; MS (m/e): 428 (MH+).

0.703 g

With trifluoroacetic acid; In isopropyl alcohol; at 100℃; for 3h;Sealed tube;

2-Chloro-5-fluoro-N4-[4-(prop-2-ynyloxy)phenyl]-4-pyrimidineamine (0.514 g, 1.85 mmol), <strong>[6973-09-7]3-(aminosulfonyl)-4-methylaniline</strong> (0.689 g, 3.70 mmol, made by reduction of commercially available 2-methyl-5-nitrobenzenesulfonamide or synthesized as described below), and trifluoroacetic acid (0.186 mL, 2.41 mmol) were combined with iPrOH (6.0 mL) in a sealed vial and heated at 100°C for 3h. The reaction mixture was cooled to room temperature and diluted with IN HCl (80 mL). N2-(3-Aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(prop-2-ynyloxy)phenyl]-2,4-pyrimidinediamine (I) was isolated as a white solid by suction filtration (0.703 g). 1H NMR (DMSO-d6): delta 10.08 (bs, 2H), 8.19 (d, J= 4.5 Hz, 1H), 7.89 (s, 1H), 7.74 (dd, J= 2.4 and 8.4 Hz, 1H), 7.58 (d, J= 8.7 Hz, 2H), 7.32 (bs, 2H), 7.23 (d, J= 8.4 Hz, 1H), 6.97 (d, J= 8.4 Hz, 2H), 4.79 (d, J= 2.1 Hz, 2H), 3.59-3.55 (m, 1H), 2.53 (s, 3H); LCMS: purity: 97percent; MS (m/e): 428 (MH+).

References: [1]Patent: US2011/28503,2011,A1 .Location in patent: Page/Page column 10.
[2]Patent: US2014/73659,2014,A1 .Location in patent: Paragraph 0108.
[3]Patent: US2014/206708,2014,A1 .Location in patent: Paragraph 0074; 0078.
[4]Patent: EP2683385,2018,B1 .Location in patent: Paragraph 0094; 0098.

22
[ 6973-09-7 ]
pazopanib [ No CAS ]

References: [1]Patent: WO2011/69053,2011,A1 .

23
[ 6973-09-7 ]
pazopanib dihydrochloride [ No CAS ]

References: [1]Patent: WO2011/69053,2011,A1 .
[2]Patent: WO2011/69053,2011,A1 .

24
[ 6973-09-7 ]
[ 1352319-35-7 ]

References: [1]Patent: WO2011/156698,2011,A2 .

25
[ 6973-09-7 ]
[ 1352319-51-7 ]

References: [1]Patent: WO2011/156698,2011,A2 .

26
[ 1352319-14-2 ]
[ 6973-09-7 ]
[ 1352319-15-3 ]

Yield	Reaction Conditions	Operation in experiment
25%	With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); tert-butyl XPhos; In 1,4-dioxane; at 20 - 80℃; for 16.5h;Inert atmosphere;	Example No.B.1.1 : ter*-Butyl-cis-4-((6-(4-methyl-3-sulf amoylphenylamino)- l/ -p r azolo [3,4- i/\|pyrimidin-l-yl)methyl)cyclohexylcarbamate; A solution of ~er~-butyl-cw-4-((6-chloro-l//-pyrazolo[3,4-i/]pyrimidin-l- yl)methyl)cyclohexylcarbamate (1.66 g, 4.53 mmol, prepared using A from Preparation No.2 and ter^butyl-czs-(4-hydroxymethyl)cyclohexylcarbamate [AMRI]), 5-amino-2- methylbenzenesulfonamide (1.10 g, 5.89 mmol, Waterstone), and sodium teri-butoxide (1.306 g, 13.59 mmol) in 1,4-dioxane (15 mL) was stirred at ambient temperature for about 30 min. In a separate 10 mL nitrogen purged vial charged with Pd2(dibenzylideneacetone)3 (0.415 g, 0.453 mmol) and 2-di-~er~-butylphosphino-2',4',6'-triisopropylbiphenyl (0.789 g, 1.86 mmol) was added 1,4-dioxane (2 mL) followed by heating to about 80 °C for about 2 min. The mixture was subsequently cooled to ambient temperature. The catalyst solution was added to the reaction mixture at ambient temperature and the reaction mixture was heated to about 80 °C for about 16 h. The reaction mixture was cooled to ambient temperature then water (100 mL) and EtOAc (50 mL) were added and the organic layer was separated. The aqueous layer was further extracted with EtOAc (2 x 50 mL) and the combined organic extracts were dried over anhydrous MgSOt, filtered through a silica gel pad, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography eluting with 50percent EtOAc in heptane to provide tert-butyl-cis-4-((6- (4-methyl-3-sulfamoylphenylamino)-lH-pyrazolo[3,4-d]pyrimidin-l- yljmethyljcyclohexylcarbamate (0.58 g, 25percento) as a light yellow solid. LC/MS (Table 2, Method a) R, = 1.38 min; MS m/z: 516 (M+H)+.

References: [1]Patent: WO2011/156698,2011,A2 .Location in patent: Page/Page column 55-56.

27
[ 3934-20-1 ]
[ 6973-09-7 ]
[ 1379982-43-0 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate; In tetrahydrofuran; ethanol; at 70 - 75℃; for 13h;	To a mixture of <strong>[6973-09-7]5-amino-2-methylbenzenesulfonamide</strong> (20 gm) in ethanol (208 ml) and tetrahydrofuran (52 ml) was added 2,4-dichloropryrimidine (44 gm) and sodium bicarbonate (36 gm) at room temperature. The contents were heated to 70 to 75°C and maintained for 13 hours. The reaction mass was then cooled to 10°C and maintained for 2 hours. The reaction mass was filtered and the solvent was distilled off under vacuum at below 50 to 55°C to obtain a residual mass. To the residual mass was added ethyl acetate (100 ml) and stirred for 1 hour, filtered. The solid obtained was dried to give 15.5 gm of 5-(4-chloropyrimidin-2ylamino)-2-methylbenzenesulfonamide.
15.5 g	With sodium hydrogencarbonate; In tetrahydrofuran; ethanol; at 20 - 75℃; for 13h;	To a mixture of <strong>[6973-09-7]5-amino-2-methylbenzenesulfonamide</strong> (20 gm) in ethanol (208 ml) and tetrahydrofuran (52 ml) was added 2,4-dichloropryrimidine (44 gm) and sodium bicarbonate (36 gm) at room temperature. The contents were heated to 70 to 75° C. and maintained for 13 hours. The reaction mass was then cooled to 10° C. and maintained for 2 hours. The reaction mass was filtered and the solvent was distilled off under vacuum at below 50 to 55° C. to obtain a residual mass. To the residual mass was added ethyl acetate (100 ml) and stirred for 1 hour, filtered. The solid obtained was dried to give 15.5 gm of 5-(4-chloropyrimidin-2ylamino)-2-methylbenzenesulfonamide

References: [1]Patent: WO2012/73254,2012,A1 .Location in patent: Page/Page column 5.
[2]Patent: US2013/245262,2013,A1 .Location in patent: Paragraph 0033.

28
[ 6973-09-7 ]
pazopanib hydrochloride [ No CAS ]

References: [1]Patent: WO2012/73254,2012,A1 .
[2]Patent: US2013/245262,2013,A1 .

29
[ 6973-09-7 ]
5-fluoro-N₂-(4-methyl-3-propionylaminosulfonylphenyl)-N₄-[4-(prop-2-ynyloxy)phenyl]-2,4-pyrimidinediamine [ No CAS ]

References: [1]Patent: US2014/73659,2014,A1 .

30
[ 6973-09-7 ]
5-fluoro-N₂-(4-methyl-3-propionylaminosulfonylphenyl)-N₄-[4-(prop-2-ynyloxy)phenyl]-2,4-pyrimidinediamine mono-sodium salt [ No CAS ]

References: [1]Patent: US2014/73659,2014,A1 .

31
[ 99-99-0 ]
[ 6973-09-7 ]

References: [1]Patent: US2014/73659,2014,A1 .
[2]Patent: US2014/206708,2014,A1 .
[3]Patent: EP2683385,2018,B1 .

32
[ 444731-75-3 ]
[ 6973-09-7 ]
pazopanib [ No CAS ]

References: [1]Chemical Biology and Drug Design,2014,vol. 83,p. 306 - 316.

33
[ 916738-12-0 ]
[ 6973-09-7 ]
5-fluoro-N₂-(4-methyl-3-propionylaminosulfonylphenyl)-N₄-[4-(prop-2-ynyloxy)phenyl]-2,4-pyrimidinediamine [ No CAS ]

References: [1]Patent: EP2683385,2018,B1 .

34
[ 6973-09-7 ]
[ 1620059-34-8 ]
[ 1620843-77-7 ]

References: [1]Chinese Chemical Letters,2014,vol. 25,p. 989 - 994.

35
[ 6973-09-7 ]
[ 1620059-33-7 ]
[ 1620843-82-4 ]

References: [1]Chinese Chemical Letters,2014,vol. 25,p. 989 - 994.

Historical Records

Technical Information

• Benzylic Oxidation • Birch Reduction • Blanc Chloromethylation • Buchwald-Hartwig C-N Bond and C-O Bond Formation Reactions • Chan-Lam Coupling Reaction • Friedel-Crafts Reaction • Hydride Reductions • Hydrogenolysis of Benzyl Ether • Leuckart-Wallach Reaction • Mannich Reaction • Petasis Reaction • Preparation of Alkylbenzene • Preparation of Amines • Reactions of Amines • Reactions of Benzene and Substituted Benzenes • Specialized Acylation Reagents-Vilsmeier Reagent • Ugi Reaction • Vilsmeier-Haack Reaction

Related Functional Groups of
[ 6973-09-7 ]

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CAS No.: 6973-09-7

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