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[ CAS No. 635702-64-6 ] {[proInfo.proName]}

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Chemical Structure| 635702-64-6
Chemical Structure| 635702-64-6
Structure of 635702-64-6 * Storage: {[proInfo.prStorage]}
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Product Details of [ 635702-64-6 ]

CAS No. :635702-64-6 MDL No. :
Formula : C21H24ClN7O2S Boiling Point : -
Linear Structure Formula :- InChI Key :MQHIQUBXFFAOMK-UHFFFAOYSA-N
M.W : 473.98 Pubchem ID :11525740
Synonyms :
GW786034 Hydrochloride;Pazopanib HCl;GW786034 HCl

Calculated chemistry of [ 635702-64-6 ]

Physicochemical Properties

Num. heavy atoms : 32
Num. arom. heavy atoms : 21
Fraction Csp3 : 0.19
Num. rotatable bonds : 5
Num. H-bond acceptors : 6.0
Num. H-bond donors : 2.0
Molar Refractivity : 128.47
TPSA : 127.41 Ų

Pharmacokinetics

GI absorption : Low
BBB permeant : No
P-gp substrate : Yes
CYP1A2 inhibitor : No
CYP2C19 inhibitor : Yes
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : Yes
Log Kp (skin permeation) : -6.44 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.0
Log Po/w (XLOGP3) : 3.87
Log Po/w (WLOGP) : 5.02
Log Po/w (MLOGP) : 2.1
Log Po/w (SILICOS-IT) : 0.89
Consensus Log Po/w : 2.38

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 0.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -5.37
Solubility : 0.00201 mg/ml ; 0.00000424 mol/l
Class : Moderately soluble
Log S (Ali) : -6.24
Solubility : 0.000271 mg/ml ; 0.000000572 mol/l
Class : Poorly soluble
Log S (SILICOS-IT) : -6.77
Solubility : 0.0000812 mg/ml ; 0.000000171 mol/l
Class : Poorly soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 2.0
Synthetic accessibility : 3.52

Safety of [ 635702-64-6 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P280-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H332-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 635702-64-6 ]

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

  • Downstream synthetic route of [ 635702-64-6 ]

[ 635702-64-6 ] Synthesis Path-Downstream   1~25

  • 1
  • [ 635702-64-6 ]
  • [ 75-75-2 ]
  • [ 635702-65-7 ]
YieldReaction ConditionsOperation in experiment
84% In water for 0.0833333h; Heating / reflux; 1.6 Example 1; 5-({4-[(2,3-dimethyl-2H-indazol-6-yl)(methyl)amino]pyrimidin-2-yl}-amino)-2- methylbenzenesulfonamide; Procedure 6; Preparation of 5-({40[(2,3-dimethyl-2H-indazol-6-yl)(methyl)amino]pyrimidin-2-yl}amino)-2-methylbenzenesulfonamide methanesulfonic acid salt In a 250 mL flask the product of Example 1, procedure 1, (1.0 g, 2.29 [MMOL)] was slurried in water (19 mL). Methanesulfonic acid (0.231 g, 2.4 [MMOL)] was added all at once and the mixture was heated to reflux for 5 min. The mixture was cooled to [0] [C] over a 1 hour period and was then isolated by filtration and air dried. [5-({4-[(2,] 3- [ DIMETHYL-2H-INDAZOL-6-YL) (METHYL) AMINO] PYRIMIDIN-2-YL} AMINO)-2-] [METHYLBENZENESULFONAMIDE] [METHANESULFONIC] acid salt (1.03 g, [84%)] was obtained as a white solid. mp = 247-248 [C.]To a round bottom flask, was added 2.6 g of the [MONOHYDROCHLORIDE] salt of Example 1, procedure 1, any form. Then added was 39 mL of isopropanol (15 volumes). The mixture was heated to 75 deg C in an oil bath, then 14 mL of 0.05N aqueous HCI (5.4 volumes) was added. The clear solution was cooled to 65 deg C, then seeded with the monohydrate of the monohydrochloride salt of Example 1, procedure 1 (0.05-0. 1 wt [%).] The cloudy solution was stirred at 65 deg C for 60 minutes, then cooled to 0 deg C [AT #0. ] 25-0.5 deg C/min. The resulting white solid was filtered and dried to constant weight under vacuum at RT to give 88% yield of 5 -({4-[(2, 3- dimethyl-2H-indazol-6-yl) [METHYLAMINO]-2-PYRIMIDINYL} AMINO)-2-METHYLBENZENE] sulfonamide [MONOHYDROCHLORIDE] monohydrate.
84% In water for 0.0833333h; Heating / reflux; 1.6 Procedure 6 Preparation of 5-({4-[(2,3-dimethyl-2H-indazol-6-yl) (methyl) amino] pyrimidin-2-yl} amino)-2-methylbenzenesulfonamide methanesulfonic acid salt. In a 250 mL flask the product of Example 1, procedure 1, (1.0 g, 2.29 mmol) was slurried in water (19 mL). Methanesulfonic acid (0.231 g, 2.4 mmol) was added all at once and the mixture was heated to reflux for 5 min. The mixture was cooled to 0 °C over a 1 hour period and was then isolated by filtration and air dried. 5-({4-[(2,3-Dimethyl-2H-indazol-6-yl) (methyl) amino] pyrimidin-2-yl)amino)-2-methylbenzenesulfonamide methanesulfonic acid salt (1.03 g, 84%) was obtained as a white solid.
  • 2
  • [ 444731-75-3 ]
  • [ 6973-09-7 ]
  • pazopanib hydrochloride [ No CAS ]
YieldReaction ConditionsOperation 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).

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YieldReaction ConditionsOperation in experiment
In water; acetonitrile at 45 - 85℃; for 1.5h; 1c To a 1 L jacketed reactor was charged with acetonitrile (563 mL), water (188 mL) the monohydrochloride salt of Example 1 , procedure 6 (50 g, 0.105 mol). The solution was stirred and heated to the jacket temperature at 85°C and a clear solution was obtained. The solution was then cooled down to 45°C and held for 90 minutes to cause crystallization of the hydrate After the 90 min hold, the solution was cooled down to 00C, held for an hour and then filtered through a filter-dryer. The filtered solids were then washed with acetonitrile (200 mL X 1) at 00C. The solids were blown in the filter-dryer with nitrogen at 25°C until the LOD was less than 25%. Acetonitrile (300 mL) was charged to the solids in filter-dryer, and stirred at 600C for at least 8 hours or until the form conversion was complete (no monohydrate remaining) as observed by DATR to form 5-({4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2- pyrimidinyl}amino)-2-methylbenzenesulfonamide monohydrochloride anhydrate. The contents of the filter-dryer were cooled to ~30°C, and the filtrate was pushed off using nitrogen pressure. The filtercake was blown with nitrogen at -60 0C under vacuum until the LOD was less than 0.5%. The contents were cooled to 20 0C yielding 37.5 g (75%) of 5-({4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl}amino)-2- methylbenzenesulfonamide monohydrochloride anhydrate.
In methanol at 20℃; for 2.83333h; Reflux; 11 Example 1 1 : Preparation of substantially pure Pazopanib HC1[000128] A 250 mL flask was charged with Pazopanib HC1 (form A, 1. 16 g ; 98.6% purity and containing 0.92% CPMI) and MeOH (75V). The mixture was stirred and Patent ApplicationAtty Docket No. 14669.0172WOU 1 heated to reflux for 10 mins resulting in dissolution. The solution was then gradually cooled to ambient temperature over 40 min and stirring was continued at the same temperature for 2 h leading to precipitation. The solid was filtered and dried under vacuum (25 mbar) at 60°C for 18 h to give Pazopanib HC1. (>99.99% purity, AMBS, CPMI and PZP-PDM1 not detected by HPLC method 1)
In methanol; water for 0.5h; Reflux; 4 Pazopanib hydrochloride (5 gm; HPLC Purity: 97.5%) as obtained in example 3 was dissolved in a mixture of methanol (100 ml) and water (10 ml) at room temperature and then heated to reflux. The reaction mass was maintained for 30 minutes at reflux and filtered. The filtrate obtained was cooled to room temperature and maintained for 2 hours at room temperature. The solid obtained was collected by filtration and dried to obtain 3.5 gm of pazopanib hydrochloride (HPLC Purity: 99.9%).
In water; acetonitrile at 45 - 85℃; for 1.5h; 1c To a 1 L jacketed reactor was charged with acetonithle (563 mL), water (188 mL) the monohydrochloride salt of Example 1 a, procedure 6 (50 g, 0.105 mol). The solution was stirred and heated to the jacket temperature at 85°C and a clear solution was obtained. The solution was then cooled down to 45°C and held for 90 minutes to cause crystallization of the hydrate After the 90 min hold, the solution was cooled down to 00C, held for an hour and then filtered through a filter-dryer. The filtered solids were then washed with acetonithle (200 mL X 1 ) at 00C. The solids were blown in the filter- dryer with nitrogen at 25°C until the LOD was less than 25%. Acetonithle (300 mL) was charged to the solids in filter-dryer, and stirred at 600C for at least 8 hours or until the form conversion was complete (no monohydrate remaining) as observed by DATR to form 5-({4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyhmidinyl}amino)-2- methylbenzenesulfonamide monohydrochloride anhydrate. The contents of the filter- dryer were cooled to ~30°C, and the filtrate was pushed off using nitrogen pressure. The filtercake was blown with nitrogen at -60 0C under vacuum until the LOD was less than 0.5%. The contents were cooled to 20 °C yielding 37.5 g (75%) of 5-({4-[(2,3- dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl}amino)-2- methylbenzenesulfonamide monohydrochloride anhydrate.

  • 4
  • [ 635702-64-6 ]
  • [ 635702-66-8 ]
YieldReaction ConditionsOperation in experiment
88% With hydrogenchloride; water In isopropyl alcohol at 65 - 75℃; 1b To a round bottom flask, was added 2.6 g of the monohydrochloride salt of Example 1a, procedure 1 , any form. Then added was 39 ml_ of isopropanol (15 volumes). The mixture was heated to 75 deg C in an oil bath, then 14 mL of 0.05N aqueous HCI (5.4 volumes) was added. The clear solution was cooled to 65 deg C, then seeded with the monohydrate of the monohydrochloride salt of Example 1 , procedure 1 (0.05-0.1 wt %). The cloudy solution was stirred at 65 deg C for 60 minutes, then cooled to 0 deg C at -0.25-0.5 deg C/min. The resulting white solid was filtered and dried to constant weight under vacuum at RT to give 88% yield of 5 -({4- [(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl}amino)-2-methylbenzene sulfonamide monohydrochloride monohydrate.
88% With hydrogenchloride; water In isopropyl alcohol at 75℃; 1.b To a round bottom flask, was added 2.6 g of the monohydrochloride salt of Example 1a, procedure 1, any form. Then added was 39 mL of isopropanol (15 volumes). The mixture was heated to 75 deg C. in an oil bath, then 14 mL of 0.05N aqueous HCl (5.4 volumes) was added. The clear solution was cooled to 65 deg C., then seeded with the monohydrate of the monohydrochloride salt of Example 1, procedure 1 (0.05-0.1 wt %). The cloudy solution was stirred at 65 deg C. for 60 minutes, then cooled to 0 deg C. at ~0.25-0.5 deg C./min. The resulting white solid was filtered and dried to constant weight under vacuum at RT to give 88% yield of 5-({4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl}amino)-2-methylbenzene sulfonamide monohydrochloride monohydrate.
88% With hydrogenchloride; water In isopropyl alcohol at 65 - 75℃; for 1h; 1.1b To a round bottom flask, was added 2.6 g of the monohydrochloride salt of Example 1 , any form. Then added was 39 ml. of isopropanol (15 volumes). The mixture was heated to 75 deg C in an oil bath, then 14 mL of 0.05N aqueous HCI (5.4 volumes) was added. The clear solution was cooled to 65 deg C, then seeded with the monohydrate of the monohydrochloride salt of Example 1 , (0.05-0.1 wt %). The cloudy solution was stirred at 65 deg C for 60 minutes, then cooled to 0 deg C at -0.25-0.5 deg C/min. The resulting white solid was filtered and dried to constant weight under vacuum at RT to give 88% yield of 5 -({4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2- pyhmidinyl}amino)-2-methylbenzene sulfonamide monohydrochloride monohydrate.
  • 5
  • [ 444731-75-3 ]
  • [ 609-55-2 ]
  • pazopanib hydrochloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
77% With hydrogenchloride; In water; isopropyl alcohol;Heating / reflux; To a solution of <strong>[444731-75-3]N-(2-chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-amine</strong> (55mg; 0.2 mmol, 1 equiv) and 5-amino-2-methylbenzenesulfonimide (37 mg; 0.2mmol, 1 equiv) in isopropanol (2ml) was added 1 drop of concentrated HCl. The reaction mixture was refluxed overnight. The reaction mixture was cooled down to room temperature and diluted with diethyl ether (2ml). The precipitate was filtered and washed with diethyl ether. The solid was then boiled in ethanol and filtered to yield the desired product as a white solid hydrochloride salt (0.07Og, 77%).1H NMR (400MHz, d6-DMSO; 11.5 (br s, IH), 8.42 (br s, IH), 7.95 (d, J = 8.0 Hz, IH), 7.85 (br s, IH), 7.62 (s, IH), 7.45 (s, 2H), 6.95 (d, J = 8.0Hz, IH), 5.87 (br s, IH, 4.03 (s, 3H), 3.75 (s, 3H), 2.65 (s, 3H), 2.57 (s, 3H).
  • 6
  • [ 635702-64-6 ]
  • [ 444731-52-6 ]
YieldReaction ConditionsOperation in experiment
With sodium carbonate In water for 0.166667h; 1 500 mg of Pazopanib hydrochloride was suspended in 20 ml of water. Saturated Na2C03 solution was added until a thick white precipitate was formed. The reaction mixture was stirred for 10 minutes, filtered, washed with water and dried at 60°C under vacuum for 2 hours.Yield: 415 mg
  • 7
  • [ 635702-64-6 ]
  • [ 444731-52-6 ]
YieldReaction ConditionsOperation in experiment
97% With sodium carbonate In methanol; water at 20℃; for 5h; 47 Example 47: Process for preparation of Pazopanib free base (PZP)[000164] PZP.HC1 ( 1 g, form A) was slurried with sodium carbonate ( 10% aq. soln) (9.0 g, 8 eq) and MeOH (9.0 g) at ambient temperature. Stirring was continued for 5 h before the solid was filtered and dried in a vacuum oven (35mbar) at 40 °C for 1 7 h to give PZP free base (0.92 g, 97% yield, chloride content not detectable)
2.5 g With triethylamine In water
With sodium hydrogencarbonate In dimethylsulfoxide-d6 69 Example 69
5-({4-[(2,3-dimethyl-2H-indazol-6-yl)(methyl)amino]pyrimidin-2-yl}amino)-2-methylbenzenesulfonamide 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) δ 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).
  • 8
  • [ 635702-64-6 ]
  • [ 635702-64-6 ]
YieldReaction ConditionsOperation in experiment
In formic acid; toluene at 20℃; for 1.5h; 16 Example 16: Preparation of Pazopanib di-HCl Form I[000133] A 20 mL vial equipped with a magnetic stirrer was charged with PZP.HC1 (200 mg) (form A). Formic acid (0.5 mL) was added at ambient temperature with stirring, leading to dissolution. Toluene (3 mL) was added drop-wise and stirring was continued at ambient temperature for 1 .5 h. The resulting precipitate was filtered and the solid was analyzed by XRD, which indicated form I.
  • 9
  • [ 444731-52-6 ]
  • [ 635702-64-6 ]
YieldReaction ConditionsOperation in experiment
With hydrogenchloride In acetonitrile at 5 - 20℃; for 19h; 40 Example 40: Process for preparation of forms XIV and XV (di-HCl salt from PZP free base)[0001 57] PZP base (SF 1661 /2, 0.6 g) was slurried with acetonitrile ( 12 mL, 20V) containing 13.6% HCI (previously prepared by bubbling HCI gas through the solvent) at 5 °C. Stirring was continued for 17 h and then the slurry was warmed to room temperature. After 2 h additional stirring the solid was isolated through filtration. Drying of the solid in a vacuum oven (25 mbar) at 60 °C for 17 h afforded Pazopanib.2HCl (CI content = 16.8%) form XIV (0.78 g, 99.7% purity).
  • 10
  • [ 6973-09-7 ]
  • pazopanib hydrochloride [ No CAS ]
  • 11
  • [ 1376676-65-1 ]
  • [ 1379982-43-0 ]
  • pazopanib hydrochloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
5-(4-Chloropyrimidin-2ylamino)-2-methylbenzenesulfonamide (17 gm) as obtained in example 1, <strong>[1376676-65-1]N,2,3-trimethyl-2H-indazol-6-amine</strong> (10 gm) as obtained in example 2 and ethanol (166 ml) were added at room temperature and then heated to reflux. The reaction mass was maintained for 3 hours at reflux and then added concentrated hydrochloric acid (1 ml). The reaction mass was maintained for 10 hours at reflux and then cooled to room temperature. The separated solid was filtered and dried to obtain 17 gm of pazopanib hydrochloride (HPLC Purity: 97.5%).
17 g 5-(4-Chloropyrimidin-2ylamino)-2-methylbenzenesulfonamide (17 gm) as obtained in example 1, <strong>[1376676-65-1]N,2,3-trimethyl-2H-indazol-6-amine</strong> (10 gm) as obtained in example 2 and ethanol (166 ml) were added at room temperature and then heated to reflux. The reaction mass was maintained for 3 hours at reflux and then added concentrated hydrochloric acid (1 ml). The reaction mass was maintained for 10 hours at reflux and then cooled to room temperature. The separated solid was filtered and dried to obtain 17 gm of pazopanib hydrochloride (HPLC Purity: 97.5%).
  • 13
  • [ 444731-73-1 ]
  • [ 635702-64-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1: 10% Pd/C; hydrogen / tetrahydrofuran; methanol 2: sodium hydride / methanol / 20 °C 3: sodium tetrahydroborate / methanol / 3 h / 20 °C 4: sodium carbonate / N,N-dimethyl-formamide / 3 h / 100 °C / Inert atmosphere 5: hydrogenchloride / isopropyl alcohol / 5 h / Reflux
Multi-step reaction with 4 steps 1: hydrogen / methanol / 5 h / 25 - 30 °C / 2625.26 - 3000.3 Torr / Autoclave 2: sodium hydrogencarbonate / methanol / 24 h / 25 - 30 °C 3: caesium carbonate / N,N-dimethyl-formamide / 6 h / 25 - 30 °C 4: hydrogenchloride / isopropyl alcohol / Reflux
Multi-step reaction with 4 steps 1.1: 10% Pd/C / methanol; water / 6 h / 25 - 30 °C 2.1: sodium hydrogencarbonate / tetrahydrofuran; ethanol / 4 - 7 h / 74 - 85 °C 3.1: caesium carbonate / N,N-dimethyl-formamide / 20 - 30 °C 4.1: methanol / 3 h / 20 °C / Heating / reflux 4.2: 4 h
Multi-step reaction with 4 steps 1.1: ammonium formate / 10% Pd/C / methanol; water / 6 h / 25 - 30 °C 2.1: sodium hydrogencarbonate / water / 8 h / 20 - 85 °C / Heating / reflux 3.1: caesium carbonate / N,N-dimethyl-formamide / 0.17 h / 20 - 25 °C 3.2: 1.33 h / 20 - 40 °C 4.1: methanol / 3 h / 20 °C / Heating / reflux 4.2: 4 h
Multi-step reaction with 4 steps 1.1: ammonium formate / 10% Pd/C / methanol; water / 6 h / 25 - 30 °C 2.1: sodium hydrogencarbonate / water / 8 h / 20 - 85 °C / Heating / reflux 3.1: potassium carbonate / N,N-dimethyl-formamide / 6 h / 135 °C / Heating / reflux 4.1: methanol / 3 h / 20 °C / Heating / reflux 4.2: 4 h

  • 15
  • [ 1376676-65-1 ]
  • pazopanib hydrochloride [ No CAS ]
  • 16
  • [ 1476040-96-6 ]
  • [ 635702-64-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: sodium tetrahydroborate / methanol / 3 h / 20 °C 2: sodium carbonate / N,N-dimethyl-formamide / 3 h / 100 °C / Inert atmosphere 3: hydrogenchloride / isopropyl alcohol / 5 h / Reflux
  • 17
  • [ 20191-74-6 ]
  • pazopanib hydrochloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
In water; acetonitrile at -5 - 73℃; Inert atmosphere; Industry scale; 4 Intermediate 4 and Final Product; Intermediate 4 Final Product(Pazopanib hydrochloride Form 1); Synthesis of 5-({4-[(2,3-dimethyl-2H-indazol-6-yl)(methyl)amino]-2- pyrimidinyl}amino)-2-methylbenzenesulfonamide Hydrochloride Monohydrate and 5-({4-[(2,3-dimethyl-2H-indazol-6-yl)(methyl)amino]-2-pyrimidinyl}amino)-2- methylbenzenesulfonamide Hydrochloride Form 1; Intermediate 3 (IM3) (1.4 kg, 2.95 mol, 1.0 equiv) is suspended in 6.1 L of acetonitrile/water, 1.6/1 mixture and is dissolved above 70 °C. The clear solution is filtered hot, maintaining the temperature above 55 °C throughout the filtration. The reactor and lines are rinsed with 7.35 L of acetonitrile at 20-60 °C. The filtered solution is heated at about 1 °C/min to 68-73 °C until dissolved. The clear solution is cooled to 43-47 °C at 0.5 to 1.5 °C/min. The solution is held at 43-47 °C for 90 minutes for nucleation of the monohydrate. The monohydrate slurry is cooled to -5 to +5 °C at less than 0.5 °C/min. The suspension is held at that temperature (-5 to +5 °C) for up to 36 hours. The product is isolated using a filter dryer with jacket temperature set at to 0 °C. The slurry is settled for at least 30 minutes prior to filtration. Mother liquors are removed using 1-2 barg of nitrogen pressure. The cake is washed with 5.6 L of premixed aqueous acetonitrile (75 vol % acetonitrile) at 0-5 °C (held rinse in the reactor until cooled to 0-5 °C). The wash is held on the cake for 30 minutes prior to filtration at 1-2 barg nitrogen pressure. The cake is deliquored at 1-2 barg nitrogen pressure, with the filter dried jacket at 25°C and the cake is smoothed cake as necessary. After the cake is deliquored, the jacket temperature was increased to 65 °C on the filter drier and vacuum dry theIntermediate 4 (IM4) while agitating the cake. The vacuum is released and the jacket temperature increased to >75 °C with continued agitation until the cake temperature >55 °C is achieved. A separate vessel is charged with 8.4 L of aqueous acetonitrile (3 vol% water) and the solution is heated to > 70 °C. (28.0 g, 2.5% w/w) micronized Final Product seeds are charged to the form conversion solution. The hot seeded aqueous acetonitrile is transferred to the filter dryer and stirred continuously until XRPD testing indicates that no monohydrate is present and the spectra is concordant with the Form 1 (anhydrate) spectra. After the XRPD indicates for complete Form 1 conversion, the conversion liquors are filtered using 1-2 barg nitrogen pressure. The cake is deliquored with the jacket at 65 °C using 1-2 barg nitrogen pressure and is smoothed as necessary. Vacuum is applied with the jacket at 60 °C and the contents are agitated until the loss on drying (LOD) was obtained <0.5% to afford the Final Product.
  • 19
  • [ 444731-74-2 ]
  • pazopanib hydrochloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: caesium carbonate / N,N-dimethyl-formamide / 20 °C / Inert atmosphere 2: hydrogenchloride / water; isopropyl alcohol / Reflux; Inert atmosphere
Multi-step reaction with 2 steps 1: caesium carbonate / N,N-dimethyl-formamide / 6 h / 25 - 30 °C 2: hydrogenchloride / isopropyl alcohol / Reflux
Multi-step reaction with 2 steps 1: caesium carbonate / N,N-dimethyl-formamide / 2 h / 20 °C 2: hydrogenchloride / isopropyl alcohol / 2 h / Reflux
Multi-step reaction with 2 steps 1.1: caesium carbonate / N,N-dimethyl-formamide / 0.17 h / 20 - 25 °C 1.2: 1.17 - 2.17 h / 20 - 30 °C 2.1: methanol / 3 h / 20 °C / Heating / reflux 2.2: 4 - 10 h / 50 - 85 °C / Heating / reflux
Multi-step reaction with 2 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 6 h / 135 °C / Heating / reflux 2.1: methanol / 3 h / 20 °C / Heating / reflux 2.2: 4 - 10 h / 50 - 85 °C / Heating / reflux
Multi-step reaction with 2 steps 1.1: caesium carbonate / N,N-dimethyl-formamide / 20 - 30 °C 2.1: methanol / 3 h / 20 °C / Heating / reflux 2.2: 4 h
Multi-step reaction with 2 steps 1.1: caesium carbonate / N,N-dimethyl-formamide / 0.17 h / 20 - 25 °C 1.2: 1.33 h / 20 - 40 °C 2.1: methanol / 3 h / 20 °C / Heating / reflux 2.2: 4 h

  • 20
  • [ 635702-64-6 ]
  • [ 1414375-49-7 ]
  • [ 1821666-75-4 ]
  • [ 2377533-93-0 ]
  • [ 2377533-94-1 ]
YieldReaction ConditionsOperation in experiment
With 4-tert-butylpyridine; chloro(meso-tetrakis(2,6-dichlorophenyl)porphyrinato)manganese(III); magnesium monoperphthalate; acetic acid In dichloromethane at 20℃; for 1.5h; Darkness;
  • 21
  • [ 67-62-9 ]
  • [ 635702-64-6 ]
  • [ 2773341-19-6 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
Stage #1: pazopanib hydrochloride With 4-tert-butylpyridine; chloro(meso-tetrakis(2,6-dichlorophenyl)porphyrinato)manganese(III); magnesium monoperphthalate; acetic acid In dichloromethane at 20℃; for 1.5h; Darkness; Stage #2: O-Methylhydroxylamin With sodium acetate In methanol; water at 37℃; for 2h;
  • 22
  • [ 6269-91-6 ]
  • pazopanib hydrochloride [ No CAS ]
  • 23
  • [ 635702-59-9 ]
  • [ 635702-64-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: dichloromethane; dimethyl sulfoxide / 25 - 70 °C / Heating / reflux 2.1: 10% Pd/C / methanol; water / 6 h / 25 - 30 °C 3.1: sodium hydrogencarbonate / tetrahydrofuran; ethanol / 4 - 7 h / 74 - 85 °C 4.1: caesium carbonate / N,N-dimethyl-formamide / 20 - 30 °C 5.1: methanol / 3 h / 20 °C / Heating / reflux 5.2: 4 h
Multi-step reaction with 5 steps 1.1: dichloromethane; dimethyl sulfoxide / 7 h / 25 - 70 °C / Heating / reflux 2.1: ammonium formate / 10% Pd/C / methanol; water / 6 h / 25 - 30 °C 3.1: sodium hydrogencarbonate / water / 8 h / 20 - 85 °C / Heating / reflux 4.1: caesium carbonate / N,N-dimethyl-formamide / 0.17 h / 20 - 25 °C 4.2: 1.33 h / 20 - 40 °C 5.1: methanol / 3 h / 20 °C / Heating / reflux 5.2: 4 h
Multi-step reaction with 5 steps 1.1: dichloromethane; dimethyl sulfoxide / 7 h / 25 - 70 °C / Heating / reflux 2.1: ammonium formate / 10% Pd/C / methanol; water / 6 h / 25 - 30 °C 3.1: sodium hydrogencarbonate / water / 8 h / 20 - 85 °C / Heating / reflux 4.1: potassium carbonate / N,N-dimethyl-formamide / 6 h / 135 °C / Heating / reflux 5.1: methanol / 3 h / 20 °C / Heating / reflux 5.2: 4 h
  • 24
  • [ 635702-64-6 ]
  • [ CAS Unavailable ]
  • [ 2401868-78-6 ]
YieldReaction ConditionsOperation in experiment
94% In methanol; water at 25 - 55℃; for 2.5h; 16 Example 16 A pazopanib monolauryl sulfate salt was prepared by the following general procedure: a. 20 g of pazopanib hydrochloride (PZB· HC1), 200 mL methanol (10V) and 400 mL purified water (20V) were combined and stirred at 50-55°C; (0281) b. 12.17 g sodium lauryl sulfate (SLS) (1 molar equivalent to the PZB-HC1) was combined with 60 mL of methanol (3 V) and 60 mL of purified water (3 V); (0282) c. The composition of step (b) was added to the composition of step (a) and stirred for 30 minutes while maintaining the temperature at 50-55°C, then cooled to room temperature for about an hour; (0283) d. 400 mL of purified water (20V) was added to the cooled reaction mass of step (c) and stirred at room temperature for 1 hour; (0284) e. The precipitate (white crystals) of step (d) was collected by filtration, washed with 100 mL of purified water (5V) to obtain crude pazopanib monolauryl sulfate (PZB-1LS); (0285) f. The crude PZB-1LS was combined with 200 mL of purified water (10 V) stirred for 30 minutes, the solids were collected by filtration, washed with 100 mL of purified water (5 V) and vacuum dried to obtain 28 g of PZB-1LS as a white powder which was exhibited a chromatographic purity 100% and a yield of 94%.
  • 25
  • [ 1142189-49-8 ]
  • pazopanib hydrochloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: copper(I) oxide / N,N-dimethyl-formamide / 100 °C 2: sodium hydrogencarbonate / N,N-dimethyl-formamide; water / 3 h / 85 °C 3: hydrogenchloride / water; ethanol / Reflux
Same Skeleton Products
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[ 635702-64-6 ]

Chemical Structure| 444731-52-6

A135375[ 444731-52-6 ]

5-((4-((2,3-Dimethyl-2H-indazol-6-yl)(methyl)amino)pyrimidin-2-yl)amino)-2-methylbenzenesulfonamide

Reason: Free-salt