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Quality Control of [ 332012-40-5 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 332012-40-5 ]

Product Details of [ 332012-40-5 ]

CAS No. :	332012-40-5	MDL No. :	MFCD18251453
Formula :	C₂₀H₁₆ClN₅O₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	-
M.W :	409.83	Pubchem ID :	-
Synonyms :	Bay 57-9352	Chemical Name :	4-(((4-((4-Chlorophenyl)amino)furo[2,3-d]pyridazin-7-yl)oxy)methyl)-N-methylpicolinamide

Safety of [ 332012-40-5 ]

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

Application In Synthesis of [ 332012-40-5 ]

* 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 [ 332012-40-5 ]

[ 332012-40-5 ] Synthesis Path-Downstream 1~19

1
[ 332012-40-5 ]
[ 104-15-4 ]
[ 332013-24-8 ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; diethyl ether for 0.166667h;	106 The product of Example 14 (1.50 g, 3.66 mmol) was stirred as a slurry in methanol (20 ml) as a solution of toluenesulfonic acid hydrate (0.701 g, 3.67 mmol) in methanol (5 ml plus 5 ml rinse) was added quickly dropwise. All materials dissolved over 5 min to yield a yellow solution. Anhydrous ether (30 ml) was added and stirring was continued for 5 minutes until solid began to precipitate. The resultant mixture was chilled with stirring in an ice/water bath for 45 minutes and then the solid title product (Example 104) was collected by filtration, washed with ether and dried at 55 °C in a vacuum oven until NMR analysis showed a lack of solvents (1.5 hours). Other compounds were prepared in a similar way by using a variety of acids rather than toluenesulfonic acid. Scale up and use of less methanol in the first step generally led to quicker precipitation of salts and a variety of solvents were used rather than ether, as indicated, to help crystalize the individual salts. In some cases the methanol was first removed by evaporation in vacuo. Final drying took between 1.5 hours and several days, depending on the quantity of material and the specific specific acid used.
	Stage #1: Telatinib; toluene-4-sulfonic acid In methanol for 0.0833333h; Stage #2: In methanol; diethyl ether at 0℃; for 0.833333h;	106 The product of Example 14 (1.50 g, 3.66 mmol) was stirred as a slurry in methanol (20 ml) as a solution of toluenesulfonic acid hydrate (0.701 g, 3.67 mmol) in methanol (5 ml plus 5 ml rinse) was added quickly dropwise. All materials dissolved over 5 min to yield a yellow solution. Anhydrous ether (30 ml) was added and stirring was continued for 5 minutes until solid began to precipitate. The resultant mixture was chilled with stirring in an ice/water bath for 45 minutes and then the solid title product (Example 104) was collected by filtration, washed with ether and dried at 55 0C in a vacuum oven until NMR analysis showed a lack of solvents (1.5 hours). Other compounds were prepared in a similar way by using a variety of acids rather than toluenesulfonic acid. Scale up and use of less methanol in the first step generally led to quicker precipitation of salts and a variety of solvents were used rather than ether, as indicated, to help crystalize the individual salts. In some cases the methanol was first removed by evaporation in vacuo. Final drying took between 1.5 hours and several days, depending on the quantity of material and the specific specific acid used.
	In methanol; diethyl ether at 0℃; for 0.916667h;	106 Examples 106-114; Preparation of salts of example 14 The product of Example 14 (1.50 g, 3.66 mmol) was stirred as a slurry in methanol (20 ml) as a solution of toluenesulfonic acid hydrate (0.701 g, 3.67 mmol) in methanol (5 ml plus 5 ml rinse) was added quickly dropwise. All materials dissolved over 5 min to yield a yellow solution. Anhydrous ether (30 ml) was added and stirring was continued for 5 minutes until solid began to precipitate. The resultant mixture was chilled with stirring in an ice/water bath for 45 minutes and then the solid title product (Example 104) was collected by filtration, washed with ether and dried at 55° C. in a vacuum oven until NMR analysis showed a lack of solvents (1.5 hours). Other compounds were prepared in a similar way by using a variety of acids rather than toluenesulfonic acid. Scale up and use of less methanol in the first step generally led to quicker precipitation of salts and a variety of solvents were used rather than ether, as indicated, to help crystalize the individual salts. In some cases the methanol was first removed by evaporation in vacuo. Final drying took between 1.5 hours and several days, depending on the quantity of material and the specific specific acid used.

Reference： [1]Current Patent Assignee: BAYER AG - EP1228063, 2009, B1 Location in patent: Page/Page column 64
[2]Current Patent Assignee: BAYER AG - WO2007/118602, 2007, A1 Location in patent: Page/Page column 90
[3]Current Patent Assignee: BAYER AG - US6689883, 2004, B1 Location in patent: Page column 101-102

2
[ CAS Unavailable ]
[ 332012-35-8 ]
[ 332012-40-5 ]
[ 332012-41-6 ]

Yield	Reaction Conditions	Operation in experiment
15.2%	With sulfuric acid; hydroxylamine-O-sulfonic acid In water at 20℃; for 1.83333h;	14; 15 To a suspension of the final product from Example 9 (19.20 g, 54.4 mmol) in N-methylformamide (200 mL) and distilled water (20 mL) at room temperature was added concentrated H2SO4 (2.9 mL, 54.4 mmol) dropwise. The mixture was stirred until it became a clear solution. To this solution was added FeSO4·7H2O (1.51 g, 5.43 mmol) in one portion, followed by the addition of hydroxylamine-O-sulfonic acid (HOSA, 1.84 g, 16.3 mmol). The additions of FeSO4·7H2O and HOSA were repeated in 10 min. intervals for 11 times. HPLC assay showed the consumption of most starting material. The reaction mixture was cooled with an ice bath. A solution of sodium citrate (600 mL, 1M, 600 mmol) was added under vigorous stirring. The resulting suspension was stirred vigorously for additional 10 min. The solid was collected by filtration, washed with water (3x100 mL), and dried under vacuum at 50°C for 16 hours. The crude product (21 g) was purified by filtering through a silica gel pad eluting with 5% CH3OH/CH2Cl2. The resulting 3.7 g product was recrystallized in CH3CN (125mL, boiled for 1.5 hours). The solid was collected by filtration, washed with CH3CN (2x15mL), and dried under vacuum at 50°C for 16 hours. The final product (4-(4-chlorophenylamino)-7-(2-methylaminocarbonyl-4-pyridylmethoxy)furo-[2,3-d]pyridazine) is a light yellow solid (3.38 g, 15.2%). mp = 223-224°C. A major byproduct was isolated through the above silica gel pad filtration. The structure of the byproduct (4-(4-chlorophenylamino)- 2-methylaminocarbonyl -7-(2-methylaminocarbonyl-4-pyridylmethoxy)furo-[2,3-d]pyridazine) was characterized by 1H NMR, 2D NMR, elemental analysis, and MS. 1H NMR (DMSO-d6, 300 MHz): δ 9.32 (br s, 1H), 8.93 (q, 1H), 8.79 (q, 1H), 8.63 (dd, 1H), 8.12 (m, 1H), 7.91 (m, 3H), 7.70 (dd, 1H), 7.35 (m, 2H), 5.76 (br s, 2H), 2.81 (d, 6H). MS mlz 467 [M+H]+.
15.2%	Stage #1: N-Methylformamide; N-(4-chlorophenyl)-7-(4-pyridinylmethoxy)-furo[2,3-d]pyridazin-4-amine With sulfuric acid; iron(II) sulfate; hydroxylamine-O-sulfonic acid In water at 20℃; for 1.83333h; Stage #2: With sodium citrate In water at 0℃; for 0.166667h;	14; 15 To a suspension of the final product from Example 9 (19.20 g, 54.4 mmol) in N-methylformamide (200 mL) and distilled water (20 mL) at room temperature was added concentrated H2SO4 (2.9 mL, 54.4 mmol) dropwise. The mixture was stirred until it became a clear solution. To this solution was added FeSO4-7H2O (1.51 g, 5.43 mmol) in one portion, followed by the addition of hydroxylamine-O-sulfonic acid (HOSA, 1.84 g, 16.3 mmol). The additions of FeSO4-7H2O and HOSA were repeated in 10 min. intervals for 11 times. HPLC assay showed the consumption of most starting material. The reaction mixture was cooled with an ice bath. A solution of sodium citrate (600 mL, IM, 600 mmol) was added under vigorous stirring. The resulting suspension was stirred vigorously for additional 10 min. The solid was collected by filtration, washed with water (3x100 mL), and dried under vacuum at 500C for 16 hours. The crude product (21 g) was purified by filtering through a silica gel pad eluting with 5% CH3OHZCH2Cl2. The resulting 3.7 g product was recrystallized in CH3CN (125mL, boiled for 1.5 hours). The solid was collected by filtration, washed with CH3CN (2x15mL), and dried under vacuum at 500C for 16 hours. The final product (4-(4-chlorophenylamino)-7-(2-methylaminocarbonyl-4-pyridylmethoxy)furo-[2,3-d]pyridazine) is a light yellow solid (3.38 g, 15.2%). mp = 223-224°C.A major byproduct was isolated through the above silica gel pad filtration. The structure of the byproduct (4-(4-chlorophenylamino)-2-methylaminocarbonyl-7-(2-methylaminocarbonyl-4- pyridylmethoxy)furo-[2,3-d]pyridazine) was characterized by 1H NMR, 2D NMR, elemental analysis, and MS. 1H NMR (DMSOd6, 300 MHz): δ 9.32 (br s, IH), 8.93 (q, IH), 8.79 (q, IH), 8.63 (dd, IH), 8.12 (m, IH), 7.91 (m, 3H), 7.70 (dd, IH), 7.35 (m, 2H), 5.76 (br s, 2H), 2.81 (d, 6H). MS m/z 467 [M+H]+.
15.2%	With sulfuric acid; iron(II) sulfate; hydroxylamine-O-sulfonic acid In water at 20℃; for 1.66667h;	Examples 14 and 15; Preparation of 4-(4-chlorophenylamino)-7-(2-methylaminocarbonyl-4-pyridylmethoxy)furo-[2,3-d]pyridazine and 4-(4-chlorophenylamino)-2-methylaminocarbonyl-7-(2-methylaminocarbonyl-4-pyridylmethoxy)furo-[2,3-d]pyridazine To a suspension of the final product from Example 9 (19.20 g, 54.4 mmol) in N-methylformamide (200 mL) and distilled water (20 mL) at room temperature was added concentrated H2SO4 (2.9 mL, 54.4 mmol) dropwise. The mixture was stirred until it became a clear solution. To this solution was added FeSO4.7H2O (1.51 g, 5.43 mmol) in one portion, followed by the addition of hydroxylamine-O-sulfonic acid (HOSA, 1.84 g, 16.3 mmol). The additions of FeSO4.7H2O and HOSA were repeated in 10 min. intervals for 11 times. HPLC assay showed the consumption of most starting material. The reaction mixture was cooled with an ice bath. A solution of sodium citrate (600 mL, 1M, 600 mmol) was added under vigorous stirring. The resulting suspension was stirred vigorously for additional 10 min. The solid was collected by filtration, washed with water (3×100 mL), and dried under vacuum at 50° C. for 16 hours. The crude product (21 g) was purified by filtering through a silica gel pad eluting with 5% CH3OH/CH2Cl2. The resulting 3.7 g product was recrystallized in CH3CN (125 mL, boiled for 1.5 hours). The solid was collected by filtration, washed with CH3CN (2×15 mL), and dried under vacuum at 50° C. for 16 hours. The final product (4-(4-chlorophenylamino)-7-(2-methylaminocarbonyl-4-pyridylmethoxy)furo-[2,3-d]pyridazine) is a light yellow solid (3.38 g, 15.2%). mp=223-224° C. [00256] A major byproduct was isolated through the above silica gel pad filtration. The structure of the byproduct (4-(4-chlorophenylamino)-2-methylaminocarbonyl-7-(2-methylaminocarbonyl-4-pyridylmethoxy)furo-[2,3-d]pyridazine) was characterized by 1H NMR, 2D NMR, elemental analysis, and MS. 1H NMR (DMSO-d6, 300 MHz): δ 9.32 (br s, 1H), 8.93 (q, 1H), 8.79 (q, 1H), 8.63 (dd, 1H), 8.12 (m, 1H), 7.91 (m, 3H), 7.70 (dd, 1H), 7.35 (m, 2H), 5.76 (br s, 2H), 2.81 (d, 6H). MS m/z 467 [M+H]+.

Reference： [1]Current Patent Assignee: BAYER AG - EP1228063, 2009, B1 Location in patent: Page/Page column 45
[2]Current Patent Assignee: BAYER AG - WO2007/118602, 2007, A1 Location in patent: Page/Page column 67; 68
[3]Current Patent Assignee: BAYER AG - US6689883, 2004, B1 Location in patent: Page column 60-61

3
[ 332013-43-1 ]
[ 332013-40-8 ]
[ 332012-40-5 ]

Yield	Reaction Conditions	Operation in experiment
46%	With potassium hydroxide; 18-crown-6 ether In toluene at 83 - 87℃;	14; 14A To a mixture of the Intermediate from Example 9, step 5 (10.0 g, 35.7 mmol), Intermediate H (12.4 g, 74.6 mmol), and 18-crown-6 (0.42 g, 1.59 mmol) in toluene (100 mL) was added KOH powder(4.4 g, 85%, 66.7 mmol) in one portion at room temperature. The reaction mixture was then heated to 85 +/- 2°C under vigorous stirring. The reaction mixture was stirred vigorously at this temperature overnight. After it was cooled to room temperature, toluene solution was decanted off and water (100 mL) was added to the gummy residue. The resulting mixture was stirred vigorously until it became a free flowing suspension. The solids were collected by filtration, washed with water (2 x 10 mL), and dried under vacuum at 45°C for 16 hours. The yellow/brown solids were suspended in acetonitrile (70 mL) and the suspension was stirred at reflux for 2 hours. After it was cooled to room temperature, the solids were collected by filtration, washed with small amount of acetonitrile, and dried under vacuum at 45°C overnight. The title product was isolated in 46% yield (6.73 g) as a light yellow solid.
46%	With potassium hydroxide; 18-crown-6 ether In toluene at 20 - 85℃;	14A EXAMPLE 14A; Preparation of 4-(4-chlorophenylamino)-7-(2-methylaminocarbonyl-4-pyridylmethoxy)furo-[2,3-d]pyridazineProcess 2 To a mixture of the Intermediate from Example 9, step 5 (10.0 g, 35.7 mmol), Intermediate H (12.4 g, 74.6 mmol), and 18-crown-6 (0.42 g, 1.59 mmol) in toluene (100 mL) was added KOH powder (4.4 g, 85%, 66.7 mmol) in one portion at room temperature. The reaction mixture was then heated to 852 C. under vigorous stirring. The reaction mixture was stirred vigorously at this temperature overnight. After it was cooled to room temperature, toluene solution was decanted off and water (100 mL) was added to the gummy residue. The resulting mixture was stirred vigorously until it became a free flowing suspension. The solids were collected by filtration, washed with water (2?10 mL), and dried under vacuum at 45 C. for 16 hours. The yellow/brown solids were suspended in acetonitrile (70 mL) and the suspension was stirred at reflux for 2 hours. After it was cooled to room temperature, the solids were collected by filtration, washed with small amount of acetonitrile, and dried under vacuum at 45 C. overnight. The title product was isolated in 46% yield (6.73 g) as a light yellow solid.

Reference： [1]Current Patent Assignee: BAYER AG - WO2007/118602, 2007, A1 Location in patent: Page/Page column 68; 69; 75; 79
[2]Current Patent Assignee: BAYER AG - US6689883, 2004, B1 Location in patent: Page column 61

4
[ 332013-43-1 ]
[ 332013-41-9 ]
[ 332012-40-5 ]

Yield	Reaction Conditions	Operation in experiment
46%	With potassium hydroxide In toluene at 20 - 87℃;	14A To a mixture of the Intermediate from Example 9, step 5 (10.0 g, 35.7 mmol), Intermediate H (12.4 g, 74.6 mmol), and 18-crown-6 (0.42 g, 1.59 mmol) in toluene (100 mL) was added KOH powder (4.4 g, 85%, 66.7 mmol) in one portion at room temperature. The reaction mixture was then heated to 85 +/- 2 °C under vigorous stirring. The reaction mixture was stirred vigorously at this temperature overnight. After it was cooled to room temperature, toluene solution was decanted off and water (100 mL) was added to the gummy residue. The resulting mixture was stirred vigorously until it became a free flowing suspension. The solids were collected by filtration, washed with water (2 x 10 mL), and dried under vacuum at 45 °C for 16 hours. The yellow/brown solids were suspended in acetonitrile (70 mL) and the suspension was stirred at reflux for 2 hours. After it was cooled to room temperature, the solids were collected by filtration, washed with small amount of acetonitrile, and dried under vacuum at 45 °C overnight. The title product was isolated in 46% yield (6.73 g) as a light yellow solid.
	Stage #1: 4-(hydroxymethyl)-N-methylpyridine-2-carboxamide; 4-chloro-7-[N-(4-chlorophenyl)amino]-[2,3-d]furopyridazine In toluene at 20℃; for 0.166667h; Stage #2: With potassium hydroxide In toluene at 80℃; for 24h;	14 One equivalent of dichloride (1) and one equivalent of M-NH2 are suspended in DME (0.3M) and water is added until a solution was formed. The reaction mixture is heated to 65 °C for 48 h. After cooling to rt, the resulting precipitate is filtered and washed with DME to provide the intermediate product (2) which is confirmed by LC/MS and NMR.. In some instances, intermediate (2) is further purified by preparative TLC or washed with other solvents. A suspension of (2) (1 equiv), carbinol (3) (3 equiv), and 18-crown-6 (10 mol %) in toluene (0.3M) is stirred at rt for 10 min. KOH (3 equiv) is then added and the reaction mixture is heated to 80 °C for 24 h. After cooling to rt, water is added and the mixture is stirred vigorously until a suspension is formed. The suspension is filtered and washed with water to provide the desired product (4). Preparative TLC and/or washing with other solvents is used to further purify final products in some examples. The final products are assigned by LC/MS and NMR spectroscopy. Final product is confirmed by LC/MS and/or NMR. The invention compounds of Examples 34 - 47, 49-74, and 81 - 82D as shown in the below table were prepared by method A-3.

Reference： [1]Current Patent Assignee: BAYER AG - EP1228063, 2009, B1 Location in patent: Page/Page column 45-46
[2]Current Patent Assignee: BAYER AG - EP1228063, 2009, B1 Location in patent: Page/Page column 50-51; 54

5
[ 332013-40-8 ]
[ 1182334-19-5 ]
[ 332012-40-5 ]

Yield	Reaction Conditions	Operation in experiment
37.7%	With potassium <i>tert</i>-butylate In tetrahydrofuran; toluene at 95℃; for 24h; Autoclave;	1.2 Synthesis of compound 2 100 L autoclave was charged with 18 L of toluene, 18 L of tetrahydrofuran, 1.8 kg of compound 1, 1.76 kg of 4-Chloro-anilino-7-chlorofuro[2,3-d]pyridazine, 2.1 kg of potassium t-butoxide, After stirring at 95 ° C for 24 hours, add water 56.3kg, feed temperature 50 to 60 filtration, the resulting filter cake plus pureWater and isopropanol beating filter cake, cake drying, received 970g, yield 37.7%, purity99%.

Reference： [1]Current Patent Assignee: EDDINGPHARM CO LTD - CN104804008, 2016, B Location in patent: Paragraph 0029; 0034; 0035

6
[ 332012-40-5 ]
[ 75-75-2 ]
[ 332013-26-0 ]

Yield	Reaction Conditions	Operation in experiment
77.4%	In methanol for 0.25h; Autoclave; Reflux; Large scale;	1.3 The synthesis of telatinib mesylate 4.0 kg of methanol was charged in a 50 L autoclave, 0.90 kg of compound 2, A methanolic solution of 212 g of methanesulfonic acid was added dropwise under reflux, Drop finished, and continue to reflow for 15 minutes, hot filter,The filtrate was added 23.2kg isopropanol, atmospheric distillation, when the system temperature reached 78°C , the liquid crystallization of 1 hour at 0°C filter, collect the filter cake. The filter cake was dried to obtain telatinib mesylate0.89 kg, yield 77.4%, purity 99%.

Reference： [1]Current Patent Assignee: EDDINGPHARM CO LTD - CN104804008, 2016, B Location in patent: Paragraph 0029; 0036; 0037

7
[ 332013-42-0 ]
[ 332012-40-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: sodium tetrahydroborate / isopropyl alcohol; methanol / 8 h / 25 °C / Large scale 1.2: 1 h / 0 °C / Large scale 2.1: potassium <i>tert</i>-butylate / toluene; tetrahydrofuran / 24 h / 95 °C / Autoclave
	Multi-step reaction with 2 steps 1.1: sodium tetrahydroborate / ethanol / 18 h / 20 °C 1.3: pH 9 2.1: potassium hydroxide; 18-crown-6 ether / toluene / 83 - 87 °C
	Multi-step reaction with 2 steps 1: sodium tetrahydroborate / ethanol / 18 h / 20 °C 2: potassium hydroxide; 18-crown-6 ether / toluene / 20 - 85 °C

Reference： [1]Current Patent Assignee: EDDINGPHARM CO LTD - CN104804008, 2016, B
[2]Current Patent Assignee: BAYER AG - WO2007/118602, 2007, A1
[3]Current Patent Assignee: BAYER AG - US6689883, 2004, B1

8
[ 13177-70-3 ]
[ 332012-40-5 ]