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[ CAS No. 850140-73-7 ] {[proInfo.proName]}

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Chemical Structure| 850140-73-7
Chemical Structure| 850140-73-7
Structure of 850140-73-7 * Storage: {[proInfo.prStorage]}
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Product Details of [ 850140-73-7 ]

CAS No. :850140-73-7 MDL No. :MFCD25974239
Formula : C32H33ClFN5O11 Boiling Point : -
Linear Structure Formula :- InChI Key :-
M.W : 718.08 Pubchem ID :-
Synonyms :
BIBW 2992MA2;Afatinib (maleate);BIBW 2992;BIBW2992 Dimaleate

Calculated chemistry of [ 850140-73-7 ]

Physicochemical Properties

Num. heavy atoms : 50
Num. arom. heavy atoms : 16
Fraction Csp3 : 0.22
Num. rotatable bonds : 13
Num. H-bond acceptors : 15.0
Num. H-bond donors : 6.0
Molar Refractivity : 178.72
TPSA : 237.81 Ų

Pharmacokinetics

GI absorption : Low
BBB permeant : No
P-gp substrate : Yes
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -10.35 cm/s

Lipophilicity

Log Po/w (iLOGP) : 4.65
Log Po/w (XLOGP3) : 0.47
Log Po/w (WLOGP) : 4.04
Log Po/w (MLOGP) : 1.05
Log Po/w (SILICOS-IT) : 3.82
Consensus Log Po/w : 2.81

Druglikeness

Lipinski : 3.0
Ghose : None
Veber : 2.0
Egan : 1.0
Muegge : 4.0
Bioavailability Score : 0.11

Water Solubility

Log S (ESOL) : -3.97
Solubility : 0.0775 mg/ml ; 0.000108 mol/l
Class : Soluble
Log S (Ali) : -5.03
Solubility : 0.00666 mg/ml ; 0.00000927 mol/l
Class : Moderately soluble
Log S (SILICOS-IT) : -7.59
Solubility : 0.0000182 mg/ml ; 0.0000000254 mol/l
Class : Poorly soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 2.0
Synthetic accessibility : 5.04

Safety of [ 850140-73-7 ]

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 [ 850140-73-7 ]

* 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 [ 850140-73-7 ]

[ 850140-73-7 ] Synthesis Path-Downstream   1~9

  • 1
  • [ 850140-72-6 ]
  • [ 110-16-7 ]
  • 2-butenamide, N-(4-((3-chloro-4-fluorophenyl)amino)-7-([(3S)-tetrahydro-3-furanyl]oxy)-6-quinazolinyl)-4-(dimethylamino)-, (2E)-, (2Z)-2-butenedioate [ No CAS ]
YieldReaction ConditionsOperation in experiment
96.5% In tetrahydrofuran; at 20℃; Example 1: Preparation of <strong>[850140-72-6]Afatinib</strong> di-maleate Form C<strong>[850140-72-6]Afatinib</strong> free base (3 g) was dissolved in tetrahydrofuran (THF) (7.6 mL) and stirred at room temperature until a clear solution was obtained. While stirring the clear solution, a solution of maleic acid (1.48 g) in THF (7.6 mL) was added dropwise at roomtemperature. After completion of this addition, a suspension containing a sticky solid was obtained. THF (60mL) was added to the suspension and this mixture was stirred at room temperature overnight. A solid precipitate formed and was collected by filtration and washed with THF (30 mL) to yield a yellowish solid. The product was dried at 40C and 20mbar (yield: 4.28 g, 96.5%). XRPD peak data for the product is provided in the Table below.
91.5% In ethanol; at 70℃; Example 3 (E)-4-Dimethylamino-But-2-Enoic Acid-(4-(3-Chloro-4-Fluoro-Phenylamino)-7-((S)-Tetra-Hydrofuran-3-Yloxy)-Quinazolin-6Yl)-Amide Dimaleate 6.0 kg (12.35 mol) of (E)-4-dimethylamino-but-2-enoic acid-(4-(3-chloro-4-fluoro-phenylamino)-7-((S)-tetrahydrofuran-3-yloxy)-quinazolin-6yl)-amide are placed in 84 litres of ethanol and heated to 70 C. and combined with a solution of 2.94 kg (25.31 mol) of maleic acid in 36 litres of ethanol. After crystallisation has set in, first the mixture is cooled to 20 C. and stirred for 2 hours, then for 3 hours at 0 C. The precipitate is suction filtered, washed with 19 litres of ethanol and dried in vacuo at 40 C. Yield: 8.11 kg (91.5%) melting point: 178 C. 1H-NMR (CD3OD): delta=2.47+2.27 (m+m, 2H), 2.96 (s, 6H), 4.03 (m, 2H), 4.07+3.92 (m+m, 2H), 4.18+4.03 (m+m, 2H), 5.32 (m, 1H), 6.26 (s, 4H), 6.80 (m, 1H), 6.99 (m, 1H), 7.27(s, 1H), 7.30 (t, 1H), 7.66 (m,1H), 7.96 (dd,1H), 8.62 (s,1H), 9.07 (s, 1H) ppm
91% In ethanol; at 0 - 50℃; for 5.5h;Large scale; First, 16 kg of absolute ethanol and 2.15 kg of maleic acid were heated to 50 C in a 100 L reaction tank to be stirred to completely dissolve. Next, 46 kg of absolute ethanol and 3.79 kg of <strong>[850140-72-6]afatinib</strong> (purity 99.86%, impurity I content 0.01%, impurity II content 0.03%) were heated to 50 C in a 50 L reaction tank, and then dissolved and immediately introduced into the above. The mixture was stirred and mixed in a 100 L reaction tank, and after the majority of the solids were precipitated in the tank, stirring was continued at 50 C for 30 min. Then, the mixture was cooled to 20 C and stirred for 2 h, and finally cooled to 0 C and stirred for 3 h.After filtration, the filter cake was rinsed with 31 kg of absolute ethanol.After drying at 40 C for 2 h, a white solid of 5.08 kg was obtained.The purity is 99.84%, and the impurity I content is 0.01%.The impurity II content was 0.09%, and the yield was 91%.
86.5% In ethanol; at 10 - 15℃;Inert atmosphere; To the reactor was added anhydrous ethanol (450 g)A mixture of 72 g of Formula II,Nitrogen protection.Temperature control at 10 ~ 15 .Slowly dropping maleic acid ethanol solution (maleic acid 72g, anhydrous ethanol 0.54Kg),Control the temperature at 10 ~ 15 ,Time consuming 2 ~ 3hr.Control the temperature at 10 ~ 15 ,Stir for 2hr.Filtration gave a white to pale yellow solid,The wet product was washed with 90 g of absolute ethanol.45 ± 2 under reduced pressure drying (-0.09MPa, water bath temperature control)(Product evenly spread out, thin, every 6 hours re-material once)Formula I 93g.Yield 86.5%Purity 99.54%Less than 0.1%EE value of 99.65%,Cis-isomer is not detected,The X-ray powder diffraction pattern shows a single crystal form (melting point at 178 C).
83% In tetrahydrofuran; at 20℃; for 1.03333h; THF (0.5 ml) was added to 200 mg (0.41 mmol) <strong>[850140-72-6]afatinib</strong> free base and the mixture was stirred at room temperature to obtain a light yellow coloured solution. A solution of 100 mg (0.8 mmol) maleic acid in 0.5 ml THF was added over the course of 2 min. Another 4 ml THF were added and the mixture was stirred for 1 h. The solids were filtered off, rinsed with 2 ml THF and dried on a rotary evaporator at 48 C / 3 mbar for 6 h to give 0.245 g (83% yield) of a white solid.DSC shows an exotherm at 125.9C followed by a minor endotherm at 156.8 and a major endotherm at 173.9C.XRPD confirms crystalline nature. IR (cm"1): 3321.2, 3034.0, 1687.6, 1643.6, 1498, 1456.6, 1353.4, 1268.4, 1067.5, 869.0,780, 654.7and 576.4.Residual solvent: THF = 3390 ppm
26.5 g In methanol; at 20 - 60℃; for 0.5h; In a round bottom flask, <strong>[850140-72-6]afatinib</strong> (20 g) was dissolved in methanol (200 mL) by stirring at 20C to 35C to obtain a solution. Maleic acid (9.5 g) was added to the solution at the same temperature to obtain a reaction mixture. The reaction mixture was heated and stirred at 55C to 60C for 30 minutes. The reaction mixture was concentrated undervacuum at 45C to 46C to obtain a solid. Cyclohexane (100 mL) was added to the solid and the mixture was stirred at 45C to 46C for 5 minutes. The solution was cooled to 20C to 30C to obtain a solid. The solid obtained was filtered and dried under vacuum at40C to 45C to obtain the crystalline Form A of <strong>[850140-72-6]afatinib</strong> dimaleate.Yield: 26.5 g
18.8 g In dimethyl sulfoxide; at 20 - 35℃; A solution of <strong>[850140-72-6]Afatinib</strong> (15.Og) in acetonitrile (300 ml) was stirred at room temperature for 30 mm.. The clear solution was filtered through 5 micron filter paper. The filtrate was charged in the flask and 2/3 of maleic acid solution[prepared by dissolving maleic acid (9.lg) in dimethylsulfoxide (lOml) and acetonitrile (lOml] was added drop wise. The reaction mass was stirred for 15-20 mm followed by addition of rest of the maleic acid solution. After complete addition the reaction mass was stirred for 1-2h at 20-35C.The solid thus formed was filtered and washed with acetonitrile (15m1) and suck dried for 10-15mm.The product thus obtained was charged in the reactor and acetonitrilec(150m1) was added.The reaction mas was stirred for 15 mm and then filtered under nitrogen. The product was washed with acetonitrile (15m1x2). The product was suck dried for 1-2h and then dried under vacuum (NLT 700 mmHg) for 5-6 h. The resulting product wascharged in a flask and ethyl acetate (600m1) was added andreaction mass was stirred for 90 mm. The solid thus formed was filtered, washed with ethyl acetate (150m1) and suck dried for 20-30 mm. and finally under vacuum (NLT 700mmHg) at 45C for 20-22h. . 18.8 g of crystalline form M of <strong>[850140-72-6]Afatinib</strong> dimaleate was obtainedWater Content: 2.54%
30 g In methanol; at 60 - 65℃; <strong>[850140-72-6]Afatinib</strong> (25 g) base and maleic acid (12.5 g) were dissolved in methanol (1125 mL) at 60-65 C. The clear solution was filtered through Hyflo to remove any undissolved particulate, cooled to 25-30 C and subjected to spray drying in a laboratory spray dryer (Model Buchi-290) with a feed rate of the solution 5-10mL/min and an inlet temperature at 65 C to yield amorphous form of <strong>[850140-72-6]afatinib</strong> dimaleate (30 g).
30 g In methanol; at 60 - 65℃; <strong>[850140-72-6]Afatinib</strong> (25 g) base and maleic acid (12.5 g) were dissolved in methanol (1125 mL) at 60-65 C. The clear solution was filtered through Hyflo to remove any undissolved particulate, cooled to 25-30 C. and subjected to spray drying in a laboratory spray dryer (Model l3uchi-290) with a feed rate of the solution 5-lOmL/min and an inlet temperature at 65 C. to yield amorphous form of <strong>[850140-72-6]afatinib</strong> dimaleate (30 g).
27 g In ethanol; water; at 0 - 5℃; for 3h;Inert atmosphere; A mixture of N-[4-[(3-chloro-4-fluorophenyl) amino]-7-[[(3S)-tetrahydro-3-thranyl]oxy]-6-quinazolinyl]- 4-(dimethylamino)-(2E)-2-butenamide compound of formula-i 0 (25 gm) and ethanol (175 ml) was stirred for 15 minutes under nitrogen atmosphere. Cooled the reaction mixture to 0-5 C. 12.62 gm of Maleic acid in 75 ml ethanol was slowly added to the reaction mixture at 0-5 C. and stirred for 3 irs at the same temperature. The solid formed was filtered under nitrogen atmosphere, washed with ethanol and dried to get the title compound. Yield: 27 g; MR: 172-178 C.

  • 2
  • [ 618061-76-0 ]
  • 2-butenamide, N-(4-((3-chloro-4-fluorophenyl)amino)-7-([(3S)-tetrahydro-3-furanyl]oxy)-6-quinazolinyl)-4-(dimethylamino)-, (2E)-, (2Z)-2-butenedioate [ No CAS ]
  • 3
  • [ 314771-76-1 ]
  • [ 850140-73-7 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: 1,1'-carbonyldiimidazole / dichloromethane / 30 - 55 °C 1.2: 3 h / 20 - 40 °C 2.1: lithium chloride; potassium hydroxide / ethanol; water / 2 h / -5 - 10 °C / Inert atmosphere 2.2: 7 h / 0 - 18 °C 3.1: ethanol / 10 - 15 °C / Inert atmosphere
  • 4
  • [ 162012-69-3 ]
  • [ 850140-73-7 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: trichlorophosphate; triethylamine / acetonitrile / 5 h / 0 - 85 °C 1.2: 3 h / 25 - 30 °C 2.1: 1-methyl-pyrrolidin-2-one / 0.17 h / 25 - 30 °C / Inert atmosphere 2.2: 1.5 h / 15 - 20 °C 3.1: acetic acid; iron / tetrahydrofuran; water / 3 h / 25 - 30 °C 3.2: 1.5 h / 0 - 5 °C 4.1: hydrogenchloride / ethyl acetate / 0.25 h / 25 - 65 °C 4.2: 3 h / 55 - 60 °C 5.1: water; ethanol / 3 h / 0 - 5 °C / Inert atmosphere
Multi-step reaction with 6 steps 1.1: trichlorophosphate; triethylamine / acetonitrile 2.1: potassium hydroxide / 1,4-dioxane 3.1: 1-methyl-pyrrolidin-2-one / 0.17 h / 25 - 30 °C / Inert atmosphere 3.2: 1.5 h / 15 - 20 °C 4.1: acetic acid; iron / tetrahydrofuran; water / 3 h / 25 - 30 °C 4.2: 1.5 h / 0 - 5 °C 5.1: hydrogenchloride / ethyl acetate / 0.25 h / 25 - 65 °C 5.2: 3 h / 55 - 60 °C 6.1: water; ethanol / 3 h / 0 - 5 °C / Inert atmosphere
  • 5
  • [ 162012-70-6 ]
  • [ 850140-73-7 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: potassium hydroxide / 1,4-dioxane 2.1: 1-methyl-pyrrolidin-2-one / 0.17 h / 25 - 30 °C / Inert atmosphere 2.2: 1.5 h / 15 - 20 °C 3.1: acetic acid; iron / tetrahydrofuran; water / 3 h / 25 - 30 °C 3.2: 1.5 h / 0 - 5 °C 4.1: hydrogenchloride / ethyl acetate / 0.25 h / 25 - 65 °C 4.2: 3 h / 55 - 60 °C 5.1: water; ethanol / 3 h / 0 - 5 °C / Inert atmosphere
  • 6
  • [ 367-21-5 ]
  • [ 850140-73-7 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: trichlorophosphate; triethylamine / acetonitrile / 5 h / 0 - 85 °C 1.2: 3 h / 25 - 30 °C 2.1: 1-methyl-pyrrolidin-2-one / 0.17 h / 25 - 30 °C / Inert atmosphere 2.2: 1.5 h / 15 - 20 °C 3.1: acetic acid; iron / tetrahydrofuran; water / 3 h / 25 - 30 °C 3.2: 1.5 h / 0 - 5 °C 4.1: hydrogenchloride / ethyl acetate / 0.25 h / 25 - 65 °C 4.2: 3 h / 55 - 60 °C 5.1: water; ethanol / 3 h / 0 - 5 °C / Inert atmosphere
  • 7
  • [ 162012-67-1 ]
  • [ 850140-73-7 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: 1-methyl-pyrrolidin-2-one / 0.17 h / 25 - 30 °C / Inert atmosphere 1.2: 1.5 h / 15 - 20 °C 2.1: acetic acid; iron / tetrahydrofuran; water / 3 h / 25 - 30 °C 2.2: 1.5 h / 0 - 5 °C 3.1: hydrogenchloride / ethyl acetate / 0.25 h / 25 - 65 °C 3.2: 3 h / 55 - 60 °C 4.1: water; ethanol / 3 h / 0 - 5 °C / Inert atmosphere
  • 8
  • [ 314771-88-5 ]
  • [ 850140-73-7 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: acetic acid; iron / tetrahydrofuran; water / 3 h / 25 - 30 °C 1.2: 1.5 h / 0 - 5 °C 2.1: hydrogenchloride / ethyl acetate / 0.25 h / 25 - 65 °C 2.2: 3 h / 55 - 60 °C 3.1: water; ethanol / 3 h / 0 - 5 °C / Inert atmosphere
  • 9
  • [ 2047333-82-2 ]
  • [ 850140-73-7 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: hydrogenchloride / ethyl acetate / 0.25 h / 25 - 65 °C 1.2: 3 h / 55 - 60 °C 2.1: water; ethanol / 3 h / 0 - 5 °C / Inert atmosphere
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