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[ CAS No. 443913-73-3 ] {[proInfo.proName]}

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Chemical Structure| 443913-73-3
Chemical Structure| 443913-73-3
Structure of 443913-73-3 * Storage: {[proInfo.prStorage]}
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Product Details of [ 443913-73-3 ]

CAS No. :443913-73-3 MDL No. :MFCD07772346
Formula : C22H24BrFN4O2 Boiling Point : -
Linear Structure Formula :- InChI Key :UHTHHESEBZOYNR-UHFFFAOYSA-N
M.W : 475.35 Pubchem ID :3081361
Synonyms :
ZD6474;CH 331;Zactima

Calculated chemistry of [ 443913-73-3 ]

Physicochemical Properties

Num. heavy atoms : 30
Num. arom. heavy atoms : 16
Fraction Csp3 : 0.36
Num. rotatable bonds : 6
Num. H-bond acceptors : 6.0
Num. H-bond donors : 1.0
Molar Refractivity : 123.26
TPSA : 59.51 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : Yes
CYP2C9 inhibitor : Yes
CYP2D6 inhibitor : Yes
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -5.7 cm/s

Lipophilicity

Log Po/w (iLOGP) : 4.31
Log Po/w (XLOGP3) : 4.93
Log Po/w (WLOGP) : 5.04
Log Po/w (MLOGP) : 3.45
Log Po/w (SILICOS-IT) : 4.31
Consensus Log Po/w : 4.41

Druglikeness

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

Water Solubility

Log S (ESOL) : -5.89
Solubility : 0.00061 mg/ml ; 0.00000128 mol/l
Class : Moderately soluble
Log S (Ali) : -5.92
Solubility : 0.000576 mg/ml ; 0.00000121 mol/l
Class : Moderately soluble
Log S (SILICOS-IT) : -8.03
Solubility : 0.00000443 mg/ml ; 0.0000000093 mol/l
Class : Poorly soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 2.0
Synthetic accessibility : 3.28

Safety of [ 443913-73-3 ]

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 [ 443913-73-3 ]

* 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 [ 443913-73-3 ]

[ 443913-73-3 ] Synthesis Path-Downstream   1~27

  • 1
  • [ 50-00-0 ]
  • [ 338992-12-4 ]
  • [ 443913-73-3 ]
YieldReaction ConditionsOperation in experiment
85% With sodium triacetoxyborohydride; acetic acid; In methanol; dichloromethane; water; at 20℃; for 2h; 37% aqueous solution of formaldehyde (40 mg, 0.52 mmol) followed by NaBH(OAc)3 (120 mg, 0.56 mmol) were added in portions to the solution of 5a (167 mg, 0.4 mmol) and acetic acid (28 mg, 0.48 mmol) in CH2Cl2 (10 mL) and methanol (20 mL). After the reaction mixture was stirred at rt for 2 h, and the solvents were removed under vacuum. The resulting residue was added aqueous NaHCO3, the precipitate was filtered, washed with water and brine, and dried to obtainwhite solid; the aqueous layer was extracted with CH2Cl2, dried over MgSO4, filtered and evaporated to provide a residue, which was washed with Et2O to obtain white solid. The combined white solid gave 6a (146 mg, 85%).
45% A solution of N-(4-bromo-2-fluorophenyl)-6-methoxy-7-(piperidin-4-ylmethoxy)quinazolin-4-amine (150 mg, 0.31 mmol, 1.00 equiv, 95%), formic acid (3 mL), and formaldehyde (3 mL, 85%) was was stirred at about 95 C. for about 4 hours and then concentrated in vacuo. After diluting the resulting residue with water (20 mL), the pH value was adjusted to 11 with 2M sodium hydroxide. The resulting solution was extracted with ethyl acetate (2*20 mL), washed with water (20 mL), washed with brine (20 mL), and then dried over anhydrous magnesium sulfate. The resulting residue was purified by silica gel column chromotography (dichloromethane/methanol 10:1) to give the title product as a white solid (70 mg, yield 45%). 1H NMR (300 MHz, DMSO) delta: 9.55 (s, 1H), 8.36 (s, 1H), 7.80 (s, 1H), 7.67 (dd, J=10.2, 2.1 Hz, 1H), 7.46-7.57 (m, 2H), 7.19 (s, 1H), 4.02 (d, J=5.7 Hz, 2H), 3.95 (s, 3H), 2.83-2.87 (m, 2H), 2.21 (s, 3H), 1.92-2.01 (m, 2H), 1.77-1.81 (m, 3H), 1.36-1.43 (m, 2H); LC-MS: m/z=475/477 (MH)+.
With sodium cyanoborohydride; In tetrahydrofuran; methanol; at 18 - 25℃; for 1h;Product distribution / selectivity; Example 2a A solution of 37% aqueous formaldehyde (50mul, 0.6mmol) followed by sodium cyanoborohydride (23mg, 0.36mmol) were added to a solution of 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(piperidin-4-ylmethoxy)quinazoline (139mg, 0.3mmol), (prepared as described in Example 1), in a mixture of THF/methanol (1.4ml/1.4ml). After stirring for 1 hour at ambient temperature, water was added and the volatiles were removed under vacuum. The residue was triturated with water, filtered, washed with water, and dried under vacuum. The solid was purified by chromatography on neutral alumina eluding with methylene chloride followed by methylene chloride/ethyl acetate (1/1) followed by methylene chloride/ethyl acetate/methanol (50/45/5). The fractions containing the expected product were evaporated under vacuum. The resulting white solid was dissolved in methylene chloride/methanol (3ml/3ml) and 3N hydrogen chloride in ether (0.5ml) was added. The volatiles were removed under vacuum. The solid was triturated with ether, filtered, washed with ether and dried under vacuum to give 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline hydrochloride (120mg, 69%). MS - ESI: 475-477 [MH]+
  • 2
  • [ 50-00-0 ]
  • [ 338992-20-4 ]
  • [ 443913-73-3 ]
YieldReaction ConditionsOperation in experiment
94 - 95% 7-(l-tert-butoxycarbonyl)piperidine-4-ylmethoxy)-4-(4-bromo-2-fluoroanilino)-6- methoxyquinazoline (100 g), water (80 ml), formic acid (120 ml) and aqueous formaldehyde (37% w/w, 26.7 g) were added to a vessel equipped with overhead stirrer, reflux condenser and purged with nitrogen. The reaction mixture was heated to 8O0C over a period of 90 minutes and stirred at this temperature for 5 hours. The reaction mixture was then cooled to 6O0C and methanol (800 ml) was added, followed by potassium hydroxide (49% w/w, 228 ml) over 2 hours. The slurry was cooled to 2O0C over 2 hours before isolating the product by filtration. The product was washed twice with aqueous methanol (2:1 methanol: water, 300 ml) and dried at 50C. Yield: 79.6 g, 94%: NMR Spectrum (pyridine-d5) 1.49 (2H5 m), 1.75-1.90 (5H5 m), 2.15 (3H, s), 2.76 (2H5 m), 3.63 (3H5 s), 3.97 (2H, d), 7.38 (IH, ddd), 7.49 (IH, dd), 7.64 (IH5 s), 7.88 (IH5 1), 7.89 (IH5 s), 9.01 (IH, s), 10.37 (IH5 s); Mass Spectrum (M+H)+ = 475.; 7-(l-tert-butoxycarbonyl)pirhoeridine-4-ylmethoxy)-4-(4-bromo-2-fluoroanilino)-6- methoxyquinazoline (100 g), water (45 ml), formic acid (120 ml) and aqueous formaldehyde (37% w/w, 101.8 g) were added to a vessel equipped with an overhead stirrer and a reflux condenser and purged with nitrogen. The reaction mixture was heated EPO <DP n="61"/>to 8O0C over a period of 90 minutes and stirred at this temperature for 5 hours. The reaction mixture was then cooled to 6O0C and methanol (800 ml) was added, followed by potassium hydroxide (49% w/w, 228 ml) over 2 hours. The slurry was cooled to 2O0C over 2 hours before isolating the product by filtration. The product was washed twice with aqueous methanol (2:1 methanol: water, 300 ml) and dried at 50C. Yield: 79.6 g, 94%; NMR Spectrum (pyridine-d5) 1.49 (2H, m), 1.75-1.90 (5H5 m), 2.15 (3H, s), 2.76 (2H, m), 3.63 (3H5 s)5 3.97 (2H5 d), 7.38 (IH5 ddd), 7.49 (IH5 dd), 7.64 (IH5 s), 7.88 (IH5 1), 7.89 (IH5 s), 9.01 (IH5 s), 10.37 (IH5 s); Mass Spectrum (M+H)+ = 475.; 7-(l-tert-butoxycarbonyl)piperidine-4-ylmethoxy)-4-(4-bromo-2-fiuoroanilino)-6- methoxyquinazoline (36 g (at) 100%w/w), water (16 ml), formic acid (44 ml) and aqueous formaldehyde (37% w/w, 36.4 g) were added to a vessel equipped with an overhead stirrer and a reflux condenser and purged with nitrogen. The reaction mixture was heated to 8O0C over a period of 90 minutes and stirred at this temperature for 7 hours. The reaction mixture was then cooled to 6O0C and methanol (376 ml) was added, followed by potassium hydroxide (49% w/w, 86 ml) over 2 hours. The slurry was seeded with ZD6474 (methanolate form, 300 mg) and cooled to 2O0C over 2 hours before isolating the product by filtration. The product was washed twice with aqueous methanol (80:20 methanol: water, 67 ml) and dried at ambient temperature. Yield: 32.4 g, 95%; NMR Spectrum (pyridine-d5) 1.49 (2H, m), 1.75-1.90 (5H, m), 2.15 (3H, s), 2.76 (2H, m), 3.63 (3H, s), 3.97 (2H, d), 7.38 (IH, ddd), 7.49 (IH, dd), 7.64 (IH, s), 7.88 (IH, t), 7.89 (IH, s), 9.01 (IH5 s), 10.37 (IH, s); Mass Spectrum (M+H)+ = 475.
90.6 - 91.4% 7-(l-te7-t-butoxycarbonyl)piperidine-4-ylmethoxy)-4-(4-bromo-2-fluoroanilino)-6- methoxyquinazoline (100 g), water (80 ml), formic acid (120 ml) and aqueous formaldehyde (38% w/w, 28.2 g) were added to a vessel equipped with overhead stirrer, reflux condenser and purged with nitrogen. The reaction mixture was heated to 8O0C over a period of 90 minutes and stirred at this temperature for 5 hours. The reaction mixture was then cooled to 2O0C and tetrahydrofuran (500 ml) was added. The reaction mixture was warmed to 4O0C and sodium hydroxide (47% w/w, 265 ml) was added, followed by water (60 ml). The aqueous phase was separated and discarded. The organic phase was adjusted to 600C and water (300 ml) and butyl acetate (300 ml) were added. The resulting mixture was stirred at 60C for 15 minutes and then the aqueous phase separated and discarded. Water (400 ml) was then added to the organic phase, which was stirred at 6O0C for 15 minutes and then the aqueous phase separated and discarded. Butyl acetate (300 ml) and tetrahydrofuran (50 ml) were added to the organic phase and set for distillation at ambient pressure. The distillation was stopped when the contents temperature reached 1040C. The slurry was then cooled to 2O0C and held for 2 hours before isolating the product by filtration. The product was washed with butyl acetate (300 ml) and dried at 500C. Yield: 76.7 g, 90.6%; NMR Spectrum (pyridine-d5) 1.49 (2H, m), 1.75-1.90 (5H, m), 2.15 (3H, s), 2.76 (2H, m), 3.63 (3H, s), 3.97 (2H5 d), 7.38 (IH, ddd), 7.49 (IH, dd), 7.64 (IH, s), 7.88 (IH, t), 7.89 (IH, s), 9.01 (IH, s), 10.37 (IH, s); Mass Spectrum (M+H)+ = 475.; 7-(l-tert-butoxycarbonyl)piperidine-4-ylmethoxy)-4-(4-bromo-2-fluoroanilino)-6- methoxyquinazoline (35.0 g), water (28 ml), formic acid (42 ml) and aqueous formaldehyde (37% w/w, 8.2 g) were added to a vessel equipped with overhead stirrer, reflux condenser and purged with nitrogen. The reaction mixture was heated to 8O0C and stirred at this temperature for 5 hours. The reaction mixture was then cooled to 4O0C and EPO <DP n="60"/>tetrahydrofuran (175 ml) was added. Sodium hydroxide (47% w/w, 61.9 ml) was added at 40C followed by water (21 ml). The aqueous phase was then separated and discarded. Water (420 ml) was added to the organic phase at 400C over a period of 30 minutes. The slurry was then cooled to 200C before isolating the product by filtration. The product was washed with water (175 ml) and dried at 50C. Yield: 27.1 g, 91.4 %; NMR Spectrum (pyridine-d5) 1.49 (2H, m), 1.75-1.90 (5H, m), 2.15 (3H, s), 2.76 (2H, m), 3.63 (3H5 s), 3.97 (2H, d), 7.38 (IH, ddd), 7.49 (IH, dd), 7.64 (IH5 s)5 7.88 (IH, t), 7.89 (IH, s), 9.01 (IH, s), 10.37 (IH, s); Mass Spectrum (M+H)+ = 475.
88% Example 2b 37% Aqueous formaldehyde (3.5ml, 42mmol) was added to a solution of 4-(4-bromo-2-fluoroanilino)-7-(1-(tert-butoxycarbonyl)piperidin-4-ylmethoxy)-6-methoxyquinazoline (3.49g, 6.22mmol), (prepared as described for the starting material in Example 1), in formic acid (35ml). After heating at 95C for 4 hours the volatiles were removed under vacuum. The residue was suspended in water and the mixture was adjusted to pH10.5 by slow addition of a solution of 2N sodium hydroxide. The suspension was extracted with ethyl acetate. The organic layer was washed with brine, dried MgSO4 and evaporated to give 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (2.61g, 88%). MS - ESI: 475-477 [MH]+ 1H NMR Spectrum: (DMSOd6) 1.3-1.45 (m, 2H), 1.8 (d, 2H), 1.7-1.9 (m, 1H), 1.95 (t, 2H), 2.2 (s, 3H), 2.85 (d, 2H), 3.96 (s, 3H), 4.05 (d, 2H), 7.19 (s, 1H), 7.5 (d, 1H), 7.55 (t, 1H), 7.67 (d, 1H), 7.81 (s, 1H), 8.37 (s, 1H), 9.54 (s, 1H)
80.3% 7-(l-tert-butoxycarbonyl)piperidine-4-ylmethoxy)-4-(4-bromo-2-fluoroanilino)-6- methoxyquinazoline (40 g), water (16 ml), formic acid (43 ml) and aqueous formaldehyde (37% w/w, 33 ml) were added to a vessel equipped with overhead stirrer, reflux condenser and thermometer. The reaction mixture was heated to 810C and stirred at this temperature for 5 hours. The reaction mixture was cooled to 6O0C and tetrahydrofuran (178 ml) was added. The temperature of the reaction mixture was adjusted to 4O0C and potassium hydroxide (49% w/w, 84 ml) was added, followed by water (22 ml). The aqueous phase was separated and discarded. The organic phase was adjusted to 6O0C and water (107 ml) and butyl acetate (107 ml) were added. The aqueous phase was separated and discarded. The organic phase was filtered, following through with tetrahydrofuran (18 ml) wash. The temperature of the filtrates was adjusted to 6O0C and butyl acetate (107 ml) was added. The reaction mixture was set for distillation at ambient pressure. The distillation was stopped when the contents temperature reached 106C. The slurry was cooled to 65C and tetrahydrofuran (107 ml) was added. The slurry was cooled to 0-50C and held for 1 hour before isolating the product by filtration. The product was washed with ethyl acetate (72 ml) and dried at 5O0C. Yield: 24.82 g, 80.3%.

  • 3
  • 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline hydrochloride [ No CAS ]
  • [ 443913-73-3 ]
YieldReaction ConditionsOperation in experiment
With sodium hydrogencarbonate; In dichloromethane; water;Saturated solution;Product distribution / selectivity; A sample of 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (free base) was generated from the 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline hydrochloride, (prepared as described above), as follows: 4-(4-Bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxyquinazoline hydrochloride (50mg) was suspended in methylene chloride (2ml) and was washed with saturated sodium hydrogen carbonate. The methylene chloride solution was dried (MgSO4) and the volatiles were removed by evaporation to give 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (free base). The NMR of the free base so generated shows only one form as described below: 1H NMR Spectrum: (DMSOd6) 1.3-1.45 (m, 2H); 1.76 (d, 2H); 1.7-1.9(m, 1H); 1.9 (t, 2H); 2.19 (s, 3H); 2.8 (d, 2H); 3.95 (s, 3H); 4.02 (d, 2H); 7.2 (s, 1H); 7.48 (d, 1H) ; 7.55 (t, 1H) ; 7.68 (dd, 1H); 7.8 (s, 1H) ; 8.38 (s, 1H) ; 9.55(br s, 1H)
YieldReaction ConditionsOperation in experiment
92% In tetrahydrofuran; acetic acid butyl ester; water;Heating / reflux;Purification / work up; ZD6474 free base was prepared according to the procedure described in Example 2b of WO 01/32651. The ZD6474 free base (10 g) was suspended in tetrahydrofuran (50 ml), water (25 ml) and n-butyl acetate (40 ml) and the suspension heated to reflux to give a solution. The aqueous phase was separated and the organic phase was filtered and washed EPO <DP n="27"/>with tetrahydrofuran (5 ml). rc-Butyl acetate (60 ml) was added and the mixture distilled at atmospheric pressure until a contents temperature of 106C was achieved. The resulting slurry of ZD6474 was cooled and the solid isolated by filtration, washed with ethyl acetate (20 ml) and dried to provide ZD6474 anhydrous (9.2 g, 92%); NMR spectrum (pyridine- d5) 1.49 (2H, m), 1.75-1.90 (5H5 m), 2.15 (3H, s), 2.76 (2H, m), 3.63 (3H, s), 3.97 (2H, d), 7.38 (IH, ddd), 7.49 (IH, dd), 7.64 (IH, s), 7.88 (IH, t), 7.89 (IH, s), 9.01 (IH, s), 10.37 (IH, s); Mass spectrum MH+ 475.
In dichloromethane; water; for 0.208333h;Purification / work up; As discussed above, in Example 2c of WO 01/32651, ZD6474 free base is isolated as a solid. In Example 2c of WO 01/32651, the hydrochloride salt of ZD6474 is converted EPO <DP n="26"/>to ZD6474 free base by suspending the hydrochloride salt in methylene chloride and washing the suspension with saturated aqueous sodium hydrogen carbonate to provide a solution of ZD6474 free base in methylene chloride. The methylene chloride solution of ZD6474 free base is then dried using magnesium sulfate and the volatiles removed by evaporation.In this example of the present application, the isolation step of Example 2c of WO 01/32651 was repeated from the step whereby a solution of ZD6474 free base in methylene chloride has been provided (which is washed with water). As a person skilled in the art would appreciate, the steps used prior to the isolation step to prepare the solution of ZD6474 free base in methylene chloride are irrelevant to the form of ZD6474 that is provided by means of the particular isolation step. Additionally, any neutralisation step(s) has no effect on the form of ZD6474 that is provided.A sample of ZD6474 (250.5 mg) was placed in a Wheaton disposable glass scintillation vial and dichloromethane (10 ml) was added. The vial was capped and the mixture was swirled gently for 10 minutes to dissolve the solid. Water (5 ml) was then added to the solution and the mixture was shaken vigorously for 30 seconds. The mixture was allowed to stand for 2 minutes and then the dichloromethane layer was removed with a glass pipette and placed in another glass scintillation vial. Magnesium sulfate was added to the solution and the mixture was swirled to fully disperse the solid. The addition of magnesium sulfate was continued until the solid no longer clumped together but formed a fine dispersion on swirling. The mixture was allowed to stand overnight. The magnesium sulfate was then removed by filtration and rinsed with dichloromethane (1 ml). The filtrate and the washings were combined and allowed to evaporate to give a fine white crystalline solid. This material was then analysed by XRPD (according to the method described hereinafter). The XRPD trace (Figure 9) shows that the material is the anhydrous form of ZD6474 (see Figure 2). As the skilled person would appreciate, any differences in peak height are due to preferred crystal orientation.
  • 5
  • [ 443913-73-3 ]
  • 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline monohydrate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With water; In tetrahydrofuran; at 20 - 50℃; for 28.333 - 292.333h;Product distribution / selectivity; ZD6474 anhydrous (50 mg) and ZD6474 monohydrate (50 mg) were slurried in different ratios of isopropanol/water having water activities of 0.3, 0.4 and 0.5 (corresponding to 30% relative humidity, 40% relative humidity and 50% relative humidity respectively) for 24 hours at 250C. The resulting material was then filtered off and air- dried. These experiments indicated that at 250C, ZD6474 anhydrous is the thermodynamically stable form at < 30% relative humidity and ZD6474 monohydrate is the thermodynamically stable form at > 40% relative humidity. Example 4: Preparation of ZD6474 MonohvdrateZD6474 free base was prepared according to the procedure described in Example 2b of WO 01/32651. The ZD6474 free base (10.06 g) was added to aqueous tetrahydrofuran (90% tetrahydrofuran / 10% water, volume/volume) at ambient temperature. The mixture was stirred and warmed to 4O0C until all solid had dissolved. Further ZD6474 free base (1.44 g) was added to the mixture at 42C and the mixture was stirred for 20 minutes to provide a clear solution. The solution was warmed to 500C and stirred at this temperature for 4 hours. The solution was then cooled to room temperature and stirred for 12 days to provide a slurry. The resulting solid was filtered under vacuum (600 to 700 mbar) and dried in air under vacuum (200 mbar) for 1 hour. Karl Fischer analysis was conducted on the dried ZD6474 product according to the method described hereinafter and yielded a figure of 3.904%, which is consistent with ZD6474 monohydrate; NMR spectrum (pyridine-d5) 1.49 (2H, m), 1.75-1.90 (5H, m), 2.15 (3H, s), 2.76 (2H, m), 3.63 (3H, s), 3.97 (2H, d), 7.38 (IH, ddd), 7.49 (IH, dd), 7.64 (IH, s), 7.88 (IH, t), 7.89 (IH, s), 9.01 (IH, s), 10.37 (IH, s); Mass spectrum MH+ 475.; 5: Alternative preparation method of ZD6474 MonohydrateThis was prepared in a temperature controlled glass reaction vessel set at 3O0C. The vessel was charged with anhydrous ZD6474. To this was added 3 relative volumes of tetrahydrofuran (stabilised) and 7 relative volumes of purified water (i.e. 3 litres of THF and 7 litres of water would be used for lkg of ZD6474). The contents were agitated to form a cream coloured slurry. The reaction turnover was typically complete in under an hour, but a small sample of the slurry can be taken after an hour, filtered, then a powder XRD spectrum taken to confirm this. The solid was isolated by filtering on a split Buchner funnel. The reaction vessel was washed with 2 relative volumes of water. The reaction vessel wash was then used as a displacement wash of the filter cake in the Buchner funnel. A further wash was performed using an additional 2 relative volumes of water added to the reaction vessel which was again used to wash the filter cake.The solid was transferred to a vacuum oven and dried at ambient temperature until dry. During drying the solid was slurried regularly. Drying was very slow, typically a 350g batch takes approximately 2 weeks to dry.
  • 6
  • [ 367-24-8 ]
  • [ 264208-72-2 ]
  • [ 443913-73-3 ]
  • 8
  • [ 162364-72-9 ]
  • [ 443913-73-3 ]
  • 9
  • [ 196603-96-0 ]
  • [ 443913-73-3 ]
  • 10
  • [ 768350-54-5 ]
  • [ 443913-73-3 ]
  • 11
  • [ 443913-73-3 ]
  • 4-((4-bromo-2-fluorophenyl)amino)-7-((1-methylpiperidin-4-yl)methoxy)quinazolin-6-ol [ No CAS ]
YieldReaction ConditionsOperation in experiment
17% With pyridine hydrochloride; at 190 - 200℃; for 1.33333h; A mixture of compound 6a (151 mg, 0.35 mmol) and pyridine hydrochloride (3.2 g, 30 mmol) was heated at 190-200 C for 80 min and then cooled to rt. Aqueous NaHCO3 was added to reaction mixture to adjust pH of solution to 9, and the solution was extracted with EtOAc (80 mL x 3). The organic layers were washed with water and brine, dried over Na2SO4, and evaporated. The residue was purified by column chromatography with eluent (20-50% MeOH/CH2Cl2) on silica gel to give 7a (26 mg, 18%) as a white solid.
  • 12
  • 2,2’,2”-nitrilotris(ethane-2,1-diyl)tris(1H-imidazole-1-carboxylate) [ No CAS ]
  • [ 107-15-3 ]
  • [ 443913-73-3 ]
  • C53H61Br2F2N11O10 [ No CAS ]
YieldReaction ConditionsOperation in experiment
ZD-G1 (210 mg, 0.42 mmol) was added to a solution of 2,2',2"-nitrilotris(ethane-2,1- diyl) tris(1H-imidazole-1-carboxylate) (85 mg, 0.22 mmol) in DMSO (2 mL). Triethylamine (400 mu, 2.80 mmol) was added to this solution. After stirring overnight in the ambient temperature, 50 muL ethyl diamine was added and then kept stirring at room temperature for 24 hours to complete the reaction. The reaction was quenched by the adding of 20 muL trifluoroacetic acid (TFA). (Figure 1) The purification of the crude product was carried out on a semipreparative reversed phase high-performance liquid chromatography (HPLC) system (Agilent 1200 series) and was performed on a Phenomenex Luna C18(2) column 100R (250 x 10.00 mm). The absorbance was monitored at 254 nm. The peak containing the ZD-G2 was collected, lyophilized and stored in the dark at -20C until use. 1H NMR (500 MHz, DMSO): 8.715 (s, 2H, Ph-NH), 7.963 (s, 2H), 7.796(d, 2H, J=2), 7.786(d, 2H, J=2), 7.796 (d, 2H, J=2), 7.547 (m, 4H), 7.502 (s, 1H, CONH), 7.265 (s, 2H), 4.272 (m, 6H, -OCH2-), 4.058 (m, 10H), 3.975(s, 6H, -OCH3), 3.345(m, 6H), 2.876 (m, 8H), 1.96 (s, 2h, -NH2), 2.095 (m, 2H), 1.824 (m, 4h), 1.242 (m, 4h). The MS spectrum of ZD-G2: m/z 1210.5 (100, [M+H]+, calcd 1209.92); 606.0([M+2H]2+).
  • 13
  • (E)-N'-(5-benzyloxy-2-cyano-4-methoxyphenyl)-N,N-dimethylformimidamide [ No CAS ]
  • [ 443913-73-3 ]
  • 14
  • (E)-N'-(2-cyano-5-hydroxy-4-methoxyphenyl)-N,N-dimethylformimidamide [ No CAS ]
  • [ 443913-73-3 ]
  • 15
  • [ 723283-25-8 ]
  • [ 443913-73-3 ]
  • 16
  • [ 166815-96-9 ]
  • [ 443913-73-3 ]
  • 17
  • [ 123855-51-6 ]
  • [ 443913-73-3 ]
  • 19
  • [ 64-18-6 ]
  • [ 338992-12-4 ]
  • [ 443913-73-3 ]
YieldReaction ConditionsOperation in experiment
84% With sodium tris(acetoxy)borohydride; acetic acid; In methanol; dichloromethane; at 20℃; for 2h; N-(4-Bromo-2-fluorophenyl)-6-methoxy-7-(piperidin-4-ylmethoxy)quinazolin-4-amine (30 mg, 0.065 mmol), sodium triacetoxyborohydride (19 mg, 0.091 mmol) was added to a flask containing formic acid (6 muL, 0.0845 mmol), acetic acid (5 muL, 0.078 mmol), DCM (1.6 mL) and methanol (3.2 mL). The flask was stirred for two hours at ambient temperature and then solvent removed under reduced pressure. Saturated NaHCO3 (3 mL) was added to the residue and the suspension filtered, washed with water (2 mL) and brine (2 mL). The filtrate was extracted with DCM (3 mL) and dried over MgSO4, solvent removed under reduced pressure, triturated with diethyl ether to afford the title compound as a white solid (6 mg, 84%). Mp: 226-228 C (lit 227-229 C 12); 1H NMR (500 MHz, d6-DMSO) delta: 1.44 (ddd, 2H, CH2, J = 3.9, 12.6, 24.8 Hz), 1.85 (d, 2H, CH2, J =12.5 Hz), 1.94-1.99 (m, 3H, CH and CH2), 2.32 (s, 3H, NCH3), 2.85 (d, 2H, CH2, J = 11.6 Hz), 3.98 (s, 3H, OCH3), 4.03 (d, 2H, OCH2, J = 5.5 Hz), 6.99 (s, 1H, ArH), 7.21 (s, 1H, ArH), 7.26 (s, 1H, ArH), 7.34 (d, 1H, ArH, J = 1.2 Hz), 7.36 (d, 1H, ArH, J = 1.2 Hz), 8.51 (s, 1H, ArH), 8.68 (brs, 1H, NH). 13C NMR (125 MHz, d6-DMSO) delta: 28.68, 34.92, 46.98, 49.32, 55.69, 70.65, 79.86, 102.82, 107.52 (d, J = 27.8), 108.91, 114.21, 114.74, 117.65, 121.21, 127.68, 131.32(d, J = 28.1 Hz), 153.04, 155.23, 155.99 (d, J = 132.3 Hz), 157.08, 158.86, 164.06. 19F NMR (471 MHz, d6-DMSO) delta: -115.86 (m, 1F). HRMS (ESI, m/z): calc?d for C21H25N4O2FBr [M+H]+ 462.1013 found: 462.1003
  • 22
  • [ 385785-02-4 ]
  • [ 443913-73-3 ]
  • 23
  • (E)-N,N'-bis(4-bromo-2-fluorophenyl)formamidine [ No CAS ]
  • [ 443913-73-3 ]
  • 24
  • [ 50-00-0 ]
  • [ 64-18-6 ]
  • [ 338992-20-4 ]
  • [ 443913-73-3 ]
YieldReaction ConditionsOperation in experiment
78% Compound 8 (224 g, 0.4 mol) was added to 1 L of methanol.Then add 200 mL of concentrated hydrochloric acid and stir at room temperature overnight.Concentrate to methanol under reduced pressure and dilute with 300 mL of water.Filtration, the filtrate was alkalized to pH 8-9 with sodium bicarbonate, and a solid precipitated. After filtration, add 250 mL of 80% formic acid and 250 mL of formaldehyde solution.Stir at room temperature overnight,Concentrate under reduced pressure and dilute with 800 mL of water.Basified with sodium bicarbonate to a pH of 8-9,filter,Drying a white solid (91.6 g, 78%), mp: 240-242 C;HPLC purity: 99.5%.
  • 25
  • 2-amino-4-hydroxy-5-methoxybenzonitrile [ No CAS ]
  • [ 443913-73-3 ]
  • 26
  • [ 443913-73-3 ]
  • [ 71-36-3 ]
  • C26H33FN4O3 [ No CAS ]
  • 27
  • 5-[2-(1,3-dioxan-2-yl)ethyl]-1-aza-5-germabicyclo[3.3.3]undecane [ No CAS ]
  • [ 443913-73-3 ]
  • N-(4-(2-(1,3-dioxan-2-yl)ethyl)-2-fluorophenyl)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazolin-4-amine [ No CAS ]
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