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Chemical Structure| 612501-45-8 Chemical Structure| 612501-45-8

Structure of 612501-45-8

Chemical Structure| 612501-45-8

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Product Details of [ 612501-45-8 ]

CAS No. :612501-45-8
Formula : C19H24ClN3O4
M.W : 393.86
SMILES Code : ClC1=NC=NC2=C1C=C(OC3CCN(C(OC(C)(C)C)=O)CC3)C(OC)=C2
MDL No. :MFCD18258904

Safety of [ 612501-45-8 ]

Application In Synthesis of [ 612501-45-8 ]

* 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 [ 612501-45-8 ]

[ 612501-45-8 ] Synthesis Path-Downstream   1~2

  • 1
  • [ 612501-45-8 ]
  • [ 2613-34-5 ]
  • [ 848491-25-8 ]
YieldReaction ConditionsOperation in experiment
85% With hydrogenchloride; In isopropyl alcohol; at 80℃; for 3h; 3-Chloro-2,4-difluoroaniline (1.7 g, 10.1 mmol) and 5N hydrogen chloride in isopropanol (2 ml) were added to a suspension of tert-butyl 4- [ (4-CHLORO-7- METHOXYQUINAZOLIN-6-YL) OXY] PIPERIDINE-1-CARBOXYLATE (4 g, 10.1 mmol, PCT Int. Appl. W02003082831, AstraZeneca) in isopropanol (50 ml). The mixture was stirred at 80C for 3 hours. After evaporation of the solvents, the residue was purified by chromatography on silica gel (eluant: 5-10% 7N methanolic ammonia in dichloromethane) to give 4- (3-CHLORO- 2, 4-DIFLUOROANILINO)-7-METHOXY-6-[(PIPERIDIN-4-YL) oxy] quinazoline (3.63 g, 85%) as a white solid. 'H NMR Spectrum : (CDCI3+ CD3CO2D) : 2.15 (m, 2H), 2.30 (m, 2H), 3.34 (m, 2H), 3.47 (m, 2H), 4.01 (s, 3H), 4.91 (m, 1H), 7.03 (m, 1H), 7.58 (m, 2H), 7.90 (s, 1H), 8.55 (s, 1H) ; Mass spectrum: MH+ 421.
85% With hydrogenchloride; In isopropyl alcohol; at 80℃; for 3h; 3-CHLORO-2, 4-DIFLUOROANILINE (1.7 g, 10.1 mmol) and 5N hydrogen chloride in isopropanol (2 ml) were added to a suspension of tert-butyl 4- [ (4-CHLORO-7-METHOXYQUINAZOLIN-6- yl) oxy] PIPERIDINE-1-CARBOXYLATE (4 g, 10.1 mmol, PCT Int. Appl. W02003082831, AstraZeneca) in isopropanol (50 ml). The mixture was stirred at 80C for 3 hours. After evaporation of the solvents, the residue was purified by chromatography on silica gel (eluant: 5-10% 7N methanolic ammonia in dichloromethane) to give 4- (3-CHLORO-2, 4-difluoroanilino) - 7-METHOXY-6-[(PIPERIDIN-4-YL) OXY] QUINAZOLINE (3.63 g, 85%) as a white solid. HNMR Spectrum: (CDC13 + CD3CO2D) : 2.15 (m, 2H), 2.30 (m, 2H), 3.34 (m, 2H), 3.47 (m, 2H), 4.01 (s, 3H), 4.91 (m, 1H), 7.03 (m, 1H), 7.58 (m, 2H), 7.90 (s, 1H), 8.55 (s, 1H) ; Mass spectrum: MH+ 421.
  • 2
  • [ 574745-97-4 ]
  • [ 109384-19-2 ]
  • [ 612501-45-8 ]
YieldReaction ConditionsOperation in experiment
With di-tert-butyl-diazodicarboxylate; triphenylphosphine; In dichloromethane; at 5 - 20℃; for 16h; Di-tert-butylazodicarboxylate (9.22 g) in methylene chloride (20 ml) was added slowly to a stirred suspension of <strong>[574745-97-4]4-chloro-6-hydroxy-7-methoxyquinazoline</strong> (5.63 g), 4-hydroxy-1- tert-butoxycarbonylpiperidine (8. 06 g) and triphenylphosphine (10.5 g) in methylene chloride (100 ml) at 5C under an atmosphere of nitrogen. The reaction mixture was allowed to warm to room temperature for 16 hours. The reaction mixture was then evaporated under vacuum and adsorbed onto silica and the product was eluted with isohexane/ethyl acetate/triethylamine (75/24/1 followed by 70/29/1). The fractions containing the desired product were combined and evaporated under vacuum to give tert-butyl 4- [ (4-chloro-7-methoxyquinazolin-6- yl) oxy] piperidine-l-carboxylate as a white solid (10.3g) ; 1H NMR Spectrum: (DMSO d6) 1.40 (s, 9H), 1.56-1. 69 (m, 2H), 1.93-2. 04 (m, 2H), 3.20-3. 31 (m, 2H), 3.60-3. 70 (m, 2H), 4.00 (s, 3H), 4.89 (m, 1H), 7.45 (s, 1H), 7.50 (s, 1H), 8. 86 (s, 1H); Mass Spectrum: (M+H) + 394.
With di-tert-butyl-diazodicarboxylate; triphenylphosphine; In dichloromethane; at 5 - 20℃; for 16h; Example 1; 4- (3-CHLORO-2-FLUOROANILINO)-6- [1- (HYDROXYACETYL) PIPERIDIN-4-YLOXY]-7- methoxyquinazoline; HATU (28.9 g) was added to a stirred solution of 4- (3-chloro-2-fluoroanilino)-7- METHOXY-6- (PIPERIDIN-4-YLOXY) quinazoline dihydrochloride (30 g), glycolic acid (5.40 g) and di-isopropylethylamine (44.70 ml) in methylene chloride (900 ml). After 1.5 hours the reaction mixture was washed with sodium hydroxide solution (2M), water and saturated brine. The resulting product was then purified by flash chromatography on silica eluting with 3% MeOH/methylene chloride. The fractions containing the desired product were combined and reduced in vacuo to give the title product as a white solid which was recrystallised from acetonitrile (29.6 g); NMR Spectrum : (DMSO d6) 1.65-1. 81 (m, 2H), 1.99-2. 10 (m, 2H), 3.26- 3.34 (m, 1H), 3.37-3. 47 (m, 1H), 3.60-3. 68 (m, 1H), 3.81-3. 89 (m, 1H), 3.95 (s, 3H), 4.14 (d, 2H), 4.50 (t, 1H), 4.78 (m, 1H), 7.25 (s, 1H), 7.30 (t, 1H), 7.46-7. 55 (m, 2H), 7.88 (s, 1H), 8.40 (s, 1H), 9.55 (s, 1H) ; Mass Spectrum: (M+H) + 460.94. THE 4- (3-CHLORO-2-FLUOROANILINO)-7-METHOXY-6- (PIPERIDIN-4-YLOXY) quinazoline dihydrochloride starting material was prepared as follows: 6-Acetoxy-4-chloro-7-methoxyquinazoline, (Example 25-5 in WO01/66099 ; 10. 0G, 39.6 mmole) was added in portions to a stirred 7N methanolic ammonia solution (220 ml) cooled to 10C in an ice/water bath. After stirring for one hour the precipitate was filtered, washed with diethylether and dried thoroughly under high vacuum to give 4-chloro-6- hydroxy-7-methoxyquinazoline (5.65 g, 67.8 %); NMR Spectrum: (DMSO d6) 3.96 (s, 3H); 7.25 (s, 1H); 7.31 (s, 1H); 8.68 (s, 1H); Mass Spectrum : (M+H) + 211 Di-tert-butylazodicarboxylate (9.22 g) in methylene chloride (20 ml) was added slowly to a stirred suspension of <strong>[574745-97-4]4-chloro-6-hydroxy-7-methoxyquinazoline</strong> (5.63 g), 4-hydroxy-1- tert-butoxycarbonylpiperidine (8.06 g) and triphenylphosphine (10.5 g) in methylene chloride (100 ml) at 5C under an atmosphere of nitrogen. The reaction mixture was allowed to warm to room temperature for 16 hours. The reaction mixture was then evaporated under vacuum and adsorbed onto silica and the product was eluted with isohexane/ethyl acetate/triethylamine (75/24/1 followed by 70/29/1). The fractions containing the desired product were combined and evaporated under vacuum to give tert-butyl 4- [ (4-CHLORO-7-METHOXYQUINAZOLIN-6- yl) oxy] piperidine-l-carboxylate as a white solid (10.3 g) ; IH NMR SPECTRUM : (DMSO d6) 1.40 (s, 9H), 1.56-1. 69 (m, 2H), 1.93-2. 04 (m, 2H), 3.20-3. 31 (m, 2H), 3.60-3. 70 (m, 2H), 4.00 (s, 3H), 4. 89 (m, 1H), 7.45 (s, 1H), 7.50 (s, 1H), 8.86 (s, 1H) ; Mass Spectrum : (M+H) + 394. 4. 0M HC1 in Dioxane (4.0 ml) was added to a suspension of tert-butyl 4- [ (4-chloro-7- methoxyquinazolin-6-yl) oxy] PIPERIDINE-1-CARBOXYLATE (2.62 g) and 3-chloro-2-fluoroaniline (1.08 g) in iso-propanol (50 ml). The reaction mixture was stirred and heated at 100C for 2 hours. The yellow precipitate was filtered hot and washed with iso-propanol followed by diethylether and dried under vacuum to give 6- (PIPERIDIN-4-YLOXY)-4- (3-CHLORO-2- fluoroanilino) -7-methoxyquinazoline as a di-hydrochloride salt (2.38 g) ; 1H NMR SPECTRUM (DMSO D6) 1.84-1. 99 (m, 2H), 2.22-2. 33 (m, 2H), 3.12-3. 33 (m, 4H), 4.00 (s, 3H), 5. 08 (m, 1H), 7.34 (t, 1H), 7.40 (s, 1H), 7.50 (t, 1H), 7.62 (t, 1H), 8.80 (s, 1H), 8. 84-8. 94 (m, 2H), 8.99-9. 11 (m, 1H); Mass Spectrum: (M+H) + 403.
 

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