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Product Details of [ 230955-75-6 ]

CAS No. :230955-75-6 MDL No. :MFCD08460968
Formula : C11H9ClN2O3 Boiling Point : -
Linear Structure Formula :- InChI Key :VWBHHSJRPOSFGG-UHFFFAOYSA-N
M.W : 252.65 Pubchem ID :22022160
Synonyms :

Calculated chemistry of [ 230955-75-6 ]

Physicochemical Properties

Num. heavy atoms : 17
Num. arom. heavy atoms : 10
Fraction Csp3 : 0.18
Num. rotatable bonds : 3
Num. H-bond acceptors : 5.0
Num. H-bond donors : 0.0
Molar Refractivity : 62.54
TPSA : 61.31 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.26 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.23
Log Po/w (XLOGP3) : 2.22
Log Po/w (WLOGP) : 2.22
Log Po/w (MLOGP) : 1.44
Log Po/w (SILICOS-IT) : 2.42
Consensus Log Po/w : 2.11

Druglikeness

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

Water Solubility

Log S (ESOL) : -3.04
Solubility : 0.229 mg/ml ; 0.000907 mol/l
Class : Soluble
Log S (Ali) : -3.14
Solubility : 0.182 mg/ml ; 0.00072 mol/l
Class : Soluble
Log S (SILICOS-IT) : -4.15
Solubility : 0.0178 mg/ml ; 0.0000703 mol/l
Class : Moderately soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 0.0
Synthetic accessibility : 1.91

Safety of [ 230955-75-6 ]

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 [ 230955-75-6 ]

* 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.

  • Upstream synthesis route of [ 230955-75-6 ]
  • Downstream synthetic route of [ 230955-75-6 ]

[ 230955-75-6 ] Synthesis Path-Upstream   1~6

  • 1
  • [ 367-21-5 ]
  • [ 230955-75-6 ]
  • [ 788136-89-0 ]
YieldReaction ConditionsOperation in experiment
93.4% With gold(I) chloride In methanol at 65℃; A substitution reaction of AuCl (4.2g, 18mmol), 6- acetoxy-4-chloro-7-methoxy-quinazoline (12.6g, 50mmol), chloro-4-fluoroaniline (12.3g, 85mmol) in 50ml of methanol at 65°C. It was filtered after reaction completion. The filtrate was concentrated, washed with petroleum ether to give 16.9 g of Intermediate gefitinib, yield 93.4percent, purity 99.91percent.
92.5% for 2 h; Reflux Was added to the reactor4-Chloro-(3H) -quinazoline (2.52 g, 10 mmol) was dissolved in isopropanol (50 mL), m-phenylenediamine (1.6 g, 11 mmol) was added and the mixture was stirred well. The mixture was heated to reflux for 2 hours. After completion of the reaction, the reaction mixture was cooled to room temperature. The resulting solid was recrystallized from ethanol to give 3.34 g of 4- (3-chloro-4-fluoro) phenylamino-6-carbethoxy-7-methoxyquinazoline in a yield of 92.5percent.
91.2% at 90℃; for 1 h; Add 4-chloro-7-methoxyquinazolin-6-yl acetate prepared in step 2 to a 250 mL round bottom flask (1.1 g), 150 mL acetonitrile, 3-chloro-4-fluoroaniline (0.96 g, 1.2 eq). The reaction system was heated to 90 ° C and the reaction was continued for 1 h. The TLC assay was complete and a large amount of precipitate was observed. After the reaction system was cooled, suction filtration, washing the filter cake with acetonitrile, and drying in an oven, the obtained white solid was 4–((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazoline. -6-yl acetate, yield 91.2percent.
81% at 88℃; for 5 h; A suspension of 4-chloro-7-methoxyquinazolin-6-yl acetate (2.52 g),3-chloro-4-fluoroaniline (1.49 g) and isopropanol (60 mL) was stirred at 88 °C for 5 h. The reaction mixture was cooled to room temperature, filtered to afford the desired compound as a solid (2.51 g, 81.00 percent).
78% for 3 h; Reflux Into a 500-mL round-bottom flask, was placed 4-chloro-7-methoxyquinazolin-6-yl acetate (9.1 g, 36.02 mmol, 1.00 equiv), 3-chloro-4-fluoroaniline (5.23 g, 35.93 mmol, 1.00 equiv) in propan-2-ol (200 mL). The resulting solution was refluxed for 3 hours. The reaction mixture was cooled to room temperature. The solids were collected by filtration. This resulted in 10.1 g (78percent) of 4-[(3-chloro-4-fluorophenyl)amino]-7-methoxyquinazolin-6-yl acetate as a brown solid. LC-MS: (ES, m/z): 362 [M+H]+ Retention time: 0.681min
2.51 g at 88℃; for 5 h; A suspension of 4-chloro-7-methoxyquinazolin-6-yl acetate (2.52 g), 3-chloro-4-fluoroaniline (1.49 g) and isopropanol (60 mL) was stirred at 88° C. for 5 h. The reaction mixture was cooled to room temperature, filtered to afford the desired compound as a solid (2.51 g, 81.00percent).

Reference: [1] Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 2, p. 870 - 879
[2] Patent: CN105693630, 2016, A, . Location in patent: Paragraph 0033
[3] Patent: CN106045980, 2016, A, . Location in patent: Paragraph 0024; 0025; 0026
[4] Patent: CN108047209, 2018, A, . Location in patent: Paragraph 0041; 0047; 0048
[5] Patent: WO2013/71697, 2013, A1, . Location in patent: Paragraph 00195
[6] Dalton Transactions, 2015, vol. 44, # 29, p. 13100 - 13111
[7] Patent: WO2018/119441, 2018, A1, . Location in patent: Paragraph 00566; 00567
[8] Patent: US2010/143295, 2010, A1,
[9] Angewandte Chemie - International Edition, 2013, vol. 52, # 33, p. 8551 - 8556[10] Angew. Chem., 2013, vol. 125, # 33, p. 8713 - 8718,6
[11] Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 14, p. 1911 - 1914
[12] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 18, p. 4908 - 4912
[13] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 14, p. 4745 - 4749
[14] Patent: US2014/206664, 2014, A1, . Location in patent: Paragraph 0225
[15] Patent: US2014/228361, 2014, A1, . Location in patent: Paragraph 0273-0274
[16] European Journal of Medicinal Chemistry, 2014, vol. 89, p. 826 - 834
[17] Patent: EP2796451, 2014, A1, . Location in patent: Paragraph 0079
[18] Patent: CN103570738, 2016, B, . Location in patent: Paragraph 0319; 0320; 0325
[19] Chinese Journal of Chemistry, 2017, vol. 35, # 11, p. 1693 - 1700
[20] Journal of Medicinal Chemistry, 2018, vol. 61, # 24, p. 11372 - 11383
  • 2
  • [ 230955-75-6 ]
  • [ 912556-91-3 ]
Reference: [1] Patent: WO2013/71697, 2013, A1,
[2] Patent: US2014/206664, 2014, A1,
[3] Patent: US2014/228361, 2014, A1,
[4] Patent: EP2796451, 2014, A1,
  • 3
  • [ 230955-75-6 ]
  • [ 574745-97-4 ]
YieldReaction ConditionsOperation in experiment
94% With ammonia In methanol at 20℃; for 1.5 h; A suspension of 4-chloro-7-methoxyquinazolin-6-yl acetate (prepared as described in Example 25-5 of WO01/66099, 10.1 g, 40 mmol) in 6N methanolic ammonia (200 ml) was stirred at room temperature for 90 minutes. The solvents were evaporated under vacuum. Water was added and the resulting suspension was filtered. The solid obtained was washed with water, ether and dried under high. vacuum in the presence-of phosphorus pentoxide to GIVE 4-CHLORO-7-METHOXYQUINAZOLIN-6-OL (7.9 G, 94percent). NMR SPECTRUM: (DMSOD6) 4.02 (S, 3H), 7.40 (s, 1H), 7.43 (s, 1H), 8. 81 (s, 1H).
86% With ammonia In methanol at 20℃; for 1.5 h; Inert atmosphere Under argon, 10 (800 mg, 3.17 mmol) was dissolved in 11.3 mL of NH3 (7 N in CH3OH) and the mixture was stirred 1.5 h at room temperature. The solvent was removed under vacuum and a trituration with Et2O afforded 11 as a beige solid (574 mg, 86percent). Mp: 300 °C (dec.); IR (ATR, ZnSe): ν (cm-1) 3019, 1555, 1497, 1465, 1350, 1188, 1157, 974, 858, 700; 1H NMR (400 MHz, DMSO-d6): δ (ppm) 10.78 (s, 1H), 8.81 (s, 1H), 7.43 (s, 1H), 7.40 (s, 1H), 4.01 (s, 3H). 13C NMR (126 MHz, DMSO-d6): δ (ppm) 158.9, 155.3, 155.2, 149.3, 146.4, 120.2, 105.9, 103.9, 56.0; HRMS-ESI calcd for C9H8ClN2O2 [M+H]+ 211.0269 found 211.0257.
84.6% With ammonium hydroxide In methanol at 20℃; for 3 h; 7-Methoxy-4-hydroxyquinazolin-6-ol acetate (4.68 g, 20 mmol) and DMF (0.4 mL) were added to 25 mL of thionyl chloride and refluxed for 5 hours. The thionyl chloride was distilled off under reduced pressure, and the mixture was steamed with chloroform (10 mL x 3) and toluene (10 mL x 2) The residual thionyl chloride was removed to give 7-methoxy-4-chloroquinazolin-6-ol acetate.Without purification, it was added to concentrated aqueous ammonia (35 mL)In methanol (70 mL) and stirred at room temperature for 3 hours. The filter cake was washed with ether to give 6-hydroxy-7-methoxy 4-chloroquinazoline, 3.61 g as a pale white solid, 84.6percent yield.
78% With ammonia In methanol at 10℃; The 10g 4- chloro-7-methoxy-quinazolin-6-yl acetate (Compound 1) was placed in a 250mL three-necked roundFlask in an ice bath was added dropwise with stirring 100mL 7Μ NH3 methanol solution, drip completed within 30 minutes. Below 10 ° C, the reaction was stirred for more than 30min. The reaction solution was filtered under reduced pressure, residue was washed twice with ether, to give 6. 5g (78percent yield) of compound 2,As a pale yellow powder.
78% With ammonia In methanol at 10℃; Cooling with ice The 10g4- chloro-7-methoxy-quinazolin-6-yl acetate (Compound 1) was placed in a 250mL three-necked round bottom flask in an ice bath was added dropwise with stirring 100mL7MNH3- methanol solution, more than 30 minutes dropwise. Below 10 , the reaction was stirred for more than 30min. The reaction solution was filtered under reduced pressure, residue was washed with diethyl ether twice to afford 6.5g (78percent yield) of Compound 2 as a pale yellow powder.
78% at 10℃; for 1 h; Cooling with ice The 10g4- chloro-7-methoxy-quinazolin-6-yl acetate (Compound 1) was placed in a 250mL three-necked roundBottom flask in an ice bath was added dropwise with stirring 100mL 7MNH3- methanol solution, drip completed within 30 minutes. 10 Hereinafter, the reaction mixture was stirred for more than 30min. The reaction solution was filtered under reduced pressure, residue was washed twice with ether, to give 6.5g(78percent yield) of compound 2 as a pale yellow powder.
78% With ammonia In methanol at 10℃; for 1 h; Cooling with ice The 10g4- chloro-7-methoxy-quinazolin-6-yl acetate (Compound 1) was placed in a 250mL three-necked round bottom flask in an ice bath was added dropwise with stirring 100mL7MNH3-Methanol solution within 30 minutes after dropping below 10 , the reaction was stirred for more than 30min.The reaction solution was filtered under reduced pressure, residue was washed with diethyl ether twice to afford 6.5g (78percent yield) of Compound 2 as a pale yellow powder.
78% at 10℃; for 1 h; Chloro-7-methoxyquinazolin-6-yl acetate (Compound 1) was placed in a 250 mL three-necked round bottom flask, 100 mL of 7 M NH3-methanol solution was added dropwise with stirring under ice-30 minutes after the drop finished. Below 10 , the reaction was stirred for more than 30min. The reaction solution was filtered under reduced pressure, and the residue was washed twice with diethyl ether to give 6.5 g (yield 78percent) of Compound 2 as a pale yellow powder.
67.8% With ammonia In methanol at 10℃; for 1 h; Example 1 (4S)-4- ({4-[(3-Chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)-N- cyclopropyl-1-methyl-D-prolinamide Example 1 HATU (0.23g) was added to an agitated solution of (4Y)-4- ( {4- [ (3-CHLORO-2- fluorophenyl) AMINO]-7-METHOXYQUINAZOLIN-6-YL} OXY)-1-METHYL-D-PROLINE (7) (0.18g), cyclopropylamine (34.4mg) and DIPEA (156mg) IN METHYLENE CHLORIDE (5M1). After 16hrs the reaction mixture was reduced in vacuo. The residues were re-dissolved in methylene chloride and washed with sodium hydroxide solution (2M) and water. The organic phase was then purified by column chromatography on silica eluting with increasingly polar mixtures of METHANOL/METHYLENE CHLORIDE (0/100-10/90). THE fractions containing the desired product were combined and evaporated to a foam which was triturated with diethylether to give the title compound as a white solid. (0. 15G). LH NMR Spectrum : (DMSO d6) 0.40-0. 48 (m, 2H), 0.57-0. 64 (M, 2H), 2.05-2. 14 (M, 1H), 2.28 (s, 3H), 2.33-2. 45 (M, 1H), 2.48-2. 56 (M, 1H + DMSO), 2. 61-2. 70 (M, 1H), 3.08 (t, 1H), 3.64 (dd, 1H), 3.94 (s, 3H), 5.06 (M, 1H), 7.20 (s, 1H), 7.28 (t, 1H), 7.44-7. 56 (M, 2H), 7.65 (s, 1H), 7.87 (d, 1H), 8.35 (s, 1H), 9.63 (s, 1H); Mass SPECTRUM : (M+H) + 486. 44 The starting material 1, 2-PYRROLIDINEDICARBOXYLIC acid, 4-hydroxy-, 1- (1, 1-DIMETHYLETHYL) 2- methyl ester, (2R, 4R) (2) was prepared as follows: 1- [3- (DIMETHYLAMINO) PROPYL]-3-ETLIYLCARBODIIMIDE hydrochloride (14.73 g) was added to a stirred suspension of 1, 2-PYRROLIDINEDICARBOXYLIC acid, 4-hydroxy-, l- (l, l-dimethylethyl) ester, (2R, 4R) (1) (13.65 g), DIMETHYLAMINOPYRIDINE (21.65 g) and methanol (5.67 g) in methylene chloride (400 ml) and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was washed with citric acid (1.0 M), saturated aqueous sodium bicarbonate solution and saturated brine, dried over MgSO4, filtered and evaporated. The residues were then purified by column chromatography on silica eluting with increasingly polar mixtures of METHANOL/METHYLENE chloride (1/99-5/95). The desired product fractions were combined and evaporated to give 1, 2-PYNOLIDINEDICARBOXYLIC acid, 4-hydroxy-, L- (L, L-DIMETHYLETHYL) 2- methyl ester, (2R, 4R) (2) as a white crystalline solid, (5.9 g). 1H NMR Spectrum : (DMSO d6) 1.32 + 1.38 (2s, 9H), 1.76-1. 87 (M, 1H), 2.24-2. 28 (M, 1H), 3.06-3. 15 (M, 1H), 3.42- 3. 51 (m, 1H), 3.60 + 3.63 (2s, 3H), 4.15-4. 24 (M, 2H), 4.92-5. 00 (M, 1H). Starting material 1, 2-Pyrrolidinedicarboxylic acid, 4-hydroxy-1- (1, 1-dimethylethyl) ester, (2R, 4R), (1), (Boc-D-cis-hyp-OH) is commercially available Starting material (3) was prepared as follows: 6-Acetoxy-4-chloro-7-methoxyquinazoline, (Example 25-5 of in W001/66099 ; 10. 0g, 39.6 MMOLE) was added in portions to a stirred 7N methanolic ammonia solution (220 ML) cooled to 10°C 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-7- METHOXYQUINAZOLIN-6-OL (3) (5.65g, 67.8percent) ; 1H 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. The starting material (4) was prepared as follows: Di-ethyl azodicarboxylate (5.71g) was added slowly to a stirred suspension of 1,2- PYNOLIDINEDICARBOXYLIC acid, 4-hydroxy-, L- (L, L-DIMETHYLETHYL) 2-methyl ester, (2R, 4R) (2) (5.9g), 4-CHLORO-7-METHOXYQUINAZOLIN-6-OL (3) (4.6g) AND TRIPHENYLPHOSPHINE (8.6g) in methylene chloride (400 ML) at 25°C under an atmosphere of nitrogen and the reaction mixture was stirred for 2 hours. The reaction mixture was then evaporated to 1/2 volume and purified by column chromatography on silica eluting with increasingly polar mixtures of METHANOL/METHYLENE chloride (1/99-3/97). The desired product fractions were combined and evaporated to give 1-tert-butyl 2-methyl (2R, 4S)-4-[(4-chloro-7-methoxyquinazolin-6- yl) oxy] pyrrolidine-1, 2-dicarboxylate (4) as a pale yellow gum. This was used in the preparation of (5) without further purification. The starting material methyl (4S)-4-({4-[(3-CHLORO-2-FLUOROPHENYL) AMINO]-7- METHOXYQUINAZOLIN-6-YL} OXY)-D-PROLINATE HYDROCHLORIDE (5) was prepared as follows: 4. 0M HCl in Dioxane (15 ml) was added to a suspension of 1-tert-butyl 2-methyl (2R, 4S)-4- [(4-chloro-7-methoxyquinazolin-6-yl0 oxy] pyrrolidine-1, 2-dicarboxylate (4) AND 3-CHLORO-2- fluoroaniline (2.89g) in acetonitrile (400 ML) and the reaction mixture was stirred and heated at 70°C for 3 hours. The resulting precipitate was filtered hot and washed with acetonitrile and diethylether and dried under vacuum to give methyl (4S)-4- (14- [ (3-CLILORO-2- FLUOROPHENYL) AMINO]-7-METHOXYQUINAZOLIN-6-YL} OXY)-D-PROLINATE HYDROCHLORIDE (S) as an off- white solid, (6. 3G). TH NMR Spectrum : (DMSO D6) 2.46-2. 60 (M, 2H), 3.37-3. 46 (M, 1H), 3.71 (s, 3H), 3.89-3. 98 (m, 4H), 4.53 (t, 1H), 5.42 (M, 1H), 7.29 (t, 1H), 7.38-7. 48 (M, 2H), 7.55 (t, 1H), 8.64 (s, 1H), 8.75 (s, 1H), 12.28 (bs, 1H); Mass Spectrum : (M+H) + 446.96 Compound (6) was prepared as follows: Methyl (4S)-4-({4-[(3-CHLORO-2-FLUOROPHENYL) AMINO]-7-METHOXYQUINAZOLIN-6-YL} OXY)-D- PROLINATE HYDROCLULORIDE (S) (6.3g), PARAFORMALDEHYDE (3.9g), sodium cyanoborohydride (3. 28G) and magnesium sulphate (3.13g) were suspended in methanol (50ml) and heated to 45°C for 4 hours under an atmosphere of nitrogen. The reaction mixture was filtered, evaporated and partitioned between ethylacetate and saturated aqueous sodium bicarbonate solution. The organics were then washed with saturated brine, dried over MGS04, filtered and evaporated. The residues were then purified by column chromatography on silica eluting with increasingly polar mixtures of methanol/methylene chloride (2-3percent) to give methyl (4S)-4-({4-[(3-CHLORO-2- FLUOROPHENYL) AMINO]-7-METHOXYQUINAZOLIN-6-YL} OXY)-1-METHYL-D-PROLINATE (6) as a yellow foam, (4.19 G). LH NMR Spectrum: (DMSO d6) 2.14-2. 23 (M, 1H), 2.34 (s, 3H), 2.53-2. 60 (M, 2H), 3.36 (t, 1H), 3.61 (dd, 1H), 3.66 (s, 3H), 3.94 (s, 3H), 5.08 (M, 1H), 7.20 (s, 1H), 7.27 (t, 1H), 7.44-7. 54 (M, 2H), 7.68 (s, 1H), 8.36 (s, 1H), 9.62 (s, 1H); Mass Spectrum : (M+H) + 460.9 Compound (7) was prepared as follows: Sodium hydroxide 2M (7 ml) was added to a stirred solution of methyl (4S)-4-({4-[(3-CHLORO- 2-fluorophenyl) AMINO]-7-METHOXYQUINAZO] IN-6-YL} OXY)-1-METHYL-D-PROLINATE (4.18g) in methanol (20 ML) and THF (10 ML) at 25°C and the reaction mixture was stirred for 4 hours. The reaction mixture was evaporated and the residue re-dissolved in water. The pH of this solution was then adjusted to 6 by the dropwise addition OF 2M HC1 (AQ) to give (4S)-4- (F 4- [ (3-CHLORO-2-FLUOROPHENYL) AMINO]-7-METHOXYQUINAZOLIN-6-YL} OXY)-1-METHYL-D-PROLINE (7) as a pale yellow solid which was filtered and washed with water and dried, (3.5 G). 1H NMR Spectrum : (DMSO d6) 2. 21-2. 31 (M, 1H), 2.35-2. 49 (M, 1H), 2.50 (s, 3H), 2.78 (dd, 1H), 3.42 (t, 1H), 3.77 (dd, 1H), 3.94 (s, 3H), 5.08 (M, 1H), 7.20 (s, 1H), 7.27 (t, 1H), 7.44-7. 54 (M, 2H), 7.74 (s, 1H), 8.37 (s, 1H), 9.75 (s, 1H) ; Mass Spectrum : (M+H) + 446. 9
67.8% at 10℃; for 1 h; 6-Acetoxy-4-chloro-7-methoxyquinazoline, (Example 25-5 of in WO01/66099 ; 10. 0g, 39.6 mmole) was added in portions to a stirred 7N methanolic ammonia solution (220 ml) cooled to 10°C 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 (5.65g, 67. 8percent) ; 1H 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
67.8% at 10℃; for 1 h; 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 3percent 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 10°C 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 percent); 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 4-chloro-6-hydroxy-7-methoxyquinazoline (5.63 g), 4-hydroxy-1- tert-butoxycarbonylpiperidine (8.06 g) and triphenylphosphine (10.5 g) in methylene chloride (100 ml) at 5°C 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 100°C 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.
58% With ammonia; water In 1,4-dioxane at 0 - 20℃; Step 6.
Product step 5 (8.54 mmol) was converted into 4-chloro-7-hydroxy-6-methoxyquinazoline or 4-chloro-6-hydroxy-7-methoxyquinazoline, respectively, (58-95percent) by reacting them with thionyl chloride (12 mL) and DMF (0.3 mL) at 85° C. for 1.5 h. Excess thionyl chloride was removed by distillation. Traces of thionyl chloride were removed by aceotropic distillation wit toluene (two times). Alternatively the products step 5 can be converted into the chlorides by reacting them with a mixture of POCl3 and PCl5. The acetyl groups were removed by hydrolysis with ammonium hydroxide (5 mL, 28-30 wt percent) in dioxane/water (100 mL/20 mL) at 0° C. to r.t.

Reference: [1] Patent: WO2005/26151, 2005, A1, . Location in patent: Page/Page column 124
[2] European Journal of Medicinal Chemistry, 2018, vol. 147, p. 130 - 149
[3] Patent: CN106986895, 2017, A, . Location in patent: Paragraph 0072; 0073; 0074; 0075; 0076
[4] Patent: CN105384699, 2016, A, . Location in patent: Paragraph 0032; 0033
[5] Patent: CN105418517, 2016, A, . Location in patent: Paragraph 0026; 0030; 0031
[6] Patent: CN105503747, 2016, A, . Location in patent: Paragraph 0032; 0033
[7] Patent: CN105461642, 2016, A, . Location in patent: Paragraph 0028; 0029
[8] Patent: CN105399689, 2016, A, . Location in patent: Paragraph 0029; 0030
[9] ACS Medicinal Chemistry Letters, 2013, vol. 4, # 8, p. 742 - 746
[10] Patent: WO2005/30757, 2005, A1, . Location in patent: Page/Page column 102-105
[11] Patent: WO2003/82831, 2003, A1, . Location in patent: Page/Page column 109
[12] Patent: WO2005/12290, 2005, A1, . Location in patent: Page/Page column 36-37
[13] Patent: US2007/149523, 2007, A1, . Location in patent: Page/Page column 13-14
[14] Patent: EP1785420, 2007, A1, . Location in patent: Page/Page column 18-19
[15] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 18, p. 6728 - 6737
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YieldReaction ConditionsOperation in experiment
95% With hydrogenchloride In acetonitrile for 1 h; Heating / reflux The 4- (3-chloro-2-fluoroanilino)-6-hydroxy-7-methoxyquinazoline starting material used above was prepared as follows: 6-Acetoxy-4-chloro-7-methoxyquinazoline (Example 25-5 in W001/66099 ; 10. 0g, 39.6 mmole) was suspended in acetonitrile (400 ml) and 3-chloro-2-fluoroaniline (6. 05g, 41. 6 mmole) and hydrogen chloride (4. 0M solution in 1,4-dioxane) (10.4 ml, 41.6 mmole) were added. The reaction mixture was refluxed for one hour and then allowed to cool to ambient temperature. The resulting precipitate was filtered off, washed with acetonitrile and diethylether to give a white solid. This solid was added in portions to a stirred 7N methanolic ammonia solution (400 ml). The mixture was stirred for two hours and the precipitate filtered, washed with acetonitrile followed by diethylether and dried under vacuum to give 4- (3-chloro- 2-fluoroanilino) -6-hydroxy-7-methoxyquinazoline as a white solid (12. 1g, 95percent) ; lH NMR Spectrum: (DMSOd6) 3.95 (s, 3H) ; 7.18 (s, lH) ; 7.20-7. 25 (m, 1H); 7.39-7. 44 (m, lH) ; 7.47- 7.52 (m, 11-1) ; 7.65 (s, lH) ; 8.31 (s, 1H) ; 9.45 (br. s, lH) ; Mass Spectrum: (M+H) + 320.
Reference: [1] Patent: WO2003/82831, 2003, A1, . Location in patent: Page/Page column 116
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  • [ 612501-52-7 ]
Reference: [1] ACS Medicinal Chemistry Letters, 2013, vol. 4, # 8, p. 742 - 746
[2] Patent: WO2014/135876, 2014, A1,
[3] Patent: US2014/255428, 2014, A1,
[4] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 18, p. 4455 - 4459
  • 6
  • [ 230955-75-6 ]
  • [ 1012054-59-9 ]
Reference: [1] Patent: US2009/111772, 2009, A1,
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