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CAS No. : | 849217-64-7 | MDL No. : | MFCD16038048 |
Formula : | C34H34F2N4O6 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | CXQHYVUVSFXTMY-UHFFFAOYSA-N |
M.W : | 632.65 | Pubchem ID : | 42642645 |
Synonyms : |
XL880;GSK1363089;EXEL-2880;GSK089
|
Num. heavy atoms : | 46 |
Num. arom. heavy atoms : | 22 |
Fraction Csp3 : | 0.32 |
Num. rotatable bonds : | 13 |
Num. H-bond acceptors : | 10.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 170.19 |
TPSA : | 116.45 Ų |
GI absorption : | Low |
BBB permeant : | No |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | Yes |
CYP2C9 inhibitor : | Yes |
CYP2D6 inhibitor : | Yes |
CYP3A4 inhibitor : | Yes |
Log Kp (skin permeation) : | -7.18 cm/s |
Log Po/w (iLOGP) : | 4.91 |
Log Po/w (XLOGP3) : | 4.19 |
Log Po/w (WLOGP) : | 5.74 |
Log Po/w (MLOGP) : | 2.62 |
Log Po/w (SILICOS-IT) : | 5.33 |
Consensus Log Po/w : | 4.56 |
Lipinski : | 1.0 |
Ghose : | None |
Veber : | 1.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -5.9 |
Solubility : | 0.0008 mg/ml ; 0.00000126 mol/l |
Class : | Moderately soluble |
Log S (Ali) : | -6.34 |
Solubility : | 0.000286 mg/ml ; 0.000000452 mol/l |
Class : | Poorly soluble |
Log S (SILICOS-IT) : | -9.65 |
Solubility : | 0.000000142 mg/ml ; 0.0000000002 mol/l |
Class : | Poorly soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 3.0 |
Synthetic accessibility : | 4.17 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | Stage #1: With oxalyl dichloride In tetrahydrofuran at 15 - 20℃; Industry scale Stage #2: With potassium carbonate In tetrahydrofuran at 15 - 20℃; for 3 h; Industry scale |
Example 3: Further Preparation and Characterization of Crystalline N-[3- fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4-ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N'- ( 4-fIuorophenyl Cyclopropane- 1,1 -dicarboxamide. Compound (I), Form B.[0078] 3.1: Preparation of Compound (I), Crystalline Form B. [0079] To a dried reactor (reactor 1 ) was added 1 -(4-fluorophenyl carbamoyl)cyclopropane carboxylic acid (21.5 kg), THF (76 kg), and N,N- dimethylformamide (DMF, 0.09 kg) which was agitated at 20 0C until dissolved. The contents of the reactor were cooled to about 15 0C and oxalyl chloride ( 12.7 kg) was added over 38 min while keeping the internal temperature in the reactor below 200C. When the addition was complete, the transfer line was rinsed with THF (3 kg) which was added into the reactor. After 1 h at about 20 0C, an additional 0.6 kg of oxalyl chloride and 2 kg of THF were added to the reactor. This process of adding additional oxalyl chloride (0.6 kg) and THF (2 kg) was repeated a second time, and then a third time at lesser amounts of oxalyl chloride (0.13 kg) with THF (2 kg).[0080] To a separate reactor (reactor 2) was added water (60 L), K2CCb ( 1 1.1 kg), 3- fluoro-4-[(6-(rnethyloxy)-7-[3-(4-moφholinyl)propyl]oxy}-4-quinolinyl)oxy]phenyl}amine (32.5 kg, see CAS Reg. No. 479690-10-3 and US 2004/0242603) and THF (177 kg) and the reactor contents were adjusted to about 15 0C. The contents of reactor 1 were added to reactor 2 while maintaining the temperature in reactor 2 at less than 20 0C. Reactor 1 was rinsed with THF (5 kg) which was transferred to reactor 2 and the temperature of the contents of reactor 2 was adjusted to about 20 0C. After about 3 h, 171 kg of 0.8 M aqueous K2CO3 and isopropyl acetate (119 kg) were added, the mixture was stirred for 10 min, settled and the lower aqueous layer was discarded. An additional 171 kg of 0.8 M aqueous K2CO3 was added, mixed, settled and the aqueous layer again discarded. Water (137 kg) was added, mixed, settled and the aqueous layer again discarded. Steam activated powdered carbon (Darco G-60 from Norit Americas, Inc.) (3.4 kg) and isopropyl acetate (3 kg) were added, stirred for about 2.5 h then transferred through a filter containing diatomaceous earth into a separate reactor (reactor 3). Reactor 2 was rinsed twice with isopropyl acetate (33 kg each) which was sent through the filter above and combined with the batch contained in reactor 3. The contents of reactor 3 were concentrated to a final volume of about 104 L under vacuum while keeping the temperature less than 50 0C. Isopropanol (161 kg) was added and again the contents of reactor 3 were concentrated to a final volume of about 104 L under vacuum while keeping the temperature less than 50 0C. Isopropanol (161 kg) was again added and the contents of reactor 3 were concentrated to a final volume of about 100 L under vacuum while keeping the temperature less than 50 0C. The contents of reactor 3 were warmed to about 75 0C, held for about 80 min, and cooled to about 55 0C. Heptane (1 kg) mixed with about 1percent isopropanol was added to the reactor while at about 55 0C and the batch was held about 70 min until crystallization was observed. Heptane mixed with about 1 percent isopropanol (46 kg) was added to the reactor while keeping the reactor contents at about 55 0C and the reactor contents were held an additional 75 min at thus temperature. The reactor contents were cooled to about 20 0C over about 5 h and held at this temperature for an additional about 12 h. The reactor contents were cooled to about 5 0C and held at this temperature for about 1 h. The contents of reactor 3 were transferred to a filter dryer and rinsed with a mixture of isopropanol (18 kg) and heptane (8 kg). The contents of the filter dryer were dried at about 50 0C over about 56 h to yield 42.8 kg (89percent) of Compound (I) Crystalline Form B as an off- white powder. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With potassium carbonate In N,N-dimethyl-formamide at 90℃; for 5 h; | To a mechanically stirred slurry of cyclopropane-l, 1-dicarboxylic acid [3-FLUORO-4- (7-HYDROXY-6-METHOXY- quinolin-4-yloxy)-phenyl]-amide (4-fluoro-phenyl) -amide (16.6 g, 32. 8 mmol) and potassium carbonate (13.6 g, 98.6 mmol) in DMF (250 mL) was added 4- (3- chloropropyl) -morpholine hydrochloride (13,7. 92 g, 39.6 mmol). The resulting mixture was heated at 90°C for 5 hours (until phenol completely consumed). The reaction mixture was allowed to cool to room temperature, then dumped into water (900 mL), followed by extraction with EtOAc (3X). The combined extracts were washed with 5percent LiCl (aq. ) (3X) and brine (1X) followed by drying over MGS04 and concentration in vacuo. The crude (18.8g) obtained as brown solid was further purified by flash chromatography [silica gel, 4-stage gradient system: 1) EtOAc; 2) EtOAc: MeOH: 7N NH3/MEOH (95: 5: 0.5) ; 3) DCM: MeOH: 7N NH3/MeOH (95: 5: 0.5) ; 4) DCM: MeOH : 7N NH3/MeOH (93: 8 : 1)], affording N- [3-FLUORO-4- ( {6- (METHYLOXY)-7- [ (3-MORPHOLIN-4-YLPROPYL) OXY] QUINOLIN-4- YL} OXY) PHENYL]-N-(4-FLUOROPHENYL) CYCLOPROPANE-1, 1-DICARBOXAMIDE was obtained as an off white solid (15.0 g, 72percent yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70.9% | With potassium carbonate In N,N-dimethyl-formamide at 85℃; for 6 h; | To a 100 ml reaction flask was added N- [3-fluoro-4 - [[6-methoxy-7-hydroxyquinolin-4-yl] oxy] phenyl] -N '- (4-fluorophenyl ) Cyclopropane-1,1-dicarboxamide 5.4 g, 1.8 g of potassium carbonate, DMF 30ml, And heated to 85 ° C with stirring. After dissolving 2.1 g of N- (3-chloropropyl) morpholine in DMF, Was added dropwise to the above reaction solution for 6 h. The reaction solution cooled to room temperature was poured into 150 ml of water, extracted with dichloromethane (100 ml x 2), Dried over anhydrous sodium sulfate overnight. Filtration, vacuum distillation of dichloromethane, Column chromatography (mobile phase V / V: dichloromethane / methanol = 8/1) 4.8 g (70.9percent) of a pale yellow solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With potassium phosphate In 1-methyl-pyrrolidin-2-one; toluene at 95℃; for 2 h; Inert atmosphere | 3A. Alternative Preparation of N1-{3-fluoro-4-[(6-(methyloxy)-7-[3-(4-morpholinyl)propyl]oxy}-4-quinolinyl)oxy]phenyl}-N1-(4-fluorophenyl)-1,1-cyclopropanedicarboxamide; A flask was charged with Pd(OAc)2 (147 mg, 0.02 eq), racemic-2-(di-tert-butylphophsphinino)-1,1'-binaphyl (47 mg, 0.04 eq) and toluene (25 mL) under N2 and the mixture was stirred at room temperature for 30 min. NMP (4 mL) and phenol (10.87 g, 1.1 eq) were added to the mixture and stirred for 5 min. K3PO4 (8.2 g, 1.3 eq) and Cl-quinoline (60) (10 g, 1 eq) were added sequentially under nitrogen. The reaction mixture was heated to 95° C. over about 30 min and stirred at 95° C. for 1.5 h.Upon completion, the mixture was cooled to 60° C., whereupon 2-methylTHF (50 mL) and 20percent NaHSO3 (60 mL) were added. The mixture was stirred at 60° C. for 1 h and the layers separated. The organic solution was cooled to 50° C. and the solution decolorized with Darco G 60 (1.2 g) at 45-50° C. for 60 min. The mixture was filtered through a pad of celite and washed with a solution of 2-MethylTHF (50 mL) and MeOH (10 mL). To the solution was added Bu3P (3.86 mL, 0.52 eq) and stirred for 30 min at room temperature. A solution of maleic acid (7.6 g, 2.2 eq) in water (60 mL) was added to the organic solution and the temperature was maintained in the range of 20-30° C. The mixture was stirred for 5 min and layers were separated. The aqueous solution was added to a slurry of 2-MethylTHF (80 mL) and Na2CO3 (1.64 g, 2.42 eq) and stirred for 10 min until the carbonate was dissolved. The organic solution was washed with 10percent brine (50 mL) and the organic solvent removed to give 17.4 g of crude product with 97percent purity (crude yield=92percent). Acetonitrile (30 mL) and NMP (5 mL) were added to the crude product. The mixture was warmed to 65-70° C. and stirred for 1 h. Water (10 mL) was added slowly. The mixture was cooled to room temperature, stirred overnight, filtered, and washed with cold acetonitrile (10 mL). The product was dried in vacuo to yield 15.6 g of desired product (yield=83percent) with >99percent purity. |
81% | With tetrabutylammomium bromide; caesium carbonate In N,N-dimethyl-formamide at 60 - 70℃; for 8 h; | 3L reaction flask332. 3 g (lmol) of compound 6,900 mL of DMF, 651.6 g (2 mol) of cesium carbonate, 336.8 g (1 mol) of compound 8, 16.1 g (0.05 mol) of TBAB, 60-70 ° C, After 8 h HPLC detection,Raw material reaction is complete,The reaction was stopped,After the system had cooled down to room temperature, 100 mL of water and 100 mL of isopropyl acetate were added. The layers were separated and the aqueous layer was extracted with 4 x 800 mL of isopropyl acetate. The combined organic layers were dried, filtered and the filtrate was dried under reduced pressure to give a brown solid 1, and the crude product was recrystallized from an ethanol / acetone solution to give a white crystalline solid (512.6g, yield: 81.0percent, HPLC: 99percent |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50.2% | Stage #1: With oxalyl dichloride; N,N-dimethyl-formamide In tetrahydrofuran at 0 - 20℃; for 2 h; Stage #2: With triethylamine In tetrahydrofuran at 0 - 20℃; for 2 h; |
To a three-necked flask was added 60 ml of tetrahydrofuran, and 1 - [[3-fluoro-4 - [[6-methoxy-7 - [[3- (morpholin-4-yl) propyl] oxy] Quinolin-4-yl] oxy] phenyl] carbamoyl] cyclopropanecarboxylic acid, and 3 drops of N, N-dimethylformamide, 0 ~ 5 drop oxalyl chloride 1.4ml, drop Bi, 10 ~ 20 stirring reaction for 2 hours, the reaction solution stand. To the 250 ml three-necked flask was added 1.4 g of p-fluoroaniline, 2.0 ml of triethylamine and 40 ml of tetrahydrofuran, and the reaction solution was added dropwise at 0 to 5 ° C, and the reaction was carried out at room temperature for 2 hours. Filtered, the solvent was evaporated under reduced pressure, 100 ml of dichloromethane was added, After dissolving, the mixture was washed with 0.5 mol / L hydrochloric acid (50 ml x 2), saturated brine (50 ml x 2) and dried over anhydrous sodium sulfate. The residue was purified by column chromatography (mobile phase V / V: dichloromethane / methanol = 8/1) to give 3.2 g (50.2percent) of a pale yellow solid. |