* 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.
Stage #1: With borane-THF; 2-methyl-but-2-ene In tetrahydrofuran at 0 - 5℃; for 1.5 h; Nitrogen atmosphere Stage #2: at 20 - 35℃; for 1.58333 h;
2-METHYL-2-BUTENE (0.59 ML, 5.60 MMOL, 2.8 EQUIV. ) WAS ADDED OVER 1 HOUR TO A COLD (0-5°C) SOLUTION OF BH3*THF COMPLEX (1.0 M SOL, 3.0 ML, 3.0 MMOL, 1.5 EQUIV. ) KEPT UNDER N2. The reaction mixture was stirred at this temperature for 30 minutes followed by the addition of
2-METHOXY-ACETIC ACID PROPARGYLAMIDE (255 MG, 2 MMOL, 1.0 EQUIV. ) DISSOLVED IN DRY THF (1 ML) over 15 minutes. The ice-bath was removed and the reaction mixture was warmed to room temperature over 20 minutes. The reaction mixture was then heated at 35°C for 1 hour. K2CO3 (0.55 G, 4 MMOL, 2.0 EQUIV. ) DISSOLVED IN DEGASSED H20 (1.2 ML) WAS ADDED OVER 30 minutes to the reaction mixture. During the addition of the first half gas evolution was observed which seized during further addition. 6-lodo- [3-methyl-4- (6-methyl-pyridine-3-yloxy)- PHENYLAMINO]-QUINAZOLINE (1.41 G, 3 MMOL, 1.5 EQUIV. ) WAS ADDED IN THREE PORTIONS GIVING A yellow suspension. PPH3 (21 mg, 0.08 mmol, 4 molpercent) and Pd (OAc) 2 (4.5 mg, 0.02 MMOL, 1 molpercent) were added each in one portion and the reaction mixture was heated to reflux (65- 68°C). After about 30 minutes a yellow solution was obtained and the reaction was monitored by HPLC assay. After 18 hours the reaction mixture was cooled to room temperature followed by the addition of half-saturated NACI solution (10 ml) and EtOAc (10 ML). The organic phase was separated, washed with H2O (5 ML) and concentrated at 50°C and a pressure of less than 200 mbar. Purification by plug filtration, Si02, EtOAc/MeOH = 9/1. The title compound was obtained as light yellow crystals (0.55 g, 59 percent). Rf = 0.16 (EtOAc/MeOH = 9/1). H-NMR (CDCI3, 250 MHz): 8 =8.71 (s, 1 H, H-2), 8.25 (d, J=1.7 Hz, 1 H, H-8), 7.90 (s, 1 H, H-7), 7.82 (s, 1H, NH), 7.79 (s, 1H, H-5), 7.66 (d, J=2.5Hz, 1H, H-4"), 7.54 (dd, JE=8. 7Hz, J2=2. 6Hz, 1H, H- 5"), 7.15-7. 07 (m, 2H, H-5APOS;, H-6APOS;), 6.91 (d, J=8.7Hz, 1 H, H-2APOS;), 6.83 (bt, 1H, NH), 6.65 (d, J=15.9Hz, 1H, H-9), 6.34 and 6.29 (dt, JE=15. 9Hz, J2=6. 1HZ, 1H, H-10), 4.14 (dt, J=6. 1Hz, 2H, CHzOMe), 3.97 (s, 2H, CH2NH), 3.45 (s, 3H, OCH3), 2.53 (s, 3H, CH3), 2.29 (s, 3H, CH3). APOS;3C-NMR (CDCI3, 75 MHz): 8= 169.76 (C=O), 157.90, 154.93, 152.367, 152.23, 150.90, 149.74, 139.34, 134.73, 134.63, 131.16, 130.77, 130.36, 128.85, 129.98, 125.47, 124.66, 123.65, 121.32, 119.51, 119.13, 115.39, 71.96, 59.26, 40.84, 23.57, 16.41. Using reverse phase high performance liquid chromatography tR (min) was found to be 6.02 for the title compound under the conditions shown in the following table. Symmetry Shield 75 x 4.6 mm RP18 Flow 1. 0 mL/min Wavelength 205/210/220/245 nm Temp. 25°C Injection Volume 10 LL of a ca. 0.5percent solution in ACN/H20 9/1 Eluent B ACN Eluent C 0.01 mmol NH40Ac in H2O pH = 6.0 Gradient 0 min B = 30percent, C = 70 percent Gradient 20 min B = 85percent, C = 15 percent
59%
Stage #1: at 0 - 5℃; for 1.5 h; Stage #2: at 0 - 35℃; for 1.5 h;
Preparation of 2-methyl-2-butene (0.59 ml, 5.60 mmol, 2.8 equiv.) was added over 1 hour to a cold (0-5° C.) solution of BH3*THF complex (1.0 M sol, 3.0 ml, 3.0 mmol, 1.5 equiv.) kept under N2. The reaction mixture was stirred at this temperature for 30 minutes followed by the addition of 2-Methoxy-acetic acid propargylamide (255 mg, 2 mmol, 1.0 equiv.) dissolved in dry THF (1 ml) over 15 minutes. The ice-bath was removed and the reaction mixture was warmed to room temperature over 20 minutes. The reaction mixture was then heated at 35° C. for 1 hour. K2CO3 (0.55 g, 4 mmol, 2.0 equiv.) dissolved in degassed H2O (1.2 ml) was added over 30 minutes to the reaction mixture. During the addition of the first half gas evolution was observed which seized during further addition. 6-Iodo-[3-methyl-4-(6-methyl-pyridine-3-yloxy)-phenylamino]-quinazoline (1.41 g, 3 mmol, 1.5 equiv.) was added in three portions giving a yellow suspension. PPh3 (21 mg, 0.08 mmol, 4 mol percent) and Pd(OAc)2 (4.5 mg, 0.02 mmol, 1 mol percent) were added each in one portion and the reaction mixture was heated to reflux (65-68° C.). After about 30 minutes a yellow solution was obtained and the reaction was monitored by HPLC assay. After 18 hours the reaction mixture was cooled to room temperature followed by the addition of half-saturated NaCl solution (10 ml) and EtOAc (10 ml). The organic phase was separated, washed with H2O (5 ml) and concentrated at 50° C. and a pressure of less than 200 mbar. Purification by plug filtration, SiO2, EtOAc/MeOH=9/1. The title compound was obtained as light yellow crystals (0.55 g, 59percent). Rf=0.16 (EtOAc/MeOH=9/1). 1H-NMR (CDCl3, 250 MHz): δ=8.71 (s, 1H, H-2), 8.25 (d, J=1.7 Hz, 1H, H-8), 7.90(s, 1H, H-7), 7.82 (s, 1H, NH), 7.79 (s, 1H, H-5), 7.66 (d, J=2.5 Hz, 1H, H-4), 7.54 (dd, J1=8.7 Hz, J2=2.6 Hz, 1H, H-5), 7.15-7.07 (m, 2H, H-5', H-6'), 6.91 (d, J=8.7 Hz, 1H, H-2'), 6.83 (bt, 1H, NH), 6.65 (d, J=15.9 Hz, 1H, H-9), 6.34 and 6.29 (dt, J1=15.9 Hz, J2=6.1 Hz, 1H, H-10), 4.14 (dt, J=6.1 Hz, 2H, CH2OMe), 3.97 (s, 2H, CH2NH), 3.45 (s, 3H, OCH3), 2.53 (s, 3H, CH3), 2.29 (s, 3H, CH3). 13C-NMR (CDCl3, 75 MHz): δ=169.76 (CO), 157.90, 154.93, 152.367, 152.23, 150.90, 149.74, 139.34, 134.73, 134.63, 131.16, 130.77, 130.36, 128.85, 129.98, 125.47, 124.66, 123.65, 121.32, 119.51, 119.13, 115.39, 71.96, 59.26, 40.84, 23.57, 16.41.
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[ 625-45-6 ]
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E-2-methoxy-N-(3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-allyl)-acetamide dinitrate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In tetrahydrofuran;
: E-2-METHOXY-N- (3- {4- [3-METHYL-4- (6-METHYL-PYRIDIN-3-YLOXY)-PHENYLAMINO]-QUINAZOLIN- 6-yl}-allyl)-acetamide free base (100 mg), prepared according to the method of either Example 1,2 or 3 was dissolved in THF and 2 molar equivalents nitric acid was added. A light yellow solid precipitated and was isolated as the product. The sample of E-2-METHOXY-N- (3- {4- [3-METHYL-4- (6-METHYL-PYRIDIN-3-YLOXY)- phenylamino]-quinazolin-6-yl}-allyl)-acetamide dinitrate was found to be crystalline by PXRD. Its DSC thermogram exhibited a sharp exotherm at the onset temperature of 148C, and had a peak temperature of 151C. Hygroscopicity :-7% (by weight) at 90% relative humidity.
E-2-methoxy-N-(3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-allyl)-acetamide camsylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In ethyl acetate;Heating / reflux;
The racemic camsylate complex was synthesized by dissolving 1 gram of E-2- METHOXY-N- (3- {4- [3-METHYL-4- (6-METHYL-PYRIDIN-3-YLOXY)- PHENYLAMINO]-QUINAZOLIN-6-YL}-ALLYL)- acetamide free base, prepared according to the method of either Example 1 or 2 in refluxing EtOAc. The acid solution was produced by dissolving 1 gram of ()-10-CAMPHORSULFONIC acid in 15 mL of EtOAc. The acid solution was added to the refluxing free base solution. The solution was allowed to reflux overnight, and then isolated by filtration. The solids were then washed with EtOAc and dried to yield racemic E-2-METHOXY-N- (3- {4- [3-METHYL-4- (6-METHYL- PYRIDIN-3-YLOXY)-PHENYLAMINO]-QUINAZOLIN-6-YL}-ALLYL)-ACETAMIDE CAMSYLATE. Both the racemic and the (+)-camsylate samples were hygroscopic to the point of deliquescence.
In ethanol; dichloromethane; ethyl acetate; for 0.166667h;Heating / reflux;
E-2-Methoxy-N- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin- 6-YL}-ALLYL)-ACETAMIDE (2 grams), prepared according to the method of Example 1,2 or 3 was dissolved in a refluxing 16: 1 (V/V) mixture of ethyl acetate (160 mL)/dichloromethane (10 mL). A solution of fumaric acid was prepared by dissolving 2 equivalents (1 gram) of fumaric acid in hot ethanol (12 mL). This acid solution was added hot to the refluxing free base solution. The resulting mixture was stirred and refluxed for approximately ten minutes, and then cooled to room temperature. Hexane (-100 mL) was added until the reaction mixture turned cloudy. The mixture was then ultrasonicated until crystals were noted. The reaction mixture was heated to approximately 70C and stirred overnight to produce a slurry. The solids were then collected via cold filtration to give the product. The fumarate was a monofumarate HEMIPENTAHYDRATE (2.5 H2O) as determined by elemental analysis.
E-2-methoxy-N-(3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-allyl)-acetamide dimesylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
99%
In ethanol; dichloromethane; acetonitrile; at 20℃; for 0.25h;
To 67.33 grams of the free base form E-2-METHOXY-N- (3- {4- [3-METHYL-4- (6-METHYL- PYRIDIN-3-YLOXY)-PHENYLAMINO]-QUINAZOLIN-6-YL}-ALLYL)-ACETAMIDE (prepared according to Example 1 above) in 400 mL of EtOH and 100 ml of CH2CI2 at room temp was added dropwise a soln of 19.17 mL (2.05) EQUIVS of METHANESULFONIC acid (CH3SO3H) in 100 ml of acetonitrile. The mixture was slurried at room temperature for 15 minutes then the methylene chloride (-100 ML) was removed. An additional 600 mL of acetonitrile was added to complete crystallization and the mixture slurried for 2 hours. The crystals were filtered under a nitrogen atmosphere and washed with 100 ml of acetonitrile. The dimesylate salt (94.48 grams) was produced in 99 % yield.
99%
In ethanol; dichloromethane; acetonitrile; at 20℃; for 0.25h;
The dimesylate salt of <strong>[383432-38-0]E-2-Methoxy-N-(3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-allyl)-acetamide</strong> is prepared as follows: To 67.33 grams of the free base form <strong>[383432-38-0]E-2-Methoxy-N-(3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-allyl)-acetamide</strong> (prepared according to Example 1 above) in 400 mL of EtOH and 100 ml of CH2Cl2 at room temp was added dropwise a soln of 19.17 mL (2.05) equivs of methanesulfonic acid (CH3SO3H) in 100 ml of acetonitrile. The mixture was slurried at room temperature for 15 minutes then the methylene chloride (~100 ml) was removed. An additional 600 mL of acetonitrile was added to complete crystallization and the mixture slurried for 2 hours. The crystals were filtered under a nitrogen atmosphere and washed with 100 ml of acetonitrile. The dimesylate salt (94.48 grams) was produced in 99% yield.
E-2-methoxy-N-(3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-allyl)-acetamide monomalate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In tetrahydrofuran;
E-2-METHOXY-N- (3- {4- [3-METHYL-4- (6-METHYL-PYRIDIN-3-YLOXY)-PHENYLAMINO]-QUINAZOLIN- 6-YL}-ALLYL)-ACETAMIDE (1 gram), prepared according to the method of either Example 1,2 or 3 was dissolved in 25mL hot THF. Malic acid of (571 mg; 2 molar equivalents of the free base) was added to the free base solution. The mixture was stirred overnight, during which time solids precipitated. With addition of 25mL additional THF, the slurry was stirred an additional day and the solids were collected by vacuum filtration to yield the MONOMALATE complex as the product. The material was indicated to be crystalline by powder X-ray diffraction.
E-2-methoxy-N-(3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-allyl)-acetamide tartrate[ No CAS ]
E-2-methoxy-N-(3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-allyl)-acetamide hemitartrate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In ethanol; dichloromethane; water; at 20℃; for 0.5h;
Several racemic E-2-METHOXY-N- (3- {4- [3-METHYL-4- (6-METHYL-PYRIDIN-3-YLOXY)- phenylamino]-quinazolin-6-yl)-allyl)-acetamide tartrates were produced. The synthesis of the monotartrate hemihydrate and hemitartrate hemihydrate were produced started with the production of amorphous material. This material was synthesized by dissolving 3 grams E-2- METHOXY-N- (3- {4- [3-METHYL-4- (6-METHYL-PYRIDIN-3-YLOXY)-PHENYLAMINO]-QUINAZOLIN-6-YL)-ALLYL)- acetamide free base in 20: 3 (v/v) ethanol (ETOH)/DICHLOROMETHANE (-50 mL). A solution of D, L-tartaric acid was prepared by dissolving 2 grams of D, L-tartaric acid in 10 mL water. The two solutions were combined and stirred at room temperature FOR-30 minutes. The solvent was reduced to yield the amorphous material.
E-2-methoxy-N-(3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-allyl)-acetamide diesylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In ethanol; dichloromethane; ethyl acetate;
E-2-METHOXY-N- (3- {4- [3-METHYL-4- (6-METHYL-PYRIDIN-3-YLOXY)-PHENYLAMINO]-QUINAZOLIN- 6-yl}-allyl)-acetamide free base, prepared according to the method of either Example 1,2 or 3 (3.00 grams) was dissolved in 40mL ethanol and 6mL methylene chloride. 2.05 molar equivalents of ethanesulfonic acid, dissolved in 10ML ethanol, was added to the solution of free base. The solution was concentrated and taken up in a minimal volume of ethanol, then ethyl acetate was added as an nonsolvent until precipitation occurred. The slurry was stirred at ambient temperature over 48 hours and isolated as E-2-METHOXY-N- (3- {4- [3-METHYL-4- (6- methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-allyl)-acetamide diesylate. The diesylate complex was crystalline by PXRD. DSC showed a clean melting onset at 146C and a peak at 149. 5C. Hygroscopicity: 45% (by weight) at 90% relative humidity.
With hydrogenchloride; In di-isopropyl ether; water; at 75℃;
A solution of E-2-METHOXY-N- (3- {4- [3-METHYL-4- (6-METHYL-PYRIDIN-3-YLOXY)- PHENYLAMINO]-QUINAZOLIN-6-YL}-AILYL)-ACETAMIDE in isopropyl alcohol was prepared by dissolving 500mg E-2-METHOXY-N- (3- {4- [3-METHYL-4- (6-METHYL-PYRIDIN-3-YLOXY)-PHENYLAMINO]-QUINAZOLIN- 6-YL}-ALLYL)-ACETAMIDE, using the procedure of Example 1,2 or 3 in 50 mL isopropanol with stirring. The solution was heated to 75C. Then, concentrated hydrochloric acid (1. 1- equivalents ; 115mg) was diluted with 6 mL of isopropanol. The diluted HCI solution was added drop-wise to the hot free base solution with stirring. After complete addition, heat was removed from solution and a microcrystalline precipitate emerged upon cooling to ambient temperature over about three hours. The thick yellow slurry was stirred one day and filtered. The fine yellow powder was collected by vacuum filtration and dried under vacuum. The yield was approximately 79%. The hydrochloride salt was determined to be an anhydrous MONOHYDROCHLORIDE salt by combustion analysis. The compound exhibited a melting endotherm at 222C by DSC at a heating rate of 5C/MIN.. Its PXRD pattern is shown in Fig 1. Characteristic X-ray powder DIFFRACTION PEAKS (2-THETA (0. 1) [% RELATIVE INTENSITY] ) : 4.6 [100], 9.3 [20. 9], 11.4 [10.6], 15.6 [3.4], 16.4 [2.8], 17.1 [11. 8], 18.4 [34.8], 18.8 [5.9], 20.1 [3.8], 20.4 [8.6], 22.6 [8.2], 23.0 [5.1], 24.0 [3.3], 25.4 [2.7], 25.8 [3.7], 27.5 [10.7], and 28.3 [3.2].
With phosphoric acid; In ethanol; water; at 45 - 55℃;
The monophosphate was prepared as the following. A free base solution was made by dissolving 5.022 grams of E-2-METHOXY-N- (3- {4- [3-METHYL-4- (6-METHYL-PYRIDIN-3-YLOXY)- PHENYLAMINO]-QUINAZOLIN-6-YL}-ALLYL)-ACETAMIDE, made according to the method of Example 1, 2 or 3 in 300 mL of ethanol and heated to 35C to a clear solution. One equivalent mole of phosphoric acid (87%, 0.77 mL) was diluted with 20 mL of ethanol. The acid solution was added to the free base ethanol solution drop-wise with stirring and heat (-45 to 55C). Yellow precipitate appeared immediately. The slurry became thick with time, 50 mL of ethyl acetate was added and the slurry was let cool to ambient temperature. The yellow crystalline powder was collected by filtration and dried under vacuum for 2 hours. The yield of the monophosphate product was about 84%. The monophosphate may contain 1-3% water. A powder x-ray diffraction pattern of the monophosphate (monohydrate) is shown in Figure 3. Characteristic X-ray powder diffraction peaks of the monophosphate (monohydrate) (2-THETA (0. 1), [% RELATIVE INTENSITY] ) : 4.9 [100], 6.5 [2.7], 10.8 [2.6], 13.1 [3], 14.3 [2], 14.9 [4. 8], 15.5 [25.1], 16.3 [2.5], 16.7 [2.9], 17.2 [4.5], 17.9 [2.1], 19.9 [17.3], 20.6 [8.2], 21.7 [4.5], 22.1 [2], 22.8 [2.4], 23.7 [3.1], 24.3 [1.9], 25.0 [8.7], 26.0 [3], 26.5 [3.9], 27.5 [2.2], 28.3 [1. 8], 29.1 [2.1], 30.1 [2.2], 35.5 [1.6], and 37.7 [1.6].
(+)-E-2-methoxy-N-(3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-allyl)-acetamide camsylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In ethanol; dichloromethane; at 20℃; for 0.333333h;
The (+)-10-camphorsulfonic acid complex was synthesized by dissolving 2 grams of E-2-METHOXY-N- (3- {4- [3-METHYL-4- (6-METHYL-PYRIDIN-3-YLOXY)-PHENYLAMINO]-QUINAZOLIN-6-YL}- allyl)-acetamide free base, prepared according to the method of Example 1,2 or 3 in 5: 2 (V/V) EtOH/Dichloromethane. The (+)-10-camphorsulfonic acid solution was produced by dissolving 1 gram of (+)-10-CAMPHORSULFONIC acid in 5 mL ETOH. The acid solution was added to the free base solution at room temperature with stirring. The reaction mixture was stirred for twenty minutes at room temperature, and the solvent volume was then reduced to yield a crude solid. A portion of the crude solid produced was dissolved in hot EtOAc. Hexanes were added until cloudy, and then the mixture was cooled to room temperature. The solution was ultrasonicated until a precipitate was noted, and then allowed to slurry at room temperature overnight. The material was isolated by filtration to yield a yellow solid. The balance of the crude solid mentioned above was dissolved in hot EtOAc (75 mL). The solution was cooled and the seed crystals of the aforementioned yellow solid were added. The reaction mixture was then heated to-75C and slurried overnight. The mixture was cooled to RT, filtered and rinsed with EtOAc to produce (+)-of E-2-METHOXY-N- (3- {4- [3- METHYL-4- (6-METHYL-PYRIDIN-3-YLOXY)-PHENYLAMINO]-QUINAZOLIN-6-YL}-ALLYL)-ACETAMIDE CAMSYLATE.
E-2-methoxy-N-(3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-allyl)-acetamide hemiedisylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In methanol; butanone;
The E-2-METHOXY-N- (3- {4- [3-METHYL-4- (6-METHYL-PYRIDIN-3-YLOXY)- PHENYLAMINO]- QUINAZOLIN-6-YL}-ALLYL)-ACETAMIDE edisylate complex was synthesized by dissolving 0.5 equivalents of 1,2 ethanedisulfonic acid in 80: 20 methyl ethyl ketone (MEK)/METHANOL (MEOH) (V/V). The E-2-METHOXY-N- (3- {4- [3-METHYL-4- (6-METHYL-PYRIDIN-3-YLOXY)-PHENYLAMINO]- QUINAZOLIN-6-YL}-ALLYL)-ACETAMIDE free base, prepared according to the method of Example 1,2 or 3 was dissolved in approximately 60: 40 MEK/MeOH (v/v), and added dropwise to the 1,2- ethanedisulfonic acid solution with stirring. Initially, an oil was formed which later crystallized into solid powders. The material was determined to be an anhydrous hemiedisylate by elemental analysis
E-2-methoxy-N-(3-(4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl)-allyl)-acetamide dicitraconate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
~ 62%
In tetrahydrofuran;
A THF free base solution was prepared by dissolving 104 mg of E-2-METHOXY-N- (3- {4- [3-methyl-4- (6-METHYL-PYRIDIN-3-YLOXY)-PHENYLAMINO]-QUINAZOLIN-6-YL}-ALLYL)-ACETAMIDE, prepared according to the method of Example 1,2 or 3 in 5 mL of THF with stirring to a clear solution. The citraconic acid solution was prepared by dissolving 64 mg of citraconic acid (approximately 2.2 equivalents) in 1 mL of THF. The citraconic acid solution was added to the free base solution dropwise with stirring. Upon completion of the addition, no precipitate was noted. The solvent volume was reduced under a nitrogen jet, and then allowed to stir while capped. After approximately 15 minutes, trace precipitation occurred. After one hour, the solution turned into thick slurry and the slurry was allowed to stir overnight. The precipitate was then isolated using a 0.45 LM Nylon-66 membrane filter by vacuum filtration. The solids produced were rinsed with several milliliters of THF, and allowed to dry under nitrogen. The yield was approximately 62%. Based on combustion analysis, the product was E-2-METHOXY-N- (3- {4- [3-METHYL-4- (6- METHYL-PYRIDIN-3-YLOXY)-PHENYLAMINO]-QUINAZOLIN-6-YL}-ALLYL)-ACETAMIDE dicitraconate.
The E-2-METHOXY-N- (3- {4- [3-METHYL-4- (6-METHYL-PYRIDIN-3-YLOXY)-PHENYLAMINO]- QUINAZOLIN-6-YL}-ALLYL)-ACETAMIDE monobesylate was prepared as the following. The E-2- METHOXY-N- (3- {4- [3-METHYL-4- (6-METHYL-PYRIDIN-3-YLOXY)-PHENYLAMINO]-QUINAZOLIN-6-YL}-ALLYL)- acetamide free base, prepared according to the method of either Example 1, 2 or 3 was dissolved 500 mg in THF. BENZENESULFONIC acid (168mg, 1 molar equivalent) was added to the free base solution. Diethyl ether was then added dropwise to the solution until cloudiness was observed. After overnight stirring, the precipitate oiled out on the sides of the flask. The oily material was scraped free and allowed to stir for an additional day. Crystalline material was collected after two days. The monobesylate had a melting onset at 135C by DSC, and a peak m. p. of 137C. The material was evaluated for hygroscopicity in relative humidity chambers. After 16 hours in the 75% RH chamber there was no significant water sorption. The 94% RH chamber caused a 6.7% weight increase after the same time period, and deliquescence was observed after 16 hours in a 100% relative humidity chamber.
E-2-methoxy-N-(3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-allyl)-acetamide dimesylate[ No CAS ]
[ 383432-38-0 ]
Yield
Reaction Conditions
Operation in experiment
With sodium hydroxide; In chloroform; water;pH 13 - 14;
The dimesylate salt produced according to the method of the preceding paragraph (90 g) was dissolved in water (-550 mL). Chloroform was added (-500 mL) to the solution followed by 1N NAOH until a white suspension/precipitate was observed (pH-13-14). The addition of chloroform before NAOH reduced gumming as the precipitate formed. The mixture was transferred to a separatory funnel (2 L) and the free base was extracted with three portions of chloroform (-300 mL). The extracts were combined (-1. 3 L), washed with water (-500 mL), dried with anhydrous magnesium sulfate, and then filtered. The chloroform filtrate was CONCENTRATED IN VACUO to provide a yellow amorphous solid/oil. This material was reslurried in ethyl acetate overnight resulting in a white solid. This material was then filtered, washed with cold ethyl acetate, and then dried in a vacuum oven at 45C to yield a white crystalline solid (-59 g). The free base was characterized by polarizing light microscopy (PLM), powder X-ray diffraction (PXRD), and differential scanning calorimetry (DSC). It is in the form of a needle, and displays three endothermic events by DSC (DSC melting points: 125C, 160C, and 167C)
The dimesylate salt produced according to the method of the preceding paragraph (90 g) was dissolved in water (550 mL). Chloroform was added (500 mL) to the solution followed by 1N NaOH until a white suspension/precipitate was observed (pH 13-14). The addition of chloroform before NaOH reduced gumming as the precipitate formed. The mixture was transferred to a separatory funnel (2 L) and the free base was extracted with three portions of chloroform (300 mL). The extracts were combined (1.3 L), washed with water (500 mL), dried with anhydrous magnesium sulfate, and then filtered. The chloroform filtrate was concentrated in vacuo to provide a yellow amorphous solid/oil. This material was reslurried in ethyl acetate overnight resulting in a white solid. This material was then filtered, washed with cold ethyl acetate, and then dried in a vacuum oven at 45 C. to yield a white crystalline solid (59 g). The free base was characterized by polarizing light microscopy (PLM), powder X-ray diffraction (PXRD), and differential scanning calorimetry (DSC). It is in the form of a needle, and displays three endothermic events by DSC (DSC melting points: 125 C., 160 C., and 167 C.)
6-(N-methoxyacetyl-3-aminopropen-1-yl)-4-[3-methyl-4-(6-methylpyridine-3-yloxy)phenylamino]quinazoline sesquisuccinate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96%
In acetonitrile; at 50℃;
A reactor tube equipped with a magnetic spin bar was charged with <strong>[383432-38-0]E-2-Methoxy-N-(3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-allyl)-acetamide</strong> free base (2.0 g, 1 equivalent) and acetonitrile (10 mL). The mixture was heated to about 50 C. Succinic acid (1.00 g, 2 equivalents) were added to the mixture. The slurry was stirred at 50 C. overnight. Acetonitrile (5 mL) was added to the slurry and the mixture was stirred at about 50 C. overnight. The slurry was cooled to 20 C. and stirred overnight. The product was isolated by vacuum filtration and the product cake was covered with 5 mL of acetonitrile and held for about 5 minutes. The wash solvent was then separated from the product cake by vacuum filtration. The product was dried in a vacuum oven at 40-45 C. overnight to afford 1.33 grams of the sesquisuccinate complex in 96% yield.
85%
In isopropyl alcohol; at 45 - 50℃; for 1h;Product distribution / selectivity;
A 50 mL round bottom flask equipped with a condenser, thermometer, and a magnetic spin bar for agitation was charged with <strong>[383432-38-0]E-2-Methoxy-N-(3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-allyl)-acetamide</strong> free base (2.0, 1.0 equiv.) and 2-propanol (20 mL). The mixture was heated to solution. A separate 75 mL reactor was charged with succinic acid (0.91 g, 1.8 equivalents) and 2-propanol (10 mL) and warmed to about 45 C. The free base solution was vacuum filtered to remove any solids and was added to the succinic acid solution over about 10 minutes. The resulting slurry was stirred at 45-50 C. for about 1 hour. The slurry was cooled to 20 C. and stirred overnight. The product was isolated by filtration and washed with 2-propanol. The product was dried in a vacuum oven at 30-40 C. for about 6 hours to afford the sesquisuccinate complex (2.34 g, 85% yield). A 50 mL round bottom flask with magnetic spin bar was charged with <strong>[383432-38-0]E-2-Methoxy-N-(3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-allyl)-acetamide</strong> free base (2.0, 1.0 equiv.) and 2-propanol (20 mL). The mixture was heated to solution. A separate 75 mL reactor was charged with succinic acid (0.91 g, 1.8 equivalents) and 2-propanol propanol (10 mL) and warmed to about 45 to 50 C. The free base solution was vacuum filtered to remove any solids and was added to the succinic acid solution over about 10 minutes. The resulting slurry was stirred at 45-50 C. for about 1 hour. The slurry was cooled to 20 C. and stirred overnight. The product was isolated by filtration and washed with 2-propanol. The product was dried in a vacuum oven at 30-40 C. for about 6 hours to afford the sesquisuccinate complex (2.34 g, 85% yield).
85 - 90%
In water; acetone; at 42 - 58℃;Product distribution / selectivity;
A suitable clean, dry reaction vessel equipped with programmable linear temperature control system was charged with acetone (130 ml), water (14 ml), succinic acid (7.55 g, 3 eq.), and E-2-Methoxy-N-(3-{4-[3-methyl4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-allyl)-acetamide free base (10.0 g, 1 equivalent). The reaction mixture was heated to about 45-58 C. to yield a solution. Once the reaction mixture dissolved in solution, the temperature was adjusted to about 45 C. The solution was vacuum filtered into a suitable clean, dry, speck and fiber-free crystallization vessel. The crystallization vessel was maintained at a jacket temperature of about 50 C. in order to maintain the reaction vessel temperature at about 45 C. The reaction vessel was rinsed with about 20 ml acetone and pressure rinsed through the filter into the crystallization vessel. The reaction mixture was stirred and the temperature of the reaction vessel was adjusted to about 42-45 C. The reaction vessel was seeded with about 1% w/w sesquisuccinate complex. After initiating crystallization by seeding, the reaction mixture was stirred at about 35-45 C. for at least about 1 hour. The vessel was slowly cooled to about 5-20 C., preferably over about 4 hours. The reaction mixture was stirred at about 5-20 C. for about 18 hours. The sesquisuccinate complex was isolated by filtration on a BUchner style funnel, and the cake was washed with acetone at about 20 C. The sesquisuccinate complex was dried to a constant weight by air-drying or in a vacuum oven ranging from about 20-60 C. Sesquisuccinate complex yield: 85-90% w/w.; EXAMPLE 2 To a 500 gallon reactor, E-2-Methoxy-N-(3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-allyl)acetamide free base (32.1 kg), succinic acid (24.2 kg), Water (44.9 L), and Acetone (417 L) were added. The mixture was heated to 50 C. and held for 1 hr at 50 C. The solution was filtered to render is speck and fiber free. The solution was collected in second 500 gallon reactor held at about 50 C. The first reactor was rinsed with Acetone (64.2 L) and filtered forward to the speck and fiber free reactor. The solution was cooled to about 40-45 C. over about 30 minutes. Seed crystals of the sesquisuccinate complex (321 g) were added at about 40-45 C. The slurry was held for 2 hours at about 40 C. The slurry was then cooled over about 1 hour to 20 C. and held for about 30 minutes. This was followed by heating back to about 40 C. over one half hour and holding at 40 C. The slurry was cooled over 3 hours to about 35 C., followed by cooling over 2 hours to about 30 C., followed by cooling over 1 hour to 25 C. The slurry was then cooled over about 4 hours to about 0 C. and held at 0 C. for 1 hour. The product was isolated by filtration on a pressurized plate filter covered with a suitable cloth filter media. The product solids were washed with acetone (64.2 L). The product solids were dried for 24 hours at 40 to 50 C. to afford 38.0 kg of the sesquisuccinate complex.; EXAMPLE 9 A suitable clean, dry reaction vessel equipped with programmable linear temperature controls was charged with acetone (130 ml), water (14 ml), succinic acid (7.55 g, 3 eq.), and free base (10.0 g). The amount of succinic acid used in the reaction can range from about 1.5 to 3.5 equivalents. The reaction mixture was stirred at about 45-58 C. to yield a solution. The temperature can be elevated up to the reflux temperature of the solvent to yield a suitable solution. Once the reaction mixture dissolved in solution, the temperature was adjusted to about 45 C. (the temperature should not drop below 42 C.). The solution was filtered in vacuo into a suitable clean, dry, spec-free crystallization vessel. The crystallization vessel was maintained at a jacket temperature of about 50 C. in order to maintain the reaction vessel temperature at about 45 C. The reaction vessel was rinsed with about 20 ml acetone and pressure rinsed through the filter into the crystallization vessel. The reaction mixture was stirred and the temperature of the reaction vessel was adjusted to about 40-45 C. After crystallization begins, the reaction mixture was stirred at about 35-45 C. for at least about 1 hour. The vessel was slowly cooled to about 5-20 C. over about 4 hours. The reaction mixture was stirred at about 20 C. for 18 hours. The sesquisuccinate complex was isolated by filtration on a Buchner funnel, and the cake was washed with acetone. The sesquisuccinate complex was dried to a constant weight using a vacuum oven ranging from about 20-60 C. to afford the sesquisuccinate complex.
83%
In tetrahydrofuran; at 50℃;Product distribution / selectivity;
A 50 mL reactor tube equipped with a magnetic spin bar was charged with <strong>[383432-38-0]E-2-Methoxy-N-(3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-allyl)-acetamide</strong> free base (1.0 g, 1 equivalent) and tetrahydrofuran (10 mL). The mixture was heated to about 50 C. Succinic acid (0.50 g, 2 equivalents) were added to the mixture to give a solution. The mixture was stirred at 50 C. overnight. The resulting slurry was cooled to 20 C. and stirred overnight. The product was isolated by vacuum filtration and the product cake was washed with 5 mL of tetrahydrofuran. The vacuum on the filtration was stopped. The product cake on the filter was covered with 10 mL of tetrahydrofuran and held for about 5 minutes. The wash solvent was separated from the product cake by vacuum filtration. After the wash solvent was removed from the cake, the vacuum was halted. The product cake on the filter was covered with 10 mL of tetrahydrofuan and held for about 5 minutes. The wash solvent was separated from the product cake by vacuum filtration. The product was dried in a vacuum oven at 40-45 C. overnight to afford 1.14 grams of the sesquisuccinate complex (83% yield).
76%
In acetone; at 20 - 50℃;Product distribution / selectivity;
A 50 mL reactor tube equipped with a magnetic spin bar was charged with <strong>[383432-38-0]E-2-Methoxy-N-(3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-allyl)-acetamide</strong> free base (1.0 g, 1 equivalent) and acetone (10 mL). The mixture was heated to about 50 C. Succinic acid (0.50 g, 2 equivalents) were added to the mixture to give a solution. The mixture was stirred at 50 C. overnight. The resulting slurry was cooled to 20 C. and stirred overnight. The product was isolated by vacuum filtration and the product cake was washed with 5 mL of acetone. The vacuum on the filtration was stopped. The product cake on the filter was covered with 10 mL of acetone and held for about 5 minutes. The wash acetone was then separated from the product cake by vacuum filtration. After the wash solvent was removed from the cake, the vacuum was halted. The product cake on the filter was covered with 10 mL of acetone and held for about 5 minutes. The wash acetone was separated from the product cake by vacuum filtration. The product was dried in a vacuum oven at 40-45 C. overnight to afford 1.05 grams of the sesquisuccinate complex (76% yield).
74%
In butan-1-ol; at 50℃;
A 50 mL reactor tube equipped with a magnetic spin bar was charged with E-2-Methoxy-N-(3{4-[3-methyl4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl{-allyl)-acetamide free base (1.0 g, 1 equivalent) and 1-butanol (15 mL). The mixture was heated to about 50 C. Succinic acid (0.50 g, 2 equivalents) were added to the mixture to give a solution. The mixture was stirred at 50 C. overnight to give a yellow slurry. The slurry was cooled to 25 C. and stirred overnight. The product was isolated by vacuum filtration and the product cake was washed with 5 mL of acetone. The vacuum on the filtration was stopped. The product cake on the filter was covered with 5 mL of 1-butanol and held for about 5 minutes. The wash solvent was then separated from the product cake by vacuum filtration. The product was dried in a vacuum oven at 40-45 C. overnight to afford 1.02 grams of the sesquisuccinate complex in 74% yield.
In tetrahydrofuran; acetone;
To a solution of <strong>[383432-38-0]E-2-Methoxy-N-(3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-allyl)-acetamide</strong> in hot THF/acetone (5/100) two equivalents of succinic acid were added. Crystals slowly formed as the solution cooled. After slurrying overnight, the crystals were filtered and rinsed with acetone. The product was isolated as a white solid and verified as the sesquisuccinate complex of <strong>[383432-38-0]E-2-Methoxy-N-(3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-allyl)-acetamide</strong> by CHN analysis. Calculated: C=61.29, H=5.61, N=10.83, Experimental: C=61.04, H=5.61, N=10.85.
6-(N-methoxyacetyl-3-aminopropen-1-yl)-4-[3-methyl-4-(6-methylpyridine-3-yloxy)phenylamino]quinazoline sesquisuccinate[ No CAS ]
[ 383432-38-0 ]
Yield
Reaction Conditions
Operation in experiment
The thus formed sesquisuccinate complex (5 grams) was mixed with water (25 mL) and chloroform (25 mL). To this mixture 1.1 equivalents of sodium hydroxide (1 normal aqueous) was added and stirred until two layers had formed. The mixture was transferred into a separatory funnel and the layers were separated. The contents of the funnel were mixed well and the layers separated. The extraction was repeated a second time with an additional aliquot of chloroform (25 mL). The water layer was then discarded and the combined chloroform layers (75 mL) were placed back into the separatory funnel with some water (25 mL). The contents of the funnel were mixed well and the layers separated. The water layer was discarded and the chloroform layer was placed into a single-neck round bottom flask. The chloroform was removed using rotary evaporation to yield a yellow oil. Ethyl acetate was added (125 mL) and stirred with the oil to yield a thick slurry. After stirring for approximately one day, the slurry was isolated via vacuum filtration using a Buchner funnel fitted with a paper filter (Whatman No.2). The solids were rinsed with ethyl acetate (25 mL), and then placed into a crystallizing dish. The dish and solids were placed into a vacuum oven at 45 C. to dry overnight to afford a pale yellow powder
Specific preferred compounds prepared using the processes of the present invention include those selected from the group consisting of: ... (+-)-[3-Methyl-4-(6-methyl-pyridin-3-yloxy)-phenyl]-(6-piperidin-3-ylethynyl-quinazolin-4-yl)-amine; [3-Methyl-4-(6-methyl-pyridin-3-yloxy)-phenyl]-(6-piperidin-4-ylethynyl-quinazolin-4-yl)-amine; 2-Methoxy-N-(3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-acetamide; 2-Fluoro-N-(3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-acetamide; E-2-Methoxy-N-(3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-allyl)-acetamide; [3-Methyl-4-(pyridin-3-yloxy)-phenyl]-(6-piperidin-4-ylethynyl-quinazolin-4-yl)-amine; 2-Methoxy-N-(1-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-ylethynyl}-cyclopropyl)-acetamide; E-N-(3-{4-[3-Chloro-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-allyl)-2-methoxy-acetamide; ...
The method according to claims 1or 2, wherein the compound prepared is selected from the group consisting of: ... (+-)-[3-Methyl-4-(6-methyl-pyridin-3-yloxy)-phenyl]-(6-piperidin-3-ylethynyl-quinazolin-4-yl)-amine; [3-Methyl-4-(6-methyl-pyridin-3-yloxy)-phenyl]-(6-piperidin-4-ylethynyl-quinazolin-4-yl)-amine; 2-Methoxy-N-(3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-acetamide; 2-Fluoro-N-(3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-acetamide; E-2-Methoxy-N-(3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-allyl)-acetamide; [3-Methyl-4-(pyridin-3-yloxy)-phenyl]-(6-piperidin-4-ylethynyl-quinazolin-4-yl)-amine; 2-Methoxy-N-(1-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-ylethynyl}-cyclopropyl)-acetamide; E-N-(3-{4-[3-Chloro-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-allyl)-2-methoxy-acetamide; ...
Specific preferred compounds of the present invention include those selected from the group consisting of: ... [3-Methyl-4-(2-methyl-pyridin-3-yloxy)-phenyl]-(6-piperidin-4-ylethynyl-quinazolin-4-yl)-amine [3-Methyl-4-(6-methyl-pyridin-3-yloxy)-phenyl]-(6-piperidin-4-ylethynyl-quinazolin-4-yl)-amine; 2-Methoxy-N-(3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-acetamide; 2-Fluoro-N-(3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-acetamide; 2-Methoxy-N-(3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-allyl)-acetamide; [3-Methyl-4-(pyridin-3-yloxy)-phenyl]-(6-piperidin-4-ylethynyl-quinazolin-4-yl)-amine; 2-Methoxy-N-(1-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-ylethynyl}-cyclopropyl)-acetamide; E-N-(3-{4-[3-Chloro-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-allyl)-2-methoxy-acetamide; ...
20
[ 537705-05-8 ]
[ 537705-07-0 ]
[ 383432-38-0 ]
Yield
Reaction Conditions
Operation in experiment
59%
2-METHYL-2-BUTENE (0.59 ML, 5.60 MMOL, 2.8 EQUIV. ) WAS ADDED OVER 1 HOUR TO A COLD (0-5C) SOLUTION OF BH3*THF COMPLEX (1.0 M SOL, 3.0 ML, 3.0 MMOL, 1.5 EQUIV. ) KEPT UNDER N2. The reaction mixture was stirred at this temperature for 30 minutes followed by the addition of 2-METHOXY-ACETIC ACID PROPARGYLAMIDE (255 MG, 2 MMOL, 1.0 EQUIV. ) DISSOLVED IN DRY THF (1 ML) over 15 minutes. The ice-bath was removed and the reaction mixture was warmed to room temperature over 20 minutes. The reaction mixture was then heated at 35C for 1 hour. K2CO3 (0.55 G, 4 MMOL, 2.0 EQUIV. ) DISSOLVED IN DEGASSED H20 (1.2 ML) WAS ADDED OVER 30 minutes to the reaction mixture. During the addition of the first half gas evolution was observed which seized during further addition. 6-lodo- [3-methyl-4- (6-methyl-pyridine-3-yloxy)- PHENYLAMINO]-QUINAZOLINE (1.41 G, 3 MMOL, 1.5 EQUIV. ) WAS ADDED IN THREE PORTIONS GIVING A yellow suspension. PPH3 (21 mg, 0.08 mmol, 4 mol%) and Pd (OAc) 2 (4.5 mg, 0.02 MMOL, 1 mol%) were added each in one portion and the reaction mixture was heated to reflux (65- 68C). After about 30 minutes a yellow solution was obtained and the reaction was monitored by HPLC assay. After 18 hours the reaction mixture was cooled to room temperature followed by the addition of half-saturated NACI solution (10 ml) and EtOAc (10 ML). The organic phase was separated, washed with H2O (5 ML) and concentrated at 50C and a pressure of less than 200 mbar. Purification by plug filtration, Si02, EtOAc/MeOH = 9/1. The title compound was obtained as light yellow crystals (0.55 g, 59 %). Rf = 0.16 (EtOAc/MeOH = 9/1). H-NMR (CDCI3, 250 MHz): 8 =8.71 (s, 1 H, H-2), 8.25 (d, J=1.7 Hz, 1 H, H-8), 7.90 (s, 1 H, H-7), 7.82 (s, 1H, NH), 7.79 (s, 1H, H-5), 7.66 (d, J=2.5Hz, 1H, H-4"), 7.54 (dd, JE=8. 7Hz, J2=2. 6Hz, 1H, H- 5"), 7.15-7. 07 (m, 2H, H-5', H-6'), 6.91 (d, J=8.7Hz, 1 H, H-2'), 6.83 (bt, 1H, NH), 6.65 (d, J=15.9Hz, 1H, H-9), 6.34 and 6.29 (dt, JE=15. 9Hz, J2=6. 1HZ, 1H, H-10), 4.14 (dt, J=6. 1Hz, 2H, CHzOMe), 3.97 (s, 2H, CH2NH), 3.45 (s, 3H, OCH3), 2.53 (s, 3H, CH3), 2.29 (s, 3H, CH3). '3C-NMR (CDCI3, 75 MHz): 8= 169.76 (C=O), 157.90, 154.93, 152.367, 152.23, 150.90, 149.74, 139.34, 134.73, 134.63, 131.16, 130.77, 130.36, 128.85, 129.98, 125.47, 124.66, 123.65, 121.32, 119.51, 119.13, 115.39, 71.96, 59.26, 40.84, 23.57, 16.41. Using reverse phase high performance liquid chromatography tR (min) was found to be 6.02 for the title compound under the conditions shown in the following table. Symmetry Shield 75 x 4.6 mm RP18 Flow 1. 0 mL/min Wavelength 205/210/220/245 nm Temp. 25C Injection Volume 10 LL of a ca. 0.5% solution in ACN/H20 9/1 Eluent B ACN Eluent C 0.01 mmol NH40Ac in H2O pH = 6.0 Gradient 0 min B = 30%, C = 70 % Gradient 20 min B = 85%, C = 15 %
59%
Preparation of 2-methyl-2-butene (0.59 ml, 5.60 mmol, 2.8 equiv.) was added over 1 hour to a cold (0-5 C.) solution of BH3*THF complex (1.0 M sol, 3.0 ml, 3.0 mmol, 1.5 equiv.) kept under N2. The reaction mixture was stirred at this temperature for 30 minutes followed by the addition of 2-Methoxy-acetic acid propargylamide (255 mg, 2 mmol, 1.0 equiv.) dissolved in dry THF (1 ml) over 15 minutes. The ice-bath was removed and the reaction mixture was warmed to room temperature over 20 minutes. The reaction mixture was then heated at 35 C. for 1 hour. K2CO3 (0.55 g, 4 mmol, 2.0 equiv.) dissolved in degassed H2O (1.2 ml) was added over 30 minutes to the reaction mixture. During the addition of the first half gas evolution was observed which seized during further addition. 6-Iodo-[3-methyl-4-(6-methyl-pyridine-3-yloxy)-phenylamino]-quinazoline (1.41 g, 3 mmol, 1.5 equiv.) was added in three portions giving a yellow suspension. PPh3 (21 mg, 0.08 mmol, 4 mol %) and Pd(OAc)2 (4.5 mg, 0.02 mmol, 1 mol %) were added each in one portion and the reaction mixture was heated to reflux (65-68 C.). After about 30 minutes a yellow solution was obtained and the reaction was monitored by HPLC assay. After 18 hours the reaction mixture was cooled to room temperature followed by the addition of half-saturated NaCl solution (10 ml) and EtOAc (10 ml). The organic phase was separated, washed with H2O (5 ml) and concentrated at 50 C. and a pressure of less than 200 mbar. Purification by plug filtration, SiO2, EtOAc/MeOH=9/1. The title compound was obtained as light yellow crystals (0.55 g, 59%). Rf=0.16 (EtOAc/MeOH=9/1). 1H-NMR (CDCl3, 250 MHz): delta=8.71 (s, 1H, H-2), 8.25 (d, J=1.7 Hz, 1H, H-8), 7.90(s, 1H, H-7), 7.82 (s, 1H, NH), 7.79 (s, 1H, H-5), 7.66 (d, J=2.5 Hz, 1H, H-4), 7.54 (dd, J1=8.7 Hz, J2=2.6 Hz, 1H, H-5), 7.15-7.07 (m, 2H, H-5', H-6'), 6.91 (d, J=8.7 Hz, 1H, H-2'), 6.83 (bt, 1H, NH), 6.65 (d, J=15.9 Hz, 1H, H-9), 6.34 and 6.29 (dt, J1=15.9 Hz, J2=6.1 Hz, 1H, H-10), 4.14 (dt, J=6.1 Hz, 2H, CH2OMe), 3.97 (s, 2H, CH2NH), 3.45 (s, 3H, OCH3), 2.53 (s, 3H, CH3), 2.29 (s, 3H, CH3). 13C-NMR (CDCl3, 75 MHz): delta=169.76 (CO), 157.90, 154.93, 152.367, 152.23, 150.90, 149.74, 139.34, 134.73, 134.63, 131.16, 130.77, 130.36, 128.85, 129.98, 125.47, 124.66, 123.65, 121.32, 119.51, 119.13, 115.39, 71.96, 59.26, 40.84, 23.57, 16.41.