| 73.2% |
In tetrahydrofuran; at 65℃; for 6h; |
To 2L three-mouth bottle nepalese pulls the handkerchief for (II) compound added to the base solution, heating to 65 C, dropping the toluene sulfonic acid monohydrate (73g, 0.384mol) tetrahydrofuran (730 ml) solution, temperature control reaction 6h, cooling and filtering, 45 C drying results in the type crude product of compound (I) (145.2g).The crude product (145g,), tetrahydrofuran/water (7/3, volume ratio ) mixed solvent (1450 ml) add 2L in three-mouth bottle, the temperature rising to 65 C full dissolved, add 20g activated carbon, stirring 30 min, the heat filters, filtrate cooling crystallization, filtration, 45 C lapatinib toluene-P-sulfonic acid drying, the compound of formula (I) 130g, HPLC purity 99.50%, yield 73.2%. |
| 72% |
In methanol; water; N,N-dimethyl-formamide; at 20 - 67℃; for 1h;Heating / reflux;Product distribution / selectivity; |
Preparation of Anhydrate Form 2 by crystallization with seeding: Lapatinib (1.0 g) was heated to reflux in a mixture of methanol (32 ml) and dimethylformamide (8 ml) so that the solid dissolved. P-toluenesulfonic acid monohydrate (0.67 g) was added at this temperature (67C) and the heat source was removed. When the temperature had dropped to 62C, 2% w/w anhydrate Form 2 seed (0.032 g), prepared by methods similar to those of Example 1 , was added to the solution. Crystals began to precipitate rapidly and the suspension was allowed to cool to ambient temperature and stirred for a further 1 hour. The product was filtered and dried in the vacuum oven at 400C. Yield 1.15 g (72%) An infrared spectrum was run on the resulting solid and was found to be consistent with Anhydrate Form 2. |
| 60% |
In 1,4-dioxane; water; at 20℃; for 1h; |
Lapatinib free base (1.0 g) was heated in a mixture of 1 ,4-dioxane (36 ml) and water (4 ml) until the solid dissolved. P-toluenesulfonic acid monohydrate (0.66 g) was added at this temperature and the solution was allowed to cool. Crystals were precipitated and the suspension was stirred at ambient temperature for a further 1 hour. The product was filtered and dried in the vacuum oven at 60C for 24 hours. Yield 0.96 g (60%). An X-ray powder diffraction pattern and an infrared spectrum were obtained and are depicted in Figure 2(a) and Figure 2(b) respectively. |
| 33% |
In tetrahydrofuran; at 50℃; for 1h; |
50 mg of the starting material (synthesized in Example 5) was added5- (4- (3-chloro-4- (3-fluorobenzyloxy) phenylamino) -quinazolin-6-yl) furan-2-carbaldehyde hydrochlorideWas added to 1 ml of dichloromethane and N, N-diisopropylethylamine (25 mg, 2 eq) was added,Stirring to dissolve,And 2- (methylsulfonyl) ethylamine (24 mg, 2 eq) was added,The mixture was stirred at room temperature (18 C) until the starting reaction was completed,Evaporated to dryness under reduced pressure DCM (dichloromethane)And dissolved in 1 ml of tetrahydrofuran, and NaHB (OAc) 3 (124 mg, 6 eq) was added,Stirring at room temperature until the reaction of the raw material is completed,An aqueous Na2CO3 solution (1 ml, 5%) was added and extracted with ethyl acetate(1 ml x 2), the organic layers were combined, washed with saturated brine (1 ml x 1), the organic layer was dried,Evaporated to dryness to give 50 mg of a brown oil.50 mg of a brown oil was dissolved in 1 ml of THF,A solution of t-toluenesulfonic acid (33 mg, 2 eq) in THF (0.5 ml) was added dropwise to a temperature of 50 C,After stirring for 1 hour, the mixture was cooled to room temperature (15 C), filtered and the filter cake was washed with THF (1 ml x 2) and dried to give 49 mg of a yellow solid which was added to 1 ml of THF / H2O (4/1)Heated to 60 C to dissolve and clarify, and slowly lower the temperature to room temperature (15 C) after stirring for 1 hour,The temperature was further reduced to 0 C, stirred for 1 hour and then filtered. The filter cake was washed with THF (1 ml * 2)After drying in vacuo, 30 mg of a yellow solid was obtained. Yield: 33%, purity 99% |
|
at 25℃; for 16h;Neat (no solvent);Product distribution / selectivity; |
Example 1To 0.1 gr solid lapatinib base Form X sample, 0.065 gr of p-toluenesulfonic acid was added to obtain a yellow solid. The resulting dry solid was stirred over 16 h at 25 C. The cake thus obtained, identified as Form I of lapatinib ditosylate. |
|
In tetrahydrofuran; at 55℃; for 2.5h; |
5- (4- [3-chloro-4- (3-fluorobenzyloxy)-anilino]-6-quinazolinyl)-furan-2- carbaldehyde 4-methylbenzenesulfonate (1 wt) and 2- (methylsulfonyl) ethylamine hydrochloride (0.4 wt, 1.6equiv) were suspended in THF (10vol). Sequentially, acetic acid (0. 35vol, 4equiv) and di-isopropylethylamine (1. 08vol, 4equiv) were added. The resulting solution was stirred at 30-35C for ca 1 hour then cooled to ca 23C. Sodium triacetoxyborohydride (0.66wt, 2equiv) was then added as a continual charge over approximately 15 minutes (some effervescence is seen at this point). The resulting mixture was stirred at ca 22C for ca 2 hours then sampled for HPLC analysis. The reaction was quenched by addition of 5M aqueous sodium hydroxide (5vol) and stirred for ca 30 minutes (some effervescence is seen at the start of the caustic addition). The aqueous phase was then separated, extracted with THF (2vol) and the combined THF extracts were then washed with 10% w/v aqueous sodium chloride solution (4vol). A solution of p-toluenesulfonic acid monohydrate (pTSA, 1.77wt, 6equiv) in THF (7 vol) 1 was prepared and warmed to ca 55C. The THF solution of N- {3-Chloro-4- [ (3-fluorobenzyl) oxy] phenyl}-6- [5- ( { [2- (methanesul phonyl) ethyl] amino} methyl)- 2-furyl]-4-quinazolinamine was added to the pTSA solution over at least 30minutes, maintaining the batch temperature at ca 553C 2. The resulting suspension was stirred at ca 55C for 2 hours, cooled to 20-25C over ca 60 minutes and aged at this temperature for ca 30 minutes. The solid was collected by filtration, washed with THF (2 x 2vol) and dried in vacuo at ca 40C to give the desired compound as a pale yellow crystalline solid. |
|
In N,N-dimethyl-formamide; |
Example 24: preparation of lapatinib ditosylate.[000125] P-toluenesulfonic acid was added to a solution of lapatinib-base in 5 V dimethylformamide, 8.03 gr (2eq) to obtain a brownish solution. The solution was seeded with lapatinib ditosylate at 4O0C, then it was stirred for lhour, to obtain a yellow suspension. Then, it was cooled to O0C for 6 hours, and stirred for 10 hours. The resulting suspension was deep-cooled to -1O0C for 2 hours, and stirred for 2 hours. The precipitate was filtered to obtain lapatinib ditosylate. |
|
In methanol; acetonitrile;Heating / reflux; |
Lapatinib ditosylate anhydrate (form 1) and monohydrate were prepared according to methods similar to those disclosed in International Patent Application No. PCT/US01 /20706, filed June 28, 2001 , and published as WO 02/02552 on January 10, 2002,Single crystal of crystalline anhydrate form 1 was obtained by evaporating a drop of a solution of crystalline anhydrate form 1 in DMSO. Crystal structure data for lapatinib ditosylate anhydrate form 1 was collected on a Bruker Smart CCD 6000 X-ray diffractometerEmpirical formula C29H28CIFN4O4S 2C7H7O3SFormula weight 925.44 Temperature 120(2) KWavelength 0.71073 ACrystal system TriclinicSpace group P -1Unit cell dimensions a = 9.1440(3) A alpha= 95.9840(10). b = 13.2319(4) A beta= 90.8060(10). c = 18.1463(6) A gamma = 100.4050(10).Volume 2146.48(12) A3Z 2Density (calculated) 1.432 Mg/m3; Seed preparation: Lapatinib ditosylate anhydrate Form 1 (~ 0.15 g) (Prepared by the addition p-toluenesulfonic acid to a solution of the free base in a mixture of methanokacetonitrile, 7:3 (40 volumes) at reflux then cooled) However, any preparation of anhydrate form 1 is suitable, i.e. not restricted to using a mixture of methanokacetonitrile, was charged to a 10 ml grinding jar and methanol (0.03 ml) was added. The contents of the jar were ground for 30 minutes by an 8mm grinding ball at 30 Hz using a Retsch mixer mill. An infrared spectrum was run on the resulting solid and was found to be consistent with Anhydrate Form 2. |
|
In water; N,N-dimethyl-formamide; at 20℃; for 0.533333h;Product distribution / selectivity; |
A mixture of Lapatinib free base (1.0 g) and p-toluenesulfonic acid monohydrate (0.66 g) was stirred in dimethylformamide (2 ml) at ambient temperature. Initially the solids dissolved but in less than 2 minutes crystals were rapidly precipitated and amassed so that more dimethylformamide (2 ml) had to be added to mobilise. The suspension was stirred at <n="28"/>ambient temperature for 30 minutes then the product was filtered, washed with dimethylformamide (2 x 2 ml) and dried in the vacuum oven at 600C for 2 hours. An X-ray powder diffraction pattern and an infrared spectrum were obtained and are depicted in Figure 3(a) and Figure 3(b) respectively. |
|
In water; acetic acid; at 20℃; for 2h;Product distribution / selectivity; |
Alternative preparation of Lapatinib ditosylate Anhydrate Form 6: Lapatinib free base (1.0 g) was stirred in acetic acid (10 ml) at ambient temperature so that the solid dissolved. P-toluenesulfonic acid monohydrate (0.67 g) was added and crystals were precipitated in less than 2 minutes. The resulting suspension was stirred for 2 hours at ambient temperature then the solid was filtered, washed with acetic acid and dried under vacuum for 3 <n="29"/>hours. An X-ray powder diffraction pattern, an infrared spectrum, and NMR were obtained and the X-ray powder diffraction pattern and an infrared spectrum were different. The NMR was consistent but contained 11.4%w/w acetic acid. The sample was dried further in the vacuum oven at 600C for 24 hours. An X-ray powder diffraction, an infrared spectrum, and an NMR were obtained and were consistent with Form 6. |
|
In methanol; for 3h;Reflux; |
(vii) Preparation of N-{3-chloro-4-[(3-fluorobenzyloxy]phenyl}-6-[5-([2-methanesulphonyI)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine ditosylate salt (or) Lapatinib ditosylate (anhydrous) 1(b)Into a two liter four-necked round bottomed flask, 1500mL of methanol, 25 g of Lapatinib base, obtained from the previous step-(vi) were charged. The mass temperature was raised to 60-65C to dissolve the solid completely, and then cooled to 45-50C and 18 g of p-toluenesulphonicacid monohydrate dissolved in 50 mL of methanol was added. The reaction mass was maintained at reflux condition for 3 hrs, cooled to 25-35C and filtered. The product was dried under vacuum at 75-80 C to get 35 g(88% of theory) of Lapatinib ditosylate salt as an yellow crystalline solid. Melting range: 237-239 CPurity: 99.8% by HPLC |
|
at 20℃; for 5h;Reflux; |
Example 4: Synthesis of N-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-6-(5-((2- (methylsulfonyl)ethylamino)methyl)furan-2-yl)quinazolin-4-amine ditosylate (lapatinib ditosylate)ITo a suspension of 2-(methylsulfonyl)ethanamine hydrochloride (SM4.HC1; 12.2 g, 76.7 mmol) in THF (600 mL) was added acetic acid (14.1 g, 235 mmol) followed by DIPEA (30.3 g, 235 mmol) were added. After stirred at ambient temperature for 0.5 h, ¾0 (4.2 g, 233 mmol) and IM3.HC1 (30.0 g, HPLC assay >99%, 58.7 mmol) were added. After being stirred at ambient temperature (20C) for 4 h, sodium triacetoxyborohydride (37.4 g, 176 mmol) was added and the mixture was stirred at ambient temperature (20C+/-5C; external temperature) until HPLC showed the completion of the reaction. A 10% aqueous solution of sodium hydroxide (90 mL) was added and the mixture was stirred for 30 min. The organic phase was washed with 25% aqueous NH4C1 (60 mL), filtered, treated with -TsOH (40.4 g, 135 mmol) and heated to reflux for 2 h. The mixture was cooled to ambient temperature and stirred for 3 h at ambient temperature. The mixture was filtered, and the filter cake was washed twice with THF (120 mL each) and was then dried under vacuum at 70+/-5C for 6 h to give 43 g (46.5 mmol) lapatinib ditosylate with 99.4% HPLC purity.Lapatinib ditosylate [H NMR (300 MHz, d6-DMSO): delta 11.41(s, 2H), 9.33 (s, 3H), 9.04 (d, / = 1.3 Hz, 2H), 8.93 (s, 2H), 8.41 (dd, J =8.8, 1.6 Hz, 2H), 7.91 (d, J = 2.6 Hz, 2H), 7.54-7.41 (m, 9H), 7.37 - 7.27 (m, 6H), 7.25 (d, / = 3.4 Hz, 2H), 7.22 - 7.13 (m, 2H), 7.08 (dd, / = 8.4, 0.6 Hz, 8H), 6.87 ( d, / = 3.5 Hz, 2H), 5.29 (s, 4H), 4.46 (s, 4H), 3.65 - 3.51 (m, 4H), 3.51 - 3.38 (m, 4H), 2.26 (s, 12H).A solution of lapatinib ditosylate was converted to its free base form, lapatinib, by washing a solution with aqueous NaOH followed by concentration. Lapatinib: XH NMR (300 MHz, d6-DMSO): delta 2.98 (t, / = 6.75 Hz, 1H), 3.04 (s, 1H), 3.29 (t, J = 6.6 Hz, 1H), 3.83 (s, 1H), 5.28 (s, 1H), 6.50 (d, / = 3.0 Hz, 1H), 7.08 (d, / = 3.3 Hz, 1H), 7.20 (m, 1H), 7.33 (m, 4H), 7.48 (m, 1H), 7.76 (m, 1H), 7.80 (d, 7 = 9 Hz, 1H), 8.04 (d, 7 = 2.75 Hz, 1H), 8.17 (dd, / = 8.7 Hz, / = 1.8 Hz, 1H), 8.56 (s, 1H), 8.75 (d, J = 1.8 Hz, 1H). |
|
In isopropyl alcohol; at 25 - 82℃;Product distribution / selectivity; |
A mixture of Lapatinib base (2 g) and isopropyl alcohol (18 mL) were heated to 70-75C. Seeds of Lapatinib ditosylate form APO-I (0.1 g) were added, followed by p-toluenesulfonic acid monohydrate (1.37 g, 2.1 eq.), and rinsed with isopropanol (2 mL). The suspension was heated to 80-82C for IS about 4 h. The mixture was cooled down slowly to 25-30C, filtered, washed with isopropanol (5 mL) and suction dried to provide Lapatinib ditosylate isopropanol solvate (APO-II). The APO-II product obtained was subjected to PXRD analysis. The results of the PXRD analysis were substantially similar to those shown in Figure 3.Lapatinib ditosylate isopropanol solvate from above was dried in vacuo at 45-50C for about 1 day to provide 3.0 g of Lapatinib ditosylate form APO-I. The APO-I product formed was subjected to PXRD analysis. The results of the PXRD analysis were substantially similar to those shown in Figure 1. |
|
In Isopropyl acetate; at 65 - 70℃; for 1h;Product distribution / selectivity; |
Example 9:Preparation of anhydrous form of lapatinib ditosylateLapatinib (63 gm) was dissolved in isopropyl acetate (1575 ml) at 25 to 30C.The contents were heated to reflux and then added p-toluenesulfonic acid (44 gm). The reaction mass was stirred for 1 hour at 65 to 70C and then cooled to 25 to 30C. The reaction mass was stirred for 1 hour at 25 to 30C and filtered. The solid obtained was dried under vacuum at 50 to 55C for 7 hours to obtain 75 gm of anhydrous form of lapatinib ditosylate. |
| 37.0 g |
In N,N-dimethyl-formamide; at 35 - 40℃; for 1h;Inert atmosphere; |
Example 7 Preparation of Lapatinib Ditosylate According to the Preferred Aspects of the Invention Synthetic Scheme Into a glass flask fitted with a condenser, thermometer, mechanical stirrer, addition funnel and nitrogen inlet are loaded (under an atmosphere of nitrogen) 25 g (1 equiv.) of 2,2,2-trifluoro-N-[5-(4-hydroxyquinazolin-6-yl) furan-2-yl]methyl}-N-[2-(methylsulphonyl)ethyl]acetamide of formula (IV, R=CF3(CO) and 250 mL (10 V) of dioxane. 17.3 g equal to 10.5 mL (2 equiv.) of phosphorus oxychloride (MW=153.33; d=1.645 g/mL) are added with caution at a temperature of 20-25 C. 11.4 g equal to 15.7 mL (2 equiv.) of triethylamine (MW=101.19; d=0.726 g/mL) are added with caution at a temperature of 20-25 C. On completion of addition, the mixture is allowed to return to room temperature and then stirred at 95-100 C. (reflux) for 1 h. The conversion is monitored by HPLC. If the reaction has gone to completion, the reaction mixture is evaporated to residue in a rotavapor at a max. temperature of 40 C. The residue is then taken up with 250 mL (10 V) of dioxane and evaporated to residue. The residue contains N-[5-(4-chloroquinazolin-6-yl)furan-2-yl]methyl}-2,2,2-trifluoro-N-[2-(methylsulphonyl)ethyl]acetamide of formula (V; R=CF3(CO), X=Cl). This is then taken up with 200 mL (8 V) of Dioxane. The preparation is heated to 55-60 C. and over a time of approx. 15 min., a solution of 14.2 g (1.0 equiv.) of 3-chloro-4-[(3-fluorobenzyl)oxy]aniline of formula (VI) (MW=251.68) dissolved in 50 mL (2 V) of dioxane added. The mixture is heated to 55-60 C. and stirred for 1 hour. The conversion is monitored by HPLC. If the reaction has gone to completion, a solution is prepared with 47 g (6 equiv.) of potassium carbonate (MW=138.21) in 250 mL (10 V) of purified water. The potassium carbonate solution is added to the reaction mixture at T=55-60 C. The reaction mixture is heated to 80-85 C. and stirred for 2 h. The conversion is monitored by HPLC. If the reaction has gone to completion, it is cooled to 20-25 C. The pH is adjusted to >12 using the required quantity of 30% sodium hydroxide. The phases are separated. The aqueous phase is extracted with 250 mL (10 V) of Isopropyl acetate. The organic phase is separated and combined with the previously separated organic phase. The combined organic phases are washed with 125 mL (5 V) of a 10% sodium chloride solution. The combined organic phases are evaporated to residue in a rotavapor at a max. temperature of 40 C. 125 mL (5 V) of DMF (dimethylformamide) are added to the residue. The preparation is heated to 35-40 C. and 22.5 g (2.1 equiv.) of p-toluenesulphonic acid monohydrate (MW=190.22) added. The preparation is stirred for 1 h at 35-40 C. then cooled to 20-25 C. It is preferable that crystallization be initiated with 250 mg (1% wt.) of Lapatinib ditosylate. On achieving precipitation, the preparation is cooled to 0-5 C. and stirred for at least 1 h. The preparation is cooled to -15/-10 C. and stirred for 2 h. The panel is filtered and washed with 12.5 mL (0.5 V) of DMF chilled to -10/-5 C. The wet product is removed and taken up with 125 mL (5 V) of DMF. The preparation is heated to 40-45 C. and stirred at said T for 1 h. The preparation is cooled spontaneously to 20-25 C. and stirred for 1 h. The preparation is cooled to 20-25 C. and stirred for 1 h. The preparation is cooled to 0-5 C. and stirred for 1 hour. The preparation is cooled to -15/-10 C. and stirred for 2 h. The preparation is filtered washing the solid with 2*12.5 mL (2*0.5 V) of DMF pre-chilled to -15/-10 C. The solid is dried at 70 C. under vacuum for at least 10 hours. 37.0 g of lapatinib ditosylate are obtained, corresponding to an overall molar yield of 71%. HPLC purity A/A % 99.9%. |
|
In tetrahydrofuran; water; at 20 - 60℃; for 3.5h; |
Compound F (1 wt) and 2- (methylsulfonyl)ethylamine (0.4 wt, 1.62 equiv. ) were suspended in THF (10 vols). Sequentially, acetic acid (0.354 vol., 4 equiv. ) and di-isopropylethylamine (DIPEA, 1.08 vol. , 4.01 equiv. ) were added. The resulting solution was stirred at 30-35C for ca 1 hour then cooled to ca 22C. Sodium tri-acetoxyborohydride (0.66 wt, 2.01 equiv. ) was then added as a continual charge over approximately 15 minutes (some effervescence is seen at this point). The resulting mixture was stirred at ca 22C for ca 2 hours then sampled for HPLC analysis. The reaction was quenched by addition of aqueous sodium hydroxide (25% w/w, 3 vols. ) followed by water (2 vols. ) and stirred for ca 30 minutes (some effervescence was seen at the start of the caustic addition). The aqueous phase was then separated, extracted with THF (2 vols) and the combined THF extracts were then washed twice with 25% w/v aqueous ammonium chloride solution (2 x 5 VOIS)2 . A solution of p-toluenesulfonic acid monohydrate (p- TSA, 0.74 wt, 2.5 equiv. ) in water (1 vol) ¹ was prepared, warmed to ca 60C, and GW572016F (Compound G) (0.002 wt) seeds were added. The THF solution of the free base of GW572016 was added to the p-TSA solution over at least 30 minutes, while maintaining the batch temperature at 60No.3C. The resulting suspension was stirred at ca 60C for 1-2 hours, cooled to 20-25C over an hour and aged at this temperature for ca 1hr. The solid was collected by filtration, washed with 95: 5 THF: Water (3 x 2 vols) and dried in vacuo at ca 35C to give GW572016F - compound G as a bright yellow crystalline solid. |
|
In tetrahydrofuran; water; at 60℃; for 2.5h; |
The aqueous phase was then separated, extracted with THF (2 vols) and the combined THF extracts were then washed twice with 25% w/v aqueous ammonium chloride solution (2 x 5 vols) (at). A solution of p-toluenesulfonic acid monohydrate (p- TSA, 0.74 wt, 2.5 equiv. ) in water (1 vol) ¹ was prepared, warmed to ca 60C, and GW572016F (Compound G) (0.002 wt) seeds were added. The THF solution of the free base of GW572016 was added to the p-TSA solution over at least 30 minutes, while maintaining the batch temperature at 60No.3C. The resulting suspension was stirred at ca 60C for 1-2 hours, cooled to 20-25C over an hour and aged at this temperature for ca 1hr. The solid was collected by filtration, washed with 95: 5 THF: Water (3 x 2 vols) and dried in vacuo at ca 35C to give GW572016F - compound G as a bright yellow crystalline solid. Expected yield 80% theory, 117% w/w. |
|
In tetrahydrofuran; water; at 20 - 63℃; for 3 - 4h; |
A solution of p-toluenesulfonic acid monohydrate (pTSA, 1.77wt, thetaequiv) in THF (7 vol)1 was prepared and warmed to ca 55C. The THF solution of N- {3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-([2-(methanesulphonyl) ethyl] amino}methyl)- 2-furyl]-4-quinazolinamine was added to the pTSA solution over at least 30minut.es, maintaining the batch temperature at ca 55+/-3C 2. The resulting suspension was stirred at ca 55C for 2 hours, cooled to 20-25C over ca 60 minutes and aged at this temperature for ca 30 minutes. The solid was collected by <n="45"/>filtration, washed with THF (2 x 2vol) and dried in vacuo at ca 400C to give the desired compound as a pale yellow crystalline solid.; A solution of p-toluenesulfonic acid monohydrate (p-TSA, 0.74 wt, 2.5 equiv.) in water (1 vol) is prepared, warmed to ca. 600C, and lambda/-(3-chloro-4-[(3-fluorophenyl)methyl]oxy}phenyl)-6-[5-([2- (methylsulfonyl)ethyl]amino}methyl)-2-furanyl]-4-quinazolinamine 4- methylbenzenesulfonate hydrate seeds are added. The THF solution of the free base is added to the p-TSA solution over at least 1 hr, maintaining the batch temperature at 60+/-3C. The resulting suspension is stirred at ca. 600C for 1-2 hours, cooled to 20-250C over an hour and aged at this temperature for ca. 1 hr. The solid is collected by filtration, washed with 95:5 THF: Water (3 x 2 vols) and dried in vacuum at ca. 35C to give lambda/-(3-chloro-4-[(3-fluorophenyl)methyl]oxy}phenyl)-6-[5-([2- (methylsulfonyl)ethyl]amino}methyl)-2-furanyl]-4-quinazolinamine 4- methylbenzenesulfonate hydrate as a bright yellow crystalline solid. |
|
In tetrahydrofuran; at 20 - 55℃; for 4h; |
The aqueous phase was then separated, extracted with THF (2vol) and the combined THF extracts were then washed with 10%w/v aqueous sodium chloride solution (4vol). A solution of p-toluenesulfonic acid monohydrate (pTSA, 1.77wt, 6equiv) in THF (7 vol) (at) was prepared and warmed to ca 55C. The THF solution of N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl)-6-[5-([2- (methanesulphonyl) ethyl] amino}methyl)- 2-furyl] -4-quinazolinamine was added to the pTSA solution over at least 30minutes, maintaining the batch temperature at ca 55No.3C 2. The resulting suspension was stirred at ca 55C for 2 hours, cooled to 20-25C over ca 60 minutes and aged at this temperature for ca 30 minutes. The solid was collected by filtration, washed with THF (2 x 2vol) and dried in vacuo at ca 40C to give the desired compound as a pale yellow crystalline solid. |
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