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Chemical Structure| 183321-74-6
Chemical Structure| 183321-74-6
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Product Details of [ 183321-74-6 ]

CAS No. :183321-74-6 MDL No. :MFCD08063588
Formula : C22H23N3O4 Boiling Point : -
Linear Structure Formula :- InChI Key :-
M.W : 393.44 Pubchem ID :-
Synonyms :
CP-358774;NSC 718781;OSI-774
Chemical Name :4-[(3-Ethynylphenyl)amino]-6,7-bis(2-methoxyethoxy)quinazoline

Safety of [ 183321-74-6 ]

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 [ 183321-74-6 ]

* 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.

  • Downstream synthetic route of [ 183321-74-6 ]

[ 183321-74-6 ] Synthesis Path-Downstream   1~96

  • 1
  • [ 1011525-96-4 ]
  • [ 950596-58-4 ]
  • [ 183321-74-6 ]
YieldReaction ConditionsOperation in experiment
With acetic acid; In toluene; for 4h;Heating / reflux; (f) Erlotinib free base:; To 2-amio-4,5-bis(2-methoxyethoxy)benzonitrile (4.57g, 0.0172moles) was added toluene (30ml), N'-(3-ethynylphenyl) N,N-dimethyl formamidine (3.44g, 0.0172moles) and acetic acid (0.5ml) refluxed the reaction mixture for about 4hrs cooled the reaction mass to room temperature, toluene layer was separated washed with water and chilled toluene layer to yield crude erlotinib and which was further recrystallized from a polar solvent such as methanol to get pure off- white crystalline compound(3g) having mp 149-153 0C.
  • 2
  • [ 183321-74-6 ]
  • [ 183319-69-9 ]
YieldReaction ConditionsOperation in experiment
100% With hydrogenchloride; In isopropyl alcohol; at 0℃; for 1h;Inert atmosphere;Product distribution / selectivity; Example 1 : Erlotinib free base (180 g) containing 15% w/w isopropyl alcohol (IPA) was charged into a three necked flask under nitrogen and cooled to O0C. The solid was exposed to hydrogen chloride gas for about 1 hour to form the hydrochloride salt with stirring. The erlotinib hydrochloride was then dried at 2O0C to 250C in a vacuum oven. The yield was quantitative. 1H NMR (DMSO-d6): £3.36 (s, 6H), 3.79 (m, 4H), 4.28 (s, 1 H), 4.31 (t, J = 4.6 Hz, 2H),4.41 (t, J = 4.8 Hz, 2H), 7.39-7.43 (m, 2H), 7.48 (t, J = 7.9 Hz, IH), 7.82 (d, J = 8.4 Hz, 1 H), 7.90 (s, 1 H), 8.51 (s, 1 H), 8.83 (s, 1 H), 1 1.68 (s, 1 H).
99% With hydrogenchloride; In ethanol; water; at 72℃; for 0.333333h; In a dry and clean 250 mL four-necked flask, add 0.5 g of erlotinib free base and 60 mL of ethanol to stir to a temperature of 72 ± 3 C. After dissolving the solid, slowly add 15 mL of 0. 0% Hydrochloric acid solution, dripping in 20min, after the completion of the drop, holding 45min, after the completion of insulation, slow down to 3 ± 3 C in 2h, filter, rinse with 5mL of ethanol, wet at 30 C Vacuum drying in a vacuum oven for 6 h gave the product, 51.4 g, yield: 99%
98.7% With hydrogenchloride; In water; acetone; at 10℃; for 2.5h; Weigh erlotinib (6.50g, 0.017mol) into acetone (195mL), cool to 10 C, add concentrated hydrochloric acid (1.65mL, 0.0204mol, 1.2eq) with stirring, add after 3 minutes, stir the reaction 2.5 hours, filtered,The obtained solid was vacuum dried at 10 to 30 C to obtain 7.01 g of erlotinib hydrochloride crystal form.The molar yield was 98.7%, and the crystal form A was determined by XRPD.
97.5% With hydrogenchloride; In 1,3-DIOXOLANE; water; at 0 - 75℃; for 1.16667h;Product distribution / selectivity; Erlotinib base (waterless, 2.00 g, 5.083 mmole) was dissolved in water-1, 3-dioxolane mixture (80 ml). The content of water was adjusted at 2 -3% v/v. Temperature of the solution was adjusted at certain value - it may range from 00C to 75C. 414 mul (mole/mole) of concentrated hydrochloric acid(44.1%w/v)(concentration determined by titrations) was added slowly (during 10 min) into solution. Solid phase was created immediately. The crystalline suspension was agitated for 1 hr while keeping the selected temperature and then cooled to 0C. The crystalline phase was separated by filtration, rinsed with 2%water-l, 3-dioxolane mixture (40 ml) and dried on the filter by blowing nitrogen through the cake to the constant weight. The drying was finished in a small laboratory oven under nitrogen ventilation at 40C for 3 hrs. Erlotinib hydrochloride Form A was obtained (molar yield about 95 %).; Example 3: Preparation of crystalline Erlotinib HCl Form A with improved filterability[0074] Erlotinib base (waterless, 2.00 g, 5.083 mmole) was dissolved in water-1, 3-dioxolane mixture (80 ml). The content of water was adjusted at 2 % v/v. Temperature of the solution was set up to 60C. 414 mul (mole/mole) of concentrated hydrochloric acid (44.1 % w/v) was added slowly (during 10 min) into solution. Solid phase was created immediately. The crystalline suspension was agitated for 1 hr while keeping the selected temperature (600C) and then cooled to 40C. The suspension was agitated for 24 hrs while keeping the temperature at 40C. After carrying out granulation the crystalline phase was separated by filtration, rinsed with 2%water-l,3- dioxolane mixture (40 ml) and dried on the filter by blowing nitrogen through the cake to the constant weight. The drying was finished in small laboratory oven under nitrogen ventilation at 40C for 3 hrs.Erlotinib hydrochloride Form A was obtained (2.13 g, yield 97.5 %). The filtration parameters of suspension: a = 26 122 sm~2 <n="15"/>b = 27 sm"1 (parameters are valid for overpressure 100 kPa, measured at comparable conditions )
97.6% With hydrogenchloride; In water; acetone;Autoclave; Heating; Large scale; At room temperature, 3500 g of erlotinib type I crystal, 175 L of acetone and 17.5 L of purified water were added to the autoclave, and the mixture was stirred and the bath was heated to completely dissolve erlotinib. A solution of 133.5 mol of hydrogen chloride gas was slowly introduced into the solution.Pass, with a cold water bath so that the reaction system slow down, precipitate a large number of solid, and then ice water cooling, to the reaction system is no longer precipitation of solid. Centrifuged, dried under reduced pressure, the finished product 3729g, the yield of 97.6%, HPLC content of 99.2%
95% With hydrogenchloride; In water; 4-methyl-2-pentanone; at 55 - 60℃;Product distribution / selectivity; Example 4Conversion of Erlotinib Base Form G2 to Erlotinib Hydrochloride; ERL-Base form G2 obtained from ex. 3 (11.5 g, corresponding to 0.025 mol and to 10 g 100% assay) was suspended in methylisobutylketone (?MIBK?) (200 mL) and H2O (50 mL), the resulting mixture was heated at 65-70 C. until a clear solution was obtained. The phases were separated and the organic layer was additionally three times washed with H2O (3×50 mL) at 65-70. The organic phase was concentrated until about 6 volumes of solvent were removed and the starting mixture volume was restored by addition of fresh MIBK. In Process Control: Karl Fisher0.4%. The mixture was heated to 55-60 C. under stirring (about 300 RPM) and 32-37% HCl (2.8 g; 0.028 mol was added causing the immediate precipitation of the hydrochloride salt. The mixture was cooled to 20-25 C. in about 1 h, and then it was kept at the same temperature for 1 h. The suspension was filtered and the solid was washed with i-PrOH (5 mL). The wet solid was dried under vacuum at 45-50 C. for 15-18 h to give ERL-HCl as a white solid (10.4 g; 0.024 mol). The yield was 95%.
95% With hydrogenchloride; In 1,3-DIOXOLANE; water; at 60℃; for 1h;Product distribution / selectivity; Erlotinib base (3g) was added to a mixture of dioxolane (78.4mL) and water (1.6mL) and the temperature of the solution was adjusted to 60C. At this temperature cone. HCl (7.63mmol) was added. Precipitation occurred immediately. The suspension was stirred for 1 h at 60C, then cooled to 0C. The solid was filtered off and dried at 110C under N2 ventilation for 4h. Crystalline Form A of ERLHCl was obtained with 95% yield
94.9% With hydrogenchloride; In water; acetonitrile; at 20℃; for 4h; EXAMPLE 32 Preparation of Stable Polymorphic Form of Erlotinib Hydrochloride [0139] Into a reaction vessel, added ERL-3 (1.0 gm, 2.54 mmol) and 35 ml acetonitrile under stirring. Stirred the RM at room temperature for 30 min. to make it clear solution. Clarified the solution by filtration. Added 0.3 ml conc. HCl and 5 ml acetonitrile dropwise in the filtrate and stirred the suspension for 4 H at room temperature. Filtered, dried at 85 C., under 2 mbar vacuum for 4 H to get 1.037 gm stable polymorphic form of Erlotinib hydrochloride (Yield=94.9%, Purity=99.01%, Assay=98.80%; XRD as in FIG. 1).
94% With hydrogenchloride; In isopropyl alcohol; at 20℃; for 2h; N-(3-Ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine hydrochloride (erlotinib hydrochloride)The obtained raw base of erlotinib (I) (19.7 g, 0.05 mol) dissloved in i-PrOH (200 ml) and saturated HC1 solution in i-PrOH (10 ml) was added with intensive stirring. The obtained suspension is stirred at room temperature for 2 h, the light-yellow precipitate filtered off, washed with i-PrOH (3 x 50 ml), dried in vacuum at room temperatureand recrystallized from MeOH (100 ml), obtaining erlotinib hydrochloride with >99% purity. Yield 20.3 g (94%).
93.86% With hydrogenchloride; In isopropyl alcohol; acetonitrile; at 70 - 75℃;Product distribution / selectivity; Example 9Preparation of Erlotinib MonohydrochlorideInto a 500 ml four necked round-bottomed flask equipped with a mechanical stirrer, reflux condenser and thermometer socket, are charged Acetonitrile (200 ml), Erlotinib base (10 g) and raised the temperature to 70-75 C. to get a clear solution. Activated carbon (2 g) was charged and maintained for 15-20 minutes. Filtered the reaction mass and washed the carbon cake with hot Acetonitrile. To the combined filtrate and washings were added isopropyl alcohol-HCl (1.1 molar equivalents) slowly added in about 10-15 minutes. Raised the temperature to 70-75 C. and maintained for 1 hour. Cooled the reaction mass to 25-30 C. and filtered the product and washed the cake with Acetonitrile and dried to get 10.25 g (93.86% by theory) of Erlotinib monohydrochloride as a white solid.Purity: 99.83% (by HPLC)
91.5% With hydrogenchloride; In pentan-1-ol; at 5 - 10℃; for 1h;Product distribution / selectivity; Example 4: Alternative preparation of erlotinib hydrochloride polymorph form A In a 2.0 litre, 4 neck, round bottom flask equipped with a mechanical stirrer, a thermometer pocket and a reflux condenser, 420 ml of 1-pentanol (16.8 volumes with respect to erlotinib base) and 25 g (0.0635 mol) of N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4- qumazoHnamine (erlotinib base) was charged at 25-30C under stirring. The reaction mixture was then cooled to 20-25C to obtain a suspension. 30 ml of 1-pentanol-HCl solution (prepared by scrubbing HC1 gas into 1-pentanol to a concentration by assay of 16- 18% (w/w)) was added drop wise over a period of 15 minutes at a temperature of 20-25C. The reaction mixture was stirred for a further 1 hotir, The product was isolated by filti-ation, washed with 25 ml of 1-pentanol, and dried under reduced pressure (50 mm Hg) at 50-55C, to give 25 g of erlotinib hydrochloride polymorph A (loss on drying < 0.5%).Molar yield s 91.5%HPLC purity >99.8%No polymorphic form B or any other polymorphic form could be detected in the product by XRPD. (Limit of detection 0.2% (w/w); limit of quantification 0.4% (w/w)). It will be understood that the present invention has been described above by way of example only. The examples are not intended to limit the scope of the invention. Various modifications and embodiments can be made without departing from the scope and spirit of the invention, which is defined by the following claims only.
91% With hydrogenchloride; In methanol; dichloromethane; water; at 25℃; for 3h; The crude Erlotinib HCl (21.5 g, 50 mmol) Into a round bottom flask, add anhydrous methanol 215mL, anhydrous sodium carbonate solid 10.6g, heated to 50 stirring 3 hours, cooled to room temperature, add distilled water 450mL, precipitation of large amounts of white solid, stirring for 1 hour, White solid (identified asN- (3-ethynylphenyl) -6,7-bis (2-methoxyethoxy) -4-quinazolinium amine)The resulting solid was added to a round bottom flask, 150 mL of anhydrous methanol and 50 mL of dichloromethane were added, and 10 mL of 12 mol / L hydrochloric acid was added dropwise at 25 C. The mixture was stirred for 3 hours to precipitate a large amount of white solid. The filter cake was washed with a small amount of dichloromethane Washed, dried with erlotinibine hydrochloride. Yield 91%,
61% With hydrogenchloride; In 1,3-DIOXOLANE; water; at 60℃; for 1h;Product distribution / selectivity; Erlotinib base (500mg) was added to a mixture of 1 , 3-dioxolane (18mL) and water (2mL) and the temperature of the solution was adjusted to 60C. At this temperature cone. HCl (1.27mmol) was added. Precipitation occurred immediately. The suspension was stirred for 1 h at 60C, and then cooled to 00C. The solid was filtered off and dried under nitrogen stream at room temperature. Crystalline Form B of Erlotinib hydrochloride was obtained with 61% yield
With hydrogenchloride; In methanol; for 0.5h; (g) [^1 7-bis-(2-methoxyethoxy)-quinazolin-4-y.]-(3-ethynylphenyl) amine hydrochloride (Erlotinib hydrochloride):; To a stirred solution of Erlotinib free base (6g) in methanol (50ml) was passed dry hydrochloric acid stirred the reaction mass for about 1/2hr the solid <n="13"/>precipitated was filtered to get the white crystalline material of erlotinib hydrochloride (6g) having the mp 228-230 0C
With hydrogenchloride; In methanol; for 0.5h; (g) [6,7-bis-(2-methoxyethoxy)-quinazolin-4-yl]-(3-ethynylphenyl) amine hydrochloride (Erlotinib hydrochloride):; To a stirred solution of Erlotinib (6g) in methanol (50ml) was passed dry hydrochloric acid stirred the reaction mass for about 1/2hr the solid precipitated was filtered to get the white crystalline material of erlotinib hydrochloride (6g) having the mp 228-230 0C
With hydrogenchloride; In methanol; isopropyl alcohol; at 30 - 35℃; for 1.5h; Example-1; Preparation of Erlotinib HCI polymorphic form-M :Into a 2 Lt. four necked round-bottomed flask provided with a mechanical stirrer, thermometer socket, reflux condenser etc are charged 1340 mL of methanol, followed by Erlotinib base 60 g. (Prepared according to the process given in Example-(l) of PCT international publication No. WO2007/060691). The reaction mass is warmed to around 40C so that Erlotinib base completely dissolves. To this reaction mass, carbon treatment is given and the filtrate is transferred to another 2 Lt. four necked flask. To this solution isopropanolic HCl (HCl content as 100% is 6.12g) is added in one lot and the reaction mass is stirred at 30-35C for about 90 minutes and filtered. The product is washed with fresh methanol and dried the wet cake to get 55.2 g of Erlotinib hydrochloride as a white crystalline powder. XRPD: Form-M (Fig-1)
With hydrogenchloride; In isopropyl alcohol; at 60 - 65℃; for 1h; ExampIe-2; Preparation of Erlotinib HCl polymorphic form-N :Into a 1 Lt. four necked round-bottomed flask provided with a mechanical stirrer, thermometer socket, reflux condenser etc, are charged 325 mL of isopropyl alcohol, followed by 25.0 g of Erlotinib base (Prepared according to the process given in Examrhole-(l) of PCT international publication No. WO2007/060691) at 70-75C so that Erlotinib base completely dissolves in the solvent. Then carbon treatment is given and the filtrate is transferred to another 1 Lt. four-necked round bottomed flask provided with all the necessary accessories. To this solution isoproponolic HCl (HCl content as 100% is 2.548 g) is added in one lot at 60-65C and maintained at this temperature for about 1 hour. The reaction mass is cooled to room temperature and filtered. The product is washed with fresh isopropyl alcohol and dried to get 25.0 g of Erlotinib hydrochloride as a white crystalline powder. XRPD: Form-N (Fig-2)
With hydrogenchloride; In dichloromethane; isopropyl alcohol; at 25 - 35℃; for 3h;Heating / reflux;Product distribution / selectivity; Example-3; Preparation of Erlotinib HCl polymorphic form-P :Into a 3 Lt. four necked round-bottomed flask provided with a mechanical stirrer, thermometer socket, reflux condenser etc, are charged 2400 mL of methylene chloride, followed by 120 g of Erlotinib base (Prepared according to the process given in Example-(l) of PCT international publication No. WO2007/060691) under stirring. The reaction mass is slightly warmed up to 37+/-1C, so that the Erlotinib base completely dissolves in the solvent. Then carbon treatment is given and the filtrate is transferred to 5 Lt three necked round bottomed flask, provided with a mechanical stirrer and other accessories. To this filtrate, Isopronolic HCl. (HCl content as 100% is 13.90 g) is added in one lot at 30-35C and then the reaction mass is refiuxed for about 3 hrs. Afterwards, the reaction mass is cooled to room temperature and filtered. The product is washed with methylene chloride and the wet cake is dried to get 119 g of Erlotinib hydrochloride as a white crystalline powder. XRPD: Form-P (Fig-3) (iii) Preparation of Erlotinib Hydrochloride, Polymorphic form-P.Into a clean and dry All Glass Reactor, are charged 110 Lts of methylene chloride, followed by 5.5 Kgs of Erlotinib base as obtained from step-(ii) above. The temperature is raised to 37+/-1C so that the solid completely dissolves. To this carbon treatment is given and the filtrate is transferred into another clean and dry All glass reactor. To this reaction mass isoproponolic HCl (HCl content as 100% is 0.6371 Kg) is added in one lot at 25-350C and then the reaction is maintained at reflux condition for 3 hrs. The reaction mass is cooled to room temperature and centrifused. The product cake is washed with methylene chloride and dried to get 5.5 Kgs of Erlotinib hydrochloride as a white crystalline powder.Purity : 99.82% (by HPLC) XRPD : Form-P (identical to Fig-3)
With hydrogenchloride; In water; for 2h;pH 1.0 - 2.0;Product distribution / selectivity; 5 g of 4-chloro-6,7-bis(2-methoxyethoxy) quinazoline was suspended in 150 ml denatured spirit (SPDS) and 4.6 g of 3-aminophenyl acetylene was charged at 25 - 300C. Further 1.0 ml of methane sulphonic acid was added. The reaction mass was stirred at 25 - 300C for 3 hours. Solid obtained was filtered, washed with SPDS and dried under vacuum. This solid was suspended in water, basified with ammonia and stirred for 10 minutes. The resulting erlotinib base was isolated, washed with water and dried under vacuum. The base was suspended in water and acidified to pH 1.0 - 2.0 using hydrochloric acid. The reaction mixture was stirred for 2 hours, filtered, washed with water and dried at 40 - 450C to obtain 5.8 g of erlotinib hydrochloride.
With hydrogenchloride; In water; for 2h;pH 1.0 - 2.0;Product distribution / selectivity; 10.0 g of 4-chloro-6,7-bis(2-methoxyethoxy) quinazoline was suspended in 300 ml methanol and 9.2 g of 3-aminophenyl acetylene was charged at 25 - 300C. Further 2.0 ml of benzoic acid was added. The reaction mass was stirred at 25 - 300C for 4 hours. Solid obtained was filtered, washed with methanol and dried under vacuum. This solid was suspended in water and then basified with sodium hydroxide and stirred for 10 minutes. The resulting erlotinib base was isolated, washed with water and dried under vacuum. The base was suspended in water and acidified to pH 1.0 - 2.0 using hydrochloric acid. The reaction mixture was stirred for 2 hours, filtered, washed with water and dried to obtain 11.2 g of erlotinib hydrochloride.
With hydrogenchloride; In water; for 2h;pH 1.0 - 2.0;Product distribution / selectivity; 15.0 g of 4-chloro-6,7-bis(2-methoxyethoxy) quinazoline was suspended in 450 ml ethanol and 13.8 g of 3-aminophenyl acetylene was added at 25 - 30C. Further 3.0 g tartaric acid was added. The reaction mass was stirred at 25 - 300C for 6 hours. Solid obtained was filtered, washed with water and dried under vacuum. This solid was suspended in water, basified with potassium hydroxide and stirred for 10 minutes. The resulting erlotinib base was isolated by filtration, washed with ethanol and dried under vacuum. The solid obtained was then suspended in water and acidified to pH 1.0 - 2.0 using hydrochloric acid. The reaction mixture was stirred for 2 hours, filtered, washed with water and dried at 40 - 45C to obtain 18.3 g of erlotinib hydrochloride.
With hydrogenchloride; In water; for 2h;pH 1.0 - 2.0;Product distribution / selectivity; 50 g of 4-chloro-6,7-bis(2-methoxyethoxy) quinazoline was suspended in 1500 ml acetonitrile and 46 g of 3-aminophenyl acetylene was added at 25 - 300C, followed by 10 ml acetic acid. The reaction mass was stirred at 25 - 30C for 30 minutes. Solid obtained was filtered, washed with water and dried under vacuum. This solid was suspended in water, basified with potassium hydroxide and stirred for 10 minutes. The resulting erlotinib base was isolated, washed with acetonitrile and dried under vacuum. The solid obtained was then suspended in water and acidified to pH 1.0 - 2.0 using hydrochloric acid. The reaction mixture was stirred for 2 hours, filtered, washed with water and dried at 40 - 45C to obtain 63 g of erlotinib hydrochloride.
With hydrogenchloride; In diethyl ether; chloroform; Erlotinib base was dissolved in minimum volume of CHCl3, diluted with several volumes of ether, and titrated with 1M HCl in ether to precipitate the title product as its hydrochloride salt.
With hydrogenchloride; In diethyl ether; chloroform; at 25 - 30℃; for 0.5h;Product distribution / selectivity; Erlotinib free base (5 gm, obtained in step-ll) is dissolved in chloroform (200 ml) at 25 - 300C to form a clear solution and then added diethyl ether (50 ml). To the resulting solution slowly added 15% diethyl ether HCI (5 ml) at 25 - 300C and stirred for 30 minutes at 25 - 300C. Filtered the material, washed with a mixture of diethyl ether (10 ml) and chloroform (10 ml), and then dried at 60 - 650C under vacuum to give 4.9 gm of erlotinib hydrochloride [HPLC purity: 99.7%; Content of N-methoxyethyl impurity: 0.24% (at 1.14 RRT)]
With hydrogenchloride; In methanol; dimethyl sulfoxide; at 25 - 30℃; for 0.5 - 0.666667h;pH 2;Product distribution / selectivity; Crude erlotinib free base (10 gm, HPLC purity: 98.2%; Content of N- methoxyethyl impurity: 0.24%) is dissolved in dimethylsulfoxide (50 ml) at 25 - 300C, to the solution added 15% methanolic HCI (100 ml) at 25 - 300C while pH of the mass adjusted to 2 and then stirred for 30 - 40 minutes at 25 - 300C. Filtered the material, washed with a mixture of dimethyl sulfoxide (10 ml) and methanol (20 ml), and then dried the material at 60 - 650C under vacuum for 5 hours to give 8.9 gm of pure erlotinib hydrochloride [HPLC purity: 99.92%; Content of N-methoxyethyl impurity: 0.02% (at 1.14 RRT)].
With hydrogenchloride; In ethyl acetate; 4-methyl-2-pentanone; at 25 - 65℃; for 1h;Product distribution / selectivity; Erlotinib free base (10 gm) is added to methyl isobutyl ketone (300 ml) under stirring at 25 - 300C, the contents are heated to 600C and then stirred at 60 - 650C to form a clear solution. To the solution slowly added 7% ethyl acetate HCI (40 ml) at 60 - 650C, the resulting mass is slowly cooled to 25 - 300C and then stirred for 1 hour. Filtered the mass, washed with methyl isobutyl ketone (20 ml) and then dried at 50 - 550C to give 9.8 gm of erlotinib hydrochloride crystalline polymorph form A having polymorph form B undetected (HPLC Purity: 99.87%, Moisture Content: 0.2%).
With hydrogenchloride; In Isopropyl acetate; ethyl acetate; at 25 - 65℃; for 3h;Product distribution / selectivity; Erlotinib free base (10 gm) is added to isopropyl acetate (400 ml) under stirring at 25 - 300C, the contents are heated to 600C and then stirred at 60 - 650C to form a clear solution. To the solution slowly added 7% ethyl acetate HCI (40 ml) at 60 - 650C and stirred for 2 hours at 60 - 650C. The resulting mass is slowly cooled to 25 - 300C and then stirred for 1 hour. Filtered the mass, washed with the mixture of isopropyl acetate (40 ml) and ethyl acetate (4 ml) and then dried at 50 - 550C to give 9.9 gm of erlotinib hydrochloride crystalline polymorph form A having polymorph form B undetected [HPLC Purity: 99.89%; Moisture Content: 0.15%; Mean particle size (D50): 5.48 mum and 90 volume-% of the particles (D90): 18.96 mum].
With hydrogenchloride; In diethyl ether; chloroform; at 25 - 30℃; for 0.5h;Product distribution / selectivity; Erlotinib free base (5 gm, obtained in reference example 3) is dissolved in chloroform (200 ml) at 25 - 300C to form a clear solution and then added diethyl ether (50 ml). To the resulting solution slowly added 15% diethyl ether HCI (5 ml) at 25 - 300C and stirred for 30 minutes at 25 - 300C. Filtered the material, washed with a mixture of diethyl ether (10 ml) and chloroform (10 ml), and then dried at 60 - 650C under vacuum to give 4.9 gm of erlotinib hydrochloride polymorph form A [HPLC purity: 99.7%; Mean particle size (D50)'. 3.50 mum and 90 volume-% of the particles (D90): 4.61 mum].
With hydrogenchloride; In water; butan-1-ol; at 30℃; for 1h;Product distribution / selectivity; Erlotinib base (anhydrous), one weight portion was dissolved at RT in 40 volume portions of solvent or solvent mixture listed in the table. Temperature of the solution was adjusted at given value (in the table). 207 mul per one gram of the base(equivalent amount) of concentrated hydrochloric acid*) was added into solution.New crystalline phase was created immediately or during one minute. The crystalline suspension was agitated for 1 hr holding the above selected temperature and then cooled to 0C. The solid was separated by filtration or centrifugation and dried in the nitrogen stream to the constant weight.*) HCl content determination was performed by titration: 44.1 % w/v
With hydrogenchloride; In water; butan-1-ol; at 30℃; for 1h;Product distribution / selectivity; Erlotinib base (anhydrous), one weight portion was dissolved at RT in 40 volume portions of solvent or solvent mixture listed in the table. Temperature of the solution was adjusted at given value (in the table). 207 mul per one gram of the base (equivalent amount) of concentrated hydrochloric acid*) was added into solution. New crystalline phase was created immediately or during one minute. The crystalline suspension was agitated for 1 hr holding the above selected temperature and then cooled to 0C. The solid was separated by filtration or centrifugation and dried in the nitrogen stream to the constant weight. Some batches were dried in a small laboratory oven under nitrogen ventilation. The drying conditions are listed in the table. *) HCl content determination was performed by titration: 44.1 % w/vTable 1 : Crystallization Conditions Leading to Form A <n="17"/>* only partial dissolution of the base at given conditions, completely dissolution of starting material was achieved after addition of HCl
With hydrogenchloride; In Dimethoxymethane; water; at 0℃; for 1h;Product distribution / selectivity; Erlotinib base (anhydrous), one weight portion was dissolved at RT in 40 volume portions of solvent or solvent mixture listed in the table. Temperature of the solution was adjusted at given value (in the table). 207 mul per one gram of the base (equivalent amount) of concentrated hydrochloric acid*) was added into solution. New crystalline phase was created immediately or during one minute. The crystalline suspension was agitated for 1 hr holding the above selected temperature and then cooled to 0C. The solid was separated by filtration or centrifugation and dried in the nitrogen stream to the constant weight. Some batches were dried in a small laboratory oven under nitrogen ventilation. The drying conditions are listed in the table. *) HCl content determination was performed by titration: 44.1 % w/vTable 1 : Crystallization Conditions Leading to Form A <n="17"/>* only partial dissolution of the base at given conditions, completely dissolution of starting material was achieved after addition of HCl
With hydrogenchloride; In dichloromethane; water; at 0℃; for 1h;Product distribution / selectivity; Erlotinib base (anhydrous), one weight portion was dissolved at RT in 40 volume portions of solvent or solvent mixture listed in the table. Temperature of the solution was adjusted at given value (in the table). 207 mul per one gram of the base(equivalent amount) of concentrated hydrochloric acid*) was added into solution.New crystalline phase was created immediately or during one minute. The crystalline suspension was agitated for 1 hr holding the above selected temperature and then cooled to 0C. The solid was separated by filtration or centrifugation and dried in the nitrogen stream to the constant weight.*) HCl content determination was performed by titration: 44.1 % w/v
With hydrogenchloride; In water; ethyl acetate; at 0℃; for 1h;Product distribution / selectivity; Erlotinib base (anhydrous), one weight portion was dissolved at RT in 40 volume portions of solvent or solvent mixture listed in the table. Temperature of the solution was adjusted at given value (in the table). 207 mul per one gram of the base (equivalent amount) of concentrated hydrochloric acid*) was added into solution. New crystalline phase was created immediately or during one minute. The crystalline suspension was agitated for 1 hr holding the above selected temperature and then cooled to 0C. The solid was separated by filtration or centrifugation and dried in the nitrogen stream to the constant weight. Some batches were dried in a small laboratory oven under nitrogen ventilation. The drying conditions are listed in the table. *) HCl content determination was performed by titration: 44.1 % w/vTable 1 : Crystallization Conditions Leading to Form A <n="17"/>* only partial dissolution of the base at given conditions, completely dissolution of starting material was achieved after addition of HCl
With hydrogenchloride; In methanol; water; toluene; at 30℃; for 1h;Product distribution / selectivity; Erlotinib base (anhydrous), one weight portion was dissolved at RT in 40 volume portions of solvent or solvent mixture listed in the table. Temperature of the solution was adjusted at given value (in the table). 207 mul per one gram of the base (equivalent amount) of concentrated hydrochloric acid*) was added into solution. New crystalline phase was created immediately or during one minute. The crystalline suspension was agitated for 1 hr holding the above selected temperature and then cooled to 0C. The solid was separated by filtration or centrifugation and dried in the nitrogen stream to the constant weight. Some batches were dried in a small laboratory oven under nitrogen ventilation. The drying conditions are listed in the table. *) HCl content determination was performed by titration: 44.1 % w/vTable 1 : Crystallization Conditions Leading to Form A <n="17"/>* only partial dissolution of the base at given conditions, completely dissolution of starting material was achieved after addition of HCl
With hydrogenchloride; In water; toluene; at 30℃; for 1h;Product distribution / selectivity; Erlotinib base (anhydrous), one weight portion was dissolved at RT in 40 volume portions of solvent or solvent mixture listed in the table. Temperature of the solution was adjusted at given value (in the table). 207 mul per one gram of the base (equivalent amount) of concentrated hydrochloric acid*) was added into solution. New crystalline phase was created immediately or during one minute. The crystalline suspension was agitated for 1 hr holding the above selected temperature and then cooled to 0C. The solid was separated by filtration or centrifugation and dried in the nitrogen stream to the constant weight. Some batches were dried in a small laboratory oven under nitrogen ventilation. The drying conditions are listed in the table. *) HCl content determination was performed by titration: 44.1 % w/vTable 1 : Crystallization Conditions Leading to Form A <n="17"/>* only partial dissolution of the base at given conditions, completely dissolution of starting material was achieved after addition of HCl
With hydrogenchloride; In water; butanone; at 20 - 50℃; for 0.5h;Product distribution / selectivity; 1 g of Erlotinib was dissolved in a mixture of 20 g butanone and 2 g of water at 50C, under stirring 0.3 g of aqueous 37% hydrochloric acid solution was added obtaining immediate precipitation. After half an hour at room temperature the <n="16"/>suspension was filtered on Buckner filter. The precipitate was rinsed with butanone and dried at 60 under vacuum for one hour obtaining 0.9 g of Erlotinib hydrochloride.
With hydrogenchloride; In diethyl ether; water; at 0℃; for 1h;Product distribution / selectivity; Erlotinib base (anhydrous), one weight portion was dissolved at RT in 40 volume portions of solvent or solvent mixture listed in the table. Temperature of the solution was adjusted at given value (in the table). 207 mul per one gram of the base(equivalent amount) of concentrated hydrochloric acid*) was added into solution.New crystalline phase was created immediately or during one minute. The crystalline suspension was agitated for 1 hr holding the above selected temperature and then cooled to 0C. The solid was separated by filtration or centrifugation and dried in the nitrogen stream to the constant weight.*) HCl content determination was performed by titration: 44.1 % w/v
With hydrogenchloride; In ethanol; water; at 0℃; for 1h;Product distribution / selectivity; Erlotinib base (anhydrous), one weight portion was dissolved at RT in 40 volume portions of solvent or solvent mixture listed in the table. Temperature of the solution was adjusted at given value (in the table). 207 mul per one gram of the base (equivalent amount) of concentrated hydrochloric acid*) was added into solution. New crystalline phase was created immediately or during one minute. The crystalline suspension was agitated for 1 hr holding the above selected temperature and then cooled to 0C. The solid was separated by filtration or centrifugation and dried in the nitrogen stream to the constant weight. Some batches were dried in a small laboratory oven under nitrogen ventilation. The drying conditions are listed in the table. *) HCl content determination was performed by titration: 44.1 % w/vTable 1 : Crystallization Conditions Leading to Form A <n="17"/>* only partial dissolution of the base at given conditions, completely dissolution of starting material was achieved after addition of HCl
With hydrogenchloride; In tert-butyl methyl ether; water; at 0℃; for 1h;Product distribution / selectivity; Erlotinib base (anhydrous), one weight portion was dissolved at RT in 40 volume portions of solvent or solvent mixture listed in the table. Temperature of the solution was adjusted at given value (in the table). 207 mul per one gram of the base (equivalent amount) of concentrated hydrochloric acid*) was added into solution. New crystalline phase was created immediately or during one minute. The crystalline suspension was agitated for 1 hr holding the above selected temperature and then cooled to 0C. The solid was separated by filtration or centrifugation and dried in the nitrogen stream to the constant weight. Some batches were dried in a small laboratory oven under nitrogen ventilation. The drying conditions are listed in the table. *) HCl content determination was performed by titration: 44.1 % w/vTable 1 : Crystallization Conditions Leading to Form A <n="17"/>* only partial dissolution of the base at given conditions, completely dissolution of starting material was achieved after addition of HCl
With hydrogenchloride; In Isopropyl acetate; water; at 0℃; for 1h;Product distribution / selectivity; Erlotinib base (anhydrous), one weight portion was dissolved at RT in 40 volume portions of solvent or solvent mixture listed in the table. Temperature of the solution was adjusted at given value (in the table). 207 mul per one gram of the base(equivalent amount) of concentrated hydrochloric acid*) was added into solution.New crystalline phase was created immediately or during one minute. The crystalline suspension was agitated for 1 hr holding the above selected temperature and then cooled to 0C. The solid was separated by filtration or centrifugation and dried in the nitrogen stream to the constant weight.*) HCl content determination was performed by titration: 44.1 % w/v
With hydrogenchloride; In water; iso-butanol; at 30℃; for 1h;Product distribution / selectivity; Erlotinib base (anhydrous), one weight portion was dissolved at RT in 40 volume portions of solvent or solvent mixture listed in the table. Temperature of the solution was adjusted at given value (in the table). 207 mul per one gram of the base(equivalent amount) of concentrated hydrochloric acid*) was added into solution.New crystalline phase was created immediately or during one minute. The crystalline suspension was agitated for 1 hr holding the above selected temperature and then cooled to 0C. The solid was separated by filtration or centrifugation and dried in the nitrogen stream to the constant weight.*) HCl content determination was performed by titration: 44.1 % w/v
With hydrogenchloride; In water; iso-butanol; at 30℃; for 1h;Product distribution / selectivity; Erlotinib base (anhydrous), one weight portion was dissolved at RT in 40 volume portions of solvent or solvent mixture listed in the table. Temperature of the solution was adjusted at given value (in the table). 207 mul per one gram of the base (equivalent amount) of concentrated hydrochloric acid*) was added into solution. New crystalline phase was created immediately or during one minute. The crystalline suspension was agitated for 1 hr holding the above selected temperature and then cooled to 0C. The solid was separated by filtration or centrifugation and dried in the nitrogen stream to the constant weight. Some batches were dried in a small laboratory oven under nitrogen ventilation. The drying conditions are listed in the table. *) HCl content determination was performed by titration: 44.1 % w/vTable 1 : Crystallization Conditions Leading to Form A <n="17"/>* only partial dissolution of the base at given conditions, completely dissolution of starting material was achieved after addition of HCl
With hydrogenchloride; In 1,3-DIOXOLANE; methanol; water; at 60℃; for 1h;Product distribution / selectivity; Erlotinib base (anhydrous), one weight portion was dissolved at RT in 40 volume portions of solvent or solvent mixture listed in the table. Temperature of the solution was adjusted at given value (in the table). 207 mul per one gram of the base(equivalent amount) of concentrated hydrochloric acid*) was added into solution.New crystalline phase was created immediately or during one minute. The crystalline suspension was agitated for 1 hr holding the above selected temperature and then cooled to 0C. The solid was separated by filtration or centrifugation and dried in the nitrogen stream to the constant weight.*) HCl content determination was performed by titration: 44.1 % w/v
With hydrogenchloride; In 1,3-DIOXOLANE; methanol; water; at 60℃; for 1h;Product distribution / selectivity; Erlotinib base (anhydrous), one weight portion was dissolved at RT in 40 volume portions of solvent or solvent mixture listed in the table. Temperature of the solution was adjusted at given value (in the table). 207 mul per one gram of the base (equivalent amount) of concentrated hydrochloric acid*) was added into solution. New crystalline phase was created immediately or during one minute. The crystalline suspension was agitated for 1 hr holding the above selected temperature and then cooled to 0C. The solid was separated by filtration or centrifugation and dried in the nitrogen stream to the constant weight. Some batches were dried in a small laboratory oven under nitrogen ventilation. The drying conditions are listed in the table. *) HCl content determination was performed by titration: 44.1 % w/vTable 1 : Crystallization Conditions Leading to Form A <n="17"/>* only partial dissolution of the base at given conditions, completely dissolution of starting material was achieved after addition of HCl
With hydrogenchloride; In 1,3-DIOXOLANE; water; at 20 - 75℃; for 1h;Product distribution / selectivity; Erlotinib base (anhydrous), one weight portion was dissolved at RT in 40 volume portions of solvent or solvent mixture listed in the table. Temperature of the solution was adjusted at given value (in the table). 207 mul per one gram of the base (equivalent amount) of concentrated hydrochloric acid*) was added into solution. New crystalline phase was created immediately or during one minute. The crystalline suspension was agitated for 1 hr holding the above selected temperature and then cooled to 0C. The solid was separated by filtration or centrifugation and dried in the nitrogen stream to the constant weight. Some batches were dried in a small laboratory oven under nitrogen ventilation. The drying conditions are listed in the table. *) HCl content determination was performed by titration: 44.1 % w/vTable 1 : Crystallization Conditions Leading to Form A <n="17"/>* only partial dissolution of the base at given conditions, completely dissolution of starting material was achieved after addition of HCl
With hydrogenchloride; In 1,3-DIOXOLANE; water; at 60℃; for 1h;Product distribution / selectivity; Erlotinib base (anhydrous), one weight portion was dissolved at RT in 40 volume portions of solvent or solvent mixture listed in the table. Temperature of the solution was adjusted at given value (in the table). 207 mul per one gram of the base(equivalent amount) of concentrated hydrochloric acid*) was added into solution.New crystalline phase was created immediately or during one minute. The crystalline suspension was agitated for 1 hr holding the above selected temperature and then cooled to 0C. The solid was separated by filtration or centrifugation and dried in the nitrogen stream to the constant weight.*) HCl content determination was performed by titration: 44.1 % w/v
With hydrogenchloride; In 2-methoxy-ethanol; water; at 30℃; for 1h;Product distribution / selectivity; Erlotinib base (anhydrous), one weight portion was dissolved at RT in 40 volume portions of solvent or solvent mixture listed in the table. Temperature of the solution was adjusted at given value (in the table). 207 mul per one gram of the base(equivalent amount) of concentrated hydrochloric acid*) was added into solution.New crystalline phase was created immediately or during one minute. The crystalline suspension was agitated for 1 hr holding the above selected temperature and then cooled to 0C. The solid was separated by filtration or centrifugation and dried in the nitrogen stream to the constant weight.*) HCl content determination was performed by titration: 44.1 % w/v
With hydrogenchloride; In 2-methoxy-ethanol; water; at 30℃; for 1h;Product distribution / selectivity; Erlotinib base (anhydrous), one weight portion was dissolved at RT in 40 volume portions of solvent or solvent mixture listed in the table. Temperature of the solution was adjusted at given value (in the table). 207 mul per one gram of the base (equivalent amount) of concentrated hydrochloric acid*) was added into solution. New crystalline phase was created immediately or during one minute. The crystalline suspension was agitated for 1 hr holding the above selected temperature and then cooled to 0C. The solid was separated by filtration or centrifugation and dried in the nitrogen stream to the constant weight. Some batches were dried in a small laboratory oven under nitrogen ventilation. The drying conditions are listed in the table. *) HCl content determination was performed by titration: 44.1 % w/vTable 1 : Crystallization Conditions Leading to Form A <n="17"/>* only partial dissolution of the base at given conditions, completely dissolution of starting material was achieved after addition of HCl
With hydrogenchloride; In methanol; water; at 0℃; for 1h;Product distribution / selectivity; Erlotinib base (anhydrous), one weight portion was dissolved at RT in 40 volume portions of solvent or solvent mixture listed in the table. Temperature of the solution was adjusted at given value (in the table). 207 mul per one gram of the base(equivalent amount) of concentrated hydrochloric acid*) was added into solution.New crystalline phase was created immediately or during one minute. The crystalline suspension was agitated for 1 hr holding the above selected temperature and then cooled to 0C. The solid was separated by filtration or centrifugation and dried in the nitrogen stream to the constant weight.*) HCl content determination was performed by titration: 44.1 % w/v
With hydrogenchloride; In methyl iso-butyl ketone (MIBK); water; at 0℃; for 1h;Product distribution / selectivity; Erlotinib base (anhydrous), one weight portion was dissolved at RT in 40 volume portions of solvent or solvent mixture listed in the table. Temperature of the solution was adjusted at given value (in the table). 207 mul per one gram of the base (equivalent amount) of concentrated hydrochloric acid*) was added into solution. New crystalline phase was created immediately or during one minute. The crystalline suspension was agitated for 1 hr holding the above selected temperature and then cooled to 0C. The solid was separated by filtration or centrifugation and dried in the nitrogen stream to the constant weight. Some batches were dried in a small laboratory oven under nitrogen ventilation. The drying conditions are listed in the table. *) HCl content determination was performed by titration: 44.1 % w/vTable 1 : Crystallization Conditions Leading to Form A <n="17"/>* only partial dissolution of the base at given conditions, completely dissolution of starting material was achieved after addition of HCl
With hydrogenchloride; In water; acetonitrile;Heating; Intermediate II is added to the reaction vial, acetonitrile, concentrated hydrochloric acid, stirring, the heating reaction. Stirring crystallization, ice water cooling to 10 C. Filtering the white solid obtained, Erlotinib hydrochloride is obtained after drying under vacuum.
With hydrogenchloride; In methanol; water; at 20℃; The product 4,5-bis (2-methoxyethoxy) -2-aminophenylacetonitrile hydrochloride from the fifth stage enters the reactor R0601, an excess of DMF-DMA is added,Synthesis of 4,5-bis (2-methoxyethoxy) -2-aminophenylacetonitrile hydrochloride and DMF-DMAThe raw material was dissolved under stirring at room temperature and the mixture was heated and refluxed for 3h. After the sampling port 06001 was sampled and analyzed, the unreacted DMF-DMA was distilled off under reduced pressure and the unreacted DMF-DMA was taken into the DMF-DMA recovery tank V0601, (E) -N'- (2-cyano-4,5-bis (2-methoxyethoxy) phenyl-N, N-dimethylformamidine into reactor R0602; Kettle R0602 added raw material between the m-aminophenylacetylene and solvent (catalyst) glacial acetic acid,After stirring and dissolving, the reaction was refluxed for 2h, sampling port 06002 sample analysis qualified, most of the acetic acid was distilled off under reduced pressure,Acetic acid into the acetic acid recovery tank V06002, and then stirred into the reactor R0602 amount of ice water,Re-access to ethyl acetate, stirring for a period of time, with ammonia to adjust the pH value of 8-9, a large number of solid precipitation,The solid-liquid mixture is sent to the filter F0601 through the material pump P0601, the filter cake is washed with ice water several times,Waste water into the waste water recovery tank V0603, filter cake into the dryer D0601, erlotinib after drying;D0601 dryer out of the erlotinib product into the reactor R0603, with stirring into the methanol,Erlotinib suspended in methanol, the reactor cooled to 20 C, and then dropwise addition of 12mol / L of concentrated hydrochloric acid,Precipitation of a large number of white solid crystals, sampling port 06003 sampling analysis, stop dropping concentrated hydrochloric acid,The reaction solution was sent to filter F0602 by material pump P0602, the filter cake was washed with methanol several times,The filtrate into the waste collection tank V0604, filter cake into the dryer D0602, erlotinib hydrochloride obtained after drying.

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  • 3
  • [ 950596-59-5 ]
  • [ 54060-30-9 ]
  • [ 183321-74-6 ]
YieldReaction ConditionsOperation in experiment
91.5% With acetic acid; In N,N-dimethyl-formamide; at 125℃; for 1h; N-dimethylformamidine, 0.72 g (6.15 mmol) of N '- [2-cyano-4,5-bis (2-methoxyethoxy) phenyl] ) Of 3-aminophenylacetylene and 8 mL of acetic acid were reacted in a 50 mL reaction flask at 125 C for 1 hour and cooled to room temperature.20 mL of ice water was added to the mixture, the pH was adjusted to 10 with aqueous ammonia, and the mixture was stirred for 1 hour, suction filtered and the filter cake washed with water until neutral.The filter cake was dried to obtain 2.15 g of erlotinib in a yield of 91.5%.
(f) [6, 7-bis-(2-methoxyethoxy)-quinazolin-4-yl]-(3-ethynylphenyI) amine:; <n="14"/>To N'-[2-cyano-4,5-bis(2-methoxyethoxy)phenyl]-N,N- dimethylformamidine(6.5g, 0.0202 moles) was added 3-ethynylaniline(2.37g, 0.0202 moles) and acetic acid(25ml) heated the reaction mixture to 125C, stirred the reaction mixture for about 3hrs, quenched in ice water, neutralized with sodium bicarbonate, extracted the product into ethyl acetate, the organic layer was dried over sodium sulfate and concentrated to yield crude material which was further crystallized from ethyl acetate to get off-white crystalline compound(delta.Og) having the mp 149-153 0C.
  • 4
  • [ 183319-69-9 ]
  • [ 183321-74-6 ]
YieldReaction ConditionsOperation in experiment
96.3% With sodium hydroxide; In water;pH 5 - 12;Product distribution / selectivity; <strong>[183319-69-9]Erlotinib hydrochloride</strong> (10.0 g) was suspended in water (60 ml) and 50% NaOH was added stepwise to the suspension under pH-control. The suspension passed through heavy dense stages in the pH range of 5-10. It reached pH between 11-12 after addition of 3 ml NaOH solution. The suspension was transferred into 500 ml bulb and ethylacetate (300 ml) was added. The pH decreased promptly to the value of 5-6 on account of alkaline ethylacetate decomposition. The mixture was heated to the reflux on rotary evaporator (RVO)-the solid phase disappeared and two liquid phases were separated. The water phase was re-extracted again with another portion of ethylacetate (300 ml). The organic layers were combined, evaporated to dryness and crystalline evaporation residue was re-slurred into small amount of ethylacetate (30 ml). The crystalline solids were filtrated off, rinsed with ethylacetate (10 ml) and dried in a small laboratory oven under nitrogen stream (150 l/hr) at 40 C./5 hrs. The yield was 96.3% (9.22 g). The obtained substance is a coarse and creamy powder. This is Erlotinib base monohydrate form G1 according to solid state analyses. (KF 4.39%).
94.3% With ammonia; In water; for 2h;pH 9.4;Product distribution / selectivity; <strong>[183319-69-9]Erlotinib hydrochloride</strong> (20.0 g) was suspended in water (800 ml) and 25% ammonia solution (11 ml) was added slowly to the suspension under pH-control. It reached pH 9.4 at the time when ammonia addition was completed. The suspension was agitated for an additional 2 hrs. Then the crystalline solids were filtrated off, rinsed with water (400 ml) and dried in a small laboratory oven under nitrogen stream (150 l/hr) at 40 C./4 hrs. The molar yield was 94.3% (18.94 g, a creamy powder). The Erlotinib base obtained by the described procedure is monohydrate form G1.
With sodium hydroxide; In water; ethyl acetate; at 20℃;Product distribution / selectivity; 3.0 g of <strong>[183319-69-9]erlotinib hydrochloride</strong> was suspended in 400 ml of demi- water/ethyl acetate (1 :1 VAV) at R.T. To the suspension/emulsion, vigorously stirred at R.T., 300 mg of NaOH dissolved in 50 ml of demi-water was added very slowly (dropwise, > 1 equivalent of OH ). As a result of this, the HCl was removed from the drug substance <n="14"/>and the drug substance was extracted into the organic phase. Some extra NaOH was added as the water-layer proved to be hardly basic afterwards and to ensure complete removal of HCl from the drug substance. The organic phase was twice washed with water and filtered over a P3-glass filter (reduced pressure), packed with prewashed Celite 545. The filtrate was dried with sodium sulphate for 15-30 minutes. The solution was filtered over a P3-glass filter (reduced pressure) to remove the sodium sulphate. Then, the solvent was evaporated under vacuum to dryness, yielding a pale beige, crystalline solid with a yield of approximately 1.85 g. (analytical data in Fig 2A, 2B, and 2C)
With sodium hydroxide; In dichloromethane; water; at 20℃; for 1h;Product distribution / selectivity; 1.5 g of <strong>[183319-69-9]erlotinib hydrochloride</strong> was suspended in 100 ml of demi- water/dichloromethane (1 : 1 V/V) at R.T. To the suspension/emulsion, vigorously stirred at R.T., 300 mg of NaOH dissolved in about 10 ml of demi-water was added slowly. As a result of this, the HCl was removed from the drug substance and the drug substance was extracted into the organic phase. Some extra 1 M NaOH (few ml) and 50 ml of dichloromethane were added as extraction appeared to be far incomplete (solid material remained in the water phase).[0054] After vigorous stirring at R.T. for 1 hour, both liquid layers appeared to be more or less clear. The organic layer was separated. Possible remaining drug substance in the water phase was extracted with an additional 50 ml of dichloromethane. The combined organic phases were filtered over a P3-glass filter (reduced pressure, packed with Celite 545), washed with 50 ml of fresh demi-water and filtered over the same filter again. The clear filtrate was dried with sodium sulphate for 1.5 hours (stirring). The solution was filtered over a P3-glass filter (reduced pressure) to remove the sodium sulphate. Then, the solvent was slowly evaporated under vacuum to dryness, yielding an off-white to pale beige, crystalline solid. No yield was determined.
With sodium acetate; In dichloromethane; N,N-dimethyl-formamide; isopropyl alcohol; at 20 - 25℃;Product distribution / selectivity; Example 3Preparation of Crystalline Erlotinib Base Form G2; 6,7-Bis-(2-methoxyethoxy)-4(3H)-quinazolinone (?MEQO?) (10 g; 0.034 mol) was suspended in CH2Cl2 (130 mL) and DMF (2 mL). Thionyl chloride (7 g; 0.059 mol) was added and a yellow and clear solution is obtained. After about 10 min the starting material precipitated again. The mixture was heated to reflux for at least 8 h (after about 5 h a solution was obtained) until residual MEQO<0.3% (In Process Control 1). The mixture (yellowish solution) was cooled to 15 C. and H2O (50 mL) was added (exothermic quench of residual thionyl chloride). The mixture pH was adjusted to 7.5-8.0 by addition of 30% NaOH (about 11.5 g) under vigorous stirring. After separation of the phases, the organic layer was washed with H2O (50 mL). The organic phase was concentrated under vacuum to a total volume of about 30-40 mL. The mixture was diluted with i-PrOH (isopropyl alcohol; 150 mL) and the mixture was concentrated until about 5 volumes of solvent were removed (In Process Control 2: residual CH2Cl2<2%, by vol.). The mixture was heated at 40 C. and 3-EBA (4.4 g; 0.038 mol) was added. The mixture was additionally diluted with i-PrOH (75 mL) in order to obtain a stirrable suspension and it was stirred at 40 C. for 8 h (In Process Control 3: residual 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline (?CMEQ?)<2%). At this stage the mixture already contains Erlotinib HCl. The reaction mixture was cooled to 20-25 C. and AcONa (2.8 g; 0.034 mol) was added. After two hours stirring, the suspension was filtered and the solid was washed with i-PrOH (25 mL). The wet solid was dried under vacuum at 45-50 C. for 3 h to give ERL-Base.
With sodium hydroxide; In methanol; chloroform; water; at 25 - 55℃; for 0.5h;Product distribution / selectivity; Crude <strong>[183319-69-9]erlotinib hydrochloride</strong> (37 gm, obtained in reference example 1), water (370 ml) and chloroform (370 ml) are taken into a reaction flask at 25 - 300C and start stirring. The contents are heated to 50 - 550C, sodium hydroxide solution is added at 50 - 550C and then stirred for 15 minutes at 500C (clear solution not observed). To the reaction mass added chloroform (200 ml) and methanol (60 ml) and stirred for 15 minutes at 500C (clear solution observed). Separated the layers at 500C, the organic layer is washed with water (200 ml) at <n="17"/>500C and then combined the organic layers. To the organic layer added methanol (60 ml) dried over sodium sulfate and distilled the total solvent under vacuum at 50 - 550C. To the residue added n-heptane (300 ml) and stirred for 30 minutes at 25 - 300C. Filtered the material, washed with n-heptane (70 ml) and then dried the material at 60 - 650C under vacuum for 3 hours 30 minutes to give 34 gm of anhydrous erlotinib free base (HPLC Purity: 98.2%, Moisture Content: 0.2%).
With sodium hydroxide; In water; ethyl acetate; at 25 - 65℃; for 0.5 - 0.583333h;pH 9 - 10;Product distribution / selectivity; Crude <strong>[183319-69-9]erlotinib hydrochloride</strong> (100 gm, obtained in reference example 1), water (400 ml) and ethyl acetate (1600 ml) are taken into a reaction flask at 25 - 300C and start stirring. The contents are heated to 600C, pH of the mass is adjusted to 9 to 10 by adding sodium hydroxide solution (30 - 40 ml) at 60 - 650C and then stirred for 30 - 35 minutes at 60 - 650C. Separated the layers at 60 - 650C, the organic layer is dried with sodium sulfate and then distilled off the solvent completely under vacuum at 500C. The residue is cooled to 25 - 300C, n- heptane (800 ml) is added and the stirred for 45 minutes to 1 hour at 25 - 300C. Filtered the compound, washed with n-heptane (200 ml) and then dried at 60 - 650C to give 90 gm of anhydrous erlotinib free base (HPLC Purity: 99.1%, Moisture Content 0.1%).Reference example 5 Erlotinib free base (5 gm, obtained in reference example 3) is dissolved in chloroform (200 ml) at 25 - 300C to form a clear solution and then added diethyl ether (50 ml). To the resulting solution slowly added 15% diethyl ether HCI (5 ml) at 25 - 300C and stirred for 30 minutes at 25 - 300C. Filtered the material, washed with a mixture of diethyl ether (10 ml) and chloroform (10 ml), and then dried at 60 - 650C under vacuum to give 4.9 gm of <strong>[183319-69-9]erlotinib hydrochloride</strong> polymorph form A [HPLC purity: 99.7%; Mean particle size (D50)'. 3.50 mum and 90 volume-% of the particles (D90): 4.61 mum].

  • 5
  • [ 54060-30-9 ]
  • [ 183322-18-1 ]
  • [ 183321-74-6 ]
YieldReaction ConditionsOperation in experiment
Ca. 96.6% In isopropyl alcohol;Reflux; Compound 4 (313 mg, 1.0 mmol) was weighed into isopropanol (5 mL)Add at room temperatureM-aminophenylacetylene(200 mg),Heated to reflux temperature (warming solution gradually clarified,A lot of white solid later appeared),Reaction for 3-4 hours,TLC detection of the reaction material (compound 4) completely disappeared,Stop heatingDrop to room temperature,Suction filtration,The filter cake was washed twice with hot isopropanol,Drying in vacuo gave a white solid (395 mg)After recrystallization from n-butanol erlotinib pure (380mg, yield of about 96.6%
Ca. 96.6% In isopropyl alcohol;Reflux; Weighing the compound 4 (313 mg, 1.0 mmol) by adding isopropanol (5 ml) in, at room temperature by adding between amino acetylene (200 mg), heating to reflux temperature (temperature in the process solution gradually clarified, later in a large number of white solid), reaction 3 - 4 hours, TLC detection reaction raw materials (compound 4) completely disappeared, stop heating, cooling down to room temperature, filtered, the filter cake is the hot isopropyl alcohol washing 2 times, vacuum drying to obtain a white solid (395 mg), after positive butanol recrystallize to get erlotinib pure product (380 mg, the yield is about 96.6%,1 H NMR consistent with the prior art, detection HPLC purity of 99.5%).
96.6% In isopropyl alcohol; at 20℃;Reflux; Compound 4 (313 mg, 1.0 mmol) was weighed into isopropanol (5 mL)M-aminophenylacetylene (200 mg) was added at room temperature,Heat to reflux temperature(The solution gradually clarified during the warming process and a large amount of white solid appeared later)After 3-4 hours of reaction, the reaction mixture (compound 4) was completely disappeared by TLC and stopped to be heated.Cooled to room temperature, suction filtered, the filter cake was washed twice with hot isopropanol,Drying in vacuo gave a white solid (395 mg)By n-butanol recrystallization erlotinib pure(380 mg, yield about 96.6%, 1H NMR consistent with the prior art, purity 99.5% by HPLC).
95.2% In ethanol; at 40 - 70℃; for 3h; 2 g of compound IV was added to 20 mL of absolute ethanol and heated to 40 C to form a homogeneous suspension,At this temperature, 10 mL of the ethanol solution of m-aminophenylacetylene was added and the temperature was gradually raised to 70 C. After about 1 h,Solution clarified, after about 2 h, the TLC monitored the disappearance of the starting material and stopped the reaction.The reaction solution was cooled to room temperature, a large amount of solid was precipitated, and the solid was collected by filtration,Dried in vacuo to give about 2.6 g of a white solid which was recrystallized from n-butanol to give the erlotinib pure product in a yield of 95.2%The purity was determined by HPLC with a purity of 99.89%.
90% With pyridine; In isopropyl alcohol; for 4h;Reflux; Contains 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline (286 mg, 0.9 mmol)The isopropanol solution was added dropwiseTo contain pyridine (79 mg, 1.0 mmol)And 3-ethynylaniline (117 mg, 1.0 mmol) In isopropanol solution.The reaction mixture was heated at reflux for 4 hours.Cool to room temperatureThe resulting precipitate is filtered,Recrystallization from methanol gave erlotinib hydrochloride.Erlotinib hydrochloride is washed with water, neutralized with ammonia,Ethyl acetate extraction,Vacuum condensation yields neutral erlotinib.
86.7% With pyridine; In isopropyl alcohol; for 4h;Inert atmosphere; Reflux; EXAMPLE 16 Preparation of Erlotinib Free Base (Crude) [0122] Into a reaction vessel, added 17 ml IPA, pyridine (0.387 ml, 4.8 mmol), 3-EBA (0.562 gm, 4.8 mmol) and ClBMEQ (1 gm, 3.2 mmol) under stirring and nitrogen purging. The RM was maintained at reflux for 4 hour. The RM was cooled to RT and filtered the solid compound then washed with IPA and added 10 ml solution of chloroform: methanol (9:1) and 10 ml saturated solution of sodium bicarbonate in the solid compound under stirring. Stirred the RM for 15 min. The organic layer was separated, dried over sodium sulphate and distilled off the solvent under vacuum at 50 C. till 2 volume remains. Into residue 20 ml toluene was added dropwise and stirred for 1 H at 0-5 C. Filtered, washed with 2 ml toluene and air dried the compound under 2 mbar Vacuum for 30 min to get 1.09 gm Erlotinib free base (crude) (Yield=86.7%, Purity=98.31%).
85% A suspension of 4-chloro-6,7-bis(2-methoxy-ethoxy)quinazoline (5.00 g) and 3-ethynylaniline (2.06 g) in IPA (100 mL) was stirred under reflux for 30 min. The resulting thick suspension was diluted with IPA (100 mL) and added to 1N NaOH (1000 mL). The mixture was stirred for 30 min. The precipitate was collected and dried in vacuum at 40 C. to furnish Erlotinib free base form G3 as a colorless solid (5.68 g; KF 4.53%; 85% yield)
70% With potassium hexamethylsilazane; In tetrahydrofuran; at 100℃; for 16h;Inert atmosphere; N-(3-acetylenephenyl)-6,7-bis(2-methoxyethoxy)-4-quinolinamide (erlotinib):Take 10ml reaction tube,Put a magnet and add it to the reaction tube4-chloro-6,7-bis(2-methoxyethoxy)quinazoline (0.5 mmol),3-ethynylaniline (0.75 mmol),The reaction tube was purged with nitrogen three times with an oil pump.Finally, KHMDS solution (0.75 ml, 1 M in THF) was added under a nitrogen atmosphere.Heat to 100 C, stir the reaction for about 16h until the conversion of the raw materials is completed, and return to room temperature.Diluted with THF (3 ml) to the reaction mixture.Filter through silica gel or diatomaceous earth, wash with THF,The crude product was concentrated in vacuo and subjected to silica gel column chromatography to give product B.(137.6mg, 70% yield),Yellow solid (chromatographic conditions: DCM/MeOH = 50/1).
With pyridine; In isopropyl alcohol; for 4h;Heating / reflux; 37 mg of 3-ethynylaniline and 90 mg of 4-chloro-6,7-bis-(2-methoxy- ethoxy)quinazoline were added to a mixture of 1.5 ml of isopropanol and 25 mul pyridine. The resulting mixture was refluxed for 4 hours under an atmosphere of dry nitrogen. During reflux the color changed from pale yellow to orange-pink. The solvent was removed in vacuo on a rotavap (water bath 40 C.) The residue was partitioned between 5 ml 10%methanol in chloroform and 5 ml saturated aqueous NaHCO3. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was dissolved in a mixture of 2.5 ml of acetone and 2.5 ml hexane and flash chromatographed on silica using 30% acetone in hexane, concentrated in vacuo on a rotavap (water bath 40 C) About 90 mg of a sticky pale yellow solid was obtained (attached to the wall of the flask) The solid was analyzed on XRPD and the results shown in Fig.4. [0058]
5 g of 4-chloro-6,7-bis(2-methoxyethoxy) quinazoline was suspended in 150 ml denatured spirit (SPDS) and 4.6 g of 3-aminophenyl acetylene was charged at 25 - 300C. Further 1.0 ml of methane sulphonic acid was added. The reaction mass was stirred at 25 - 300C for 3 hours. Solid obtained was filtered, washed with SPDS and dried under vacuum. This solid was suspended in water, basified with ammonia and stirred for 10 minutes. The resulting erlotinib base was isolated, washed with water and dried under vacuum. The base was suspended in water and acidified to pH 1.0 - 2.0 using hydrochloric acid. The reaction mixture was stirred for 2 hours, filtered, washed with water and dried at 40 - 450C to obtain 5.8 g of erlotinib hydrochloride.
10.0 g of 4-chloro-6,7-bis(2-methoxyethoxy) quinazoline was suspended in 300 ml methanol and 9.2 g of 3-aminophenyl acetylene was charged at 25 - 300C. Further 2.0 ml of benzoic acid was added. The reaction mass was stirred at 25 - 300C for 4 hours. Solid obtained was filtered, washed with methanol and dried under vacuum. This solid was suspended in water and then basified with sodium hydroxide and stirred for 10 minutes. The resulting erlotinib base was isolated, washed with water and dried under vacuum. The base was suspended in water and acidified to pH 1.0 - 2.0 using hydrochloric acid. The reaction mixture was stirred for 2 hours, filtered, washed with water and dried to obtain 11.2 g of erlotinib hydrochloride.
15.0 g of 4-chloro-6,7-bis(2-methoxyethoxy) quinazoline was suspended in 450 ml ethanol and 13.8 g of 3-aminophenyl acetylene was added at 25 - 30C. Further 3.0 g tartaric acid was added. The reaction mass was stirred at 25 - 300C for 6 hours. Solid obtained was filtered, washed with water and dried under vacuum. This solid was suspended in water, basified with potassium hydroxide and stirred for 10 minutes. The resulting erlotinib base was isolated by filtration, washed with ethanol and dried under vacuum. The solid obtained was then suspended in water and acidified to pH 1.0 - 2.0 using hydrochloric acid. The reaction mixture was stirred for 2 hours, filtered, washed with water and dried at 40 - 45C to obtain 18.3 g of erlotinib hydrochloride.
50 g of 4-chloro-6,7-bis(2-methoxyethoxy) quinazoline was suspended in 1500 ml acetonitrile and 46 g of 3-aminophenyl acetylene was added at 25 - 300C, followed by 10 ml acetic acid. The reaction mass was stirred at 25 - 30C for 30 minutes. Solid obtained was filtered, washed with water and dried under vacuum. This solid was suspended in water, basified with potassium hydroxide and stirred for 10 minutes. The resulting erlotinib base was isolated, washed with acetonitrile and dried under vacuum. The solid obtained was then suspended in water and acidified to pH 1.0 - 2.0 using hydrochloric acid. The reaction mixture was stirred for 2 hours, filtered, washed with water and dried at 40 - 45C to obtain 63 g of erlotinib hydrochloride.
ExamplesExample 1: Preparation of crude erlotinib base4-chloro-6,7-bis-(2-methoxyetiioxy)quinazoline (50 g, 0.1598 mol) was added to methanol (900 ml, 18 vol.) and die mixture was heated to 35-40C to obtain a uniform suspension. 3- Emynylaniline (20.6 g, 0.1758 mol) was mixed with 100 ml (2 vol,) of metiianol and added drop wise into the uniform suspension of 4-cUoio-6,7-bis-(2-methoxyethoxy)quinazoline over a period of 15 min at 35-40C. The temperature of the reaction mixture was slowly raised to 60-65C and maintained for 2-3 hours. The reaction was monitored by TLC as well as HPLC. When the 4-cUoro-6,7-bis-(2-medioxyethoxy)-quinazoline content in the reaction mixture was not more than 3%, the reaction mixture was cooled to 25-30C and crude erlotinib hydrochloride was isolated by filtration. The cake was washed with 100 ml (2 vol.) of methanol and suck dried.The wet cake of crude erlotinib hydrochloride was added to 500 ml (10 vol.) of methanol under stirring at 25-30C to obtain a suspension. Sodium carbonate (33.8 g, 0.3197 mol) was added to the mixture at 25-30C and stirred for one hour at 25-30C. 500 ml (10 vol.) of water was added to the reaction mixture and stirred for one hour. The crude erlotinib base was isolated by filtration and suck dried before adding it to 250 ml (5 vol.) of water at25-30C and stirred for 30 min. The erlotinib base was isolated by filtration and washed with 50 ml (1 vol.) of water and suck dried to get 70 g as a wet cake. This wet cake was dried under reduced pressure at 100 mm Hg for 3 hour at 60-65C to afford 63g of erlotinib base as an off-white powder.Molar yield = 100%HPLC purity >99%.
81 mg With pyridine; In isopropyl alcohol; for 4h;Reflux; Inert atmosphere; 3-Ethynylaniline (37 mg, 0.32 mmol.), and 4-chloro-6,7-bis-(2-methoxy-ethoxy)-quinazoline (90 mg, 0.29 mmol)were added to isopropanol (1.5 mL) containing pyridine (25 mL, 0.32 mmol) and the mixture was refluxed 4 hours underan atomospher of dry nitrogen. The solvent was removed , in vacuo, and the residue partitioned between 10% methanolin CHCl3 and saturated aqueous NaHCO3. The organic phase was dried over Na2SO4, filtered and concentrated invacuo. The residue was flash chromatographed on silica using 30% acetone in hexanes to afford 81 mg of the free baseof the title product as a pale yellow solid. The free-base was dissolved in a minimum volume of CHCl3, diluted withseveral volumes of ether, and titrated with 1 M HCl in ether to precipitate the title product as its hydrochloride salt; 90mg; 71%; mp 228-230 C.
In N,N-dimethyl-formamide; acetonitrile; for 3h;Heating; cast the resulting intermediate, 3-amino-acetylene, acetonitrile, DMF in the three-port flask, the heating reaction 3 hours. Ice water cooling to 10 C, filtering to obtain white solid, acetonitrile secondary pulping. Intermediate II the finished product obtained after drying under vacuum
4-chloro-6,7-bis (2-methoxyethoxy) quinazoline (10 g, 32 mmol) was placed in a round bottom flask, 180 mL of anhydrous methanol was added, stirred at room temperature until dissolved in the solid, Was slowly added 3-ethynylaniline (4.5 g, 38.4 mmol) at 30 C for 3 hours. The solvent was evaporated under reduced pressure to give a white solid which was washed with a small amount of petroleum ether to give the crude Erlotinidine hydrochloride.The crude Erlotinib HCl (21.5 g, 50 mmol) Into a round bottom flask, add anhydrous methanol 215mL, anhydrous sodium carbonate solid 10.6g, heated to 50 stirring 3 hours, cooled to room temperature, add distilled water 450mL, precipitation of large amounts of white solid, stirring for 1 hour, White solid (identified asN- (3-ethynylphenyl) -6,7-bis (2-methoxyethoxy) -4-quinazolinium amine)

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YieldReaction ConditionsOperation in experiment
Specific preferred compounds of formula I include the following: ... (7-aminoquinazolin-4-yl)-(3-ethynylphenyl)-amine; (3-ethynylphenyl)-(7-methoxyquinazolin-4-yl)-amine; (6-carbomethoxyquinazolin-4-yl)-(3-ethynylphenyl)-amine; (7-carbomethoxyquinazolin-4-yl)-(3-ethynylphenyl)-amine; [6,7-bis(2-methoxyethoxy)quinazolin-4-yl]-(3-ethynylphenyl)-amine; (3-azidophenyl)-(6,7-dimethoxyquinazolin-4-yl)-amine; (3-azido-5-chlorophenyl)-(6,7-dimethoxyquinazolin-4-yl)-amine; (4-azidophenyl)-(6,7-dimethoxyquinazolin-4-yl)-amine; ...
The compound of claim 1 selected from the group consisting of: ... (7-aminoquinazolin-4-yl)-(3-ethynylphenyl)-amine; (3-ethynylphenyl)-(7-methoxyquinazolin-4-yl)-amine; (6-carbomethoxyquinazolin-4-yl)-(3-ethynylphenyl)-amine; (7-carbomethoxyquinazolin-4-yl)-(3-ethynylphenyl)-amine; [6,7-bis(2-methoxyethoxy)quinazolin-4-yl]-(3-ethynylphenyl)-amine; (3-azidophenyl)-(6,7-dimethoxyquinazolin-4-yl)-amine; (3-azido-5-chlorophenyl)-(6,7-dimethoxyquinazolin-4-yl)-amine; (4-azidophenyl)-(6,7-dimethoxyquinazolin-4-yl)-amine; ...
The invention most particularly relates to compounds of the formula I selected from the group consisting of ... (7-aminoquinazolin-4-yl)-(3-ethynylphenyl)-amine; (3-ethynylphenyl)-(7-methoxyquinazolin-4-yl)-amine; (6-carbomethoxyquinazolin-4-yl)-(3-ethynylphenyl)-amine; (7-carbomethoxyquinazolin-4-yl)-(3-ethynylphenyl)-amine; [6,7-bis(2-methoxyethoxy)quinazolin-4-yl]-(3-ethynylphenyl)amine; (3-azidophenyl)-(6,7-dimethoxyquinazolin-4-yl)amine; (4-azidophenyl)-(6,7-dimethoxyquinazolin-4-yl)amine; (3-azido-5-chlorophenyl)-(6,7-dimethoxyquinazolin-4-yl)amine; ...
The compound of claim 1 selected from the group consisting of: ... (7-aminoquinazolin-4-yl)-(3-ethynylphenyl)-amine; (3-ethynylphenyl)-(7-methoxyquinazolin-4-yl)-amine; (6-carbomethoxyquinazolin-4-yl)-(3-ethynylphenyl)-amine; (7-carbomethoxyquinazolin-4-yl)-(3-ethynylphenyl)-amine; [6,7-bis(2-methoxyethoxy)quinazolin-4-yl]-(3-ethynylphenyl)amine; (3-azidophenyl)-(6,7-dimethoxyquinazolin-4-yl)amine; (3-azido-5-chlorophenyl)-(6,7-dimethoxyquinazolin-4-yl)amine; (4-azidophenyl)-(6,7-dimethoxyquinazolin-4-yl)amine; ...
In butanone; at 10 - 65℃;Purification / work up; (ii) Purification of Erlotinib baseErlotinib base of high purity is obtained by adopting the following purification method. Into a clean and dry All Glass Reactor, are charged 90 Lts of methylethyl ketone, followed by 9 Kgs of Erlotinib base obtained by the process described in Step-(i) above. The temperature is raised to 60-65C to dissolve the solid completely. Carbon treatment is given and the filtrate is cooled to 100C and centrifuged the crystallized product and <n="9"/>washed the cake with methyethyl ketone and the wet cake is dried to get 5.9 Kgs of Erlotinib base of high purity, as a pale yellow coloured crystalline solid. Purity : 99.74% (by HPLC)Melting range: 154-155C
Particularly preferred medicament combinations according to the invention contain as EGFR-inhibitors 2e those compounds which are selected from the group comprising 4-[(3-chloro-4-fluorophenyl)amino]-6-[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline (2e.1), 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline (2e.2), 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline (2e.3), 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline (2e.4), 4-[(3-ethynyl-phenyl)amino]-6,7-bis-(2-methoxy-ethoxy)-quinazoline (2e.5), 4-[(3-chloro-4-fluorophenyl)amino]-6-[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline (2e.6), 4-[(3-ethynyl-phenyl)amino]-6-[4-(5,5-dimethyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-quinazoline (2e.7), 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline (2e.8), 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-quinazoline (2e.9), ...
With sodium hydroxide; In methanol; chloroform; water; at 50℃; for 0.5h;Purification / work up; Crude erlotinib hydrochloride (37 gm, obtained in step-l), water (370 ml) and chloroform (370 ml) are taken into a reaction flask at 25 - 300C and start stirring. The contents are heated to 50 - 550C, sodium hydroxide solution is added at 50 - 550C and then stirred for 15 minutes at 500C (clear solution not observed). To the reaction mass added chloroform (200 ml) and methanol (60 ml) and stirred for 15 minutes at 500C (clear solution observed). Separated the layers at 500C, the organic layer is washed with water (200 ml) at 500C and then combined the organic layers. To the organic layer added methanol (60 ml) dried over sodium sulfate and distilled the total solvent under vacuum at 50 - 550C. To1 the residue added n-heptane (300 ml) and stirred for 30 minutes at 25 - 300C. Filtered the material, washed with n-heptane (70 ml) and then dried the material at 60 - 650C under vacuum for 3 hours 30 minutes to give 34 gm of erlotinib free base [HPLC purity: 98.2%; Content of N-methoxyethyl impurity: 0.24% (at 1.14 RRT)]

  • 7
  • [ 938185-06-9 ]
  • [ 4296-15-5 ]
  • [ 183321-74-6 ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate; In N,N-dimethyl-formamide; at 45 - 50℃; for 12h; ExampIe-4; Preparation of Erlotinib Hydrocloride, polymorphic form-P :(i) Preparation of N-(3-ethynyIphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazoIinamine (Erlotinib base).For the preparation of Erlotinib base, the starting intermediate N-(3-ethynyl phenyl)-6,7- dihydroxy-4-quinazolinamine, is obtained from the process described in steps (i) to (v) of Example-(l) of PCT international publication No. WO 2007/060691.Into a clean and dry stainless steel reactor, are charged 250 Lts of dimethyl formamide, followed by 30 Kgs of potassium carbonate (anhydrous) and 10 Kgs of N-(3-ethynyl phenyl)-6,7-dihydroxy-4-quinazolinamine under nitrogen atmosphere. To this reaction mixture 14.0 Kgs of 2-Iodo ethyl methyl ether is added and maintained at 45-5O0C for about 12 hrs and the reaction is found to be completed by HPLC -Test. Then the reaction mass is cooled to room temperature and the mass is centrifuzed to remove the inorganic salt .To the collected filtrate, demineralized water is slowly added, under stirring below 35C, so that the product is crystallized out. Then the product is centrifuged and washed with water and the wet cake is dried to get 9.8 Kgs (69% by theory) of Erlotinib base as a brownish yellow coloured crystalline solid. Purity : 99.17% (by HPLC)Melting range: 151-153C
With potassium carbonate; In N,N-dimethyl-formamide; at 45 - 50℃; (vi) Preparation of N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine (Erlotinib base) of formula (1)Into a 2.0 L four necked round bottomed flask equipped with a mechanical stirrer, reflux condenser, thermometer socket, are charged dimethylformamide (1250 ml), anhydrous potassium carbonate (150 g), N-(3-ethynylphenyl)-6,7-hydroxy-4-quinazolinamine (50 g) obtained from the process described in step (v) above. To the reaction mixture, 2-iodo-ethylmethyl ether (70 g) was added in about 10-15 minutes. Then slowly raised the temperature to 45 and maintained for 12 hours at 45-50 C. and the reaction was found to be over by HPLC. Then cooled the reaction mass to 30-35 C. and filtered to remove the inorganic salt. Washed the cake with DMF. The solvent was removed by distillation under reduced pressure. Cooled the reaction mass to 30-35 C. and extracted the product by the addition of water and methylene chloride. The organic layer was separated and washed with water and dried over sodium sulfate. The solvent was removed under reduced pressure to get the residue which was triturated with toluene and the product was obtained by filtration and dried to get crude erlotinib base (N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine) (42 g) (59.1% by theory) as a light yellow colored crystalline solid.Purity: 99% (by HPLC).Melting range: 151-153 C.; (vii) Recrystallization of Erlotinib BaseInto a 1.0 L four necked round bottomed flask equipped with a mechanical stirrer, reflux condenser and thermometer socket, are charged ethyl acetate (480 ml), Erlotinib base (40 g) obtained by the process described in step (vi) above and slowly raised the temperature to 75-80 C. to dissolve the base completely. Then activated carbon (6 g) was charged and maintained for 15-20 minutes. Filtered and washed the carbon cake with hot ethyl acetate. The combined filtrate and washings were cooled to 25-30 C. and then cooled further to 0-5 C. The reaction mass was maintained at 0-5 C. for 1 hour, filtered, washed with chilled ethyl acetate and dried to get 36 g of pure erlotinib base of formula (1) as light yellow colored crystalline solid.MR: 154-155 C.Purity: 99.65% (by HPLC).IR (KBr): 3250, 2927, 1619, 1576, 1502, 1428, 1332, 1255, 1217, 1153, 1130, 1094, 1066, 1032, 979, 940, 849, 770, 662, and 588 cm-1.1H NMR (300 MHz, DMSO-d6): 3.29 (s, 6H); 3.73 (t, 4H); 3.92 (s, 1H); 4.11-4.21 (m, 4H); 7.14 (s, 1H); 7.38-7.48 (m, 2H); 7.53-7.75 (dd, 1H); 7.86 (s, 1H); 8.37 (s, 1H); 8.84 (s, 1H); 11.44 (s, 1H).13C NMR (75 MHz, DMSO-d6): 58.37, 68.60, 69.17, 69.66, 69.90, 81.09, 82.91, 100.28, 105.02, 107.12, 121.77, 125.19, 127.42, 128.78, 129.03, 135.16, 137.16, 148.19, 149.12, 155.30, 157.70.Mass: 394 (M+1).
YieldReaction ConditionsOperation in experiment
In 1,4-dioxane; at -30 - 80℃;Purification / work up; <strong>[183321-74-6]Erlotinib</strong> base (127 mg) was dissolved in 1,4-dioxane (6 ml) at 80 C. The solution was allowed to cool to 25 C. and put in the refrigerator at -30 C. where the solution was frozen. The frozen solution was transferred to the lyophylisator and a vacuum of 1 mBar was applied, which provided the freeze drying of 1,4-diolane affording amorphous <strong>[183321-74-6]erlotinib</strong> base.
With pyrographite; In butan-1-ol; at 80 - 85℃; for 1h;Purification / work up; Example 2: Further purification of crude <strong>[183321-74-6]erlotinib</strong> base60 g of crude <strong>[183321-74-6]erlotinib</strong> base was added to 480 ml (8 vol,) of 1-butanol under stirring at 25- 30C. The mixture was heated to 80-85C to obtain a clear solution and maintained for one hour at 80-90C. The solution was slowly cooled to 25-30C and the product was isolated by filtration and washed with 120 ml (2 vol.) of 1-butanol. The wet cake was again added to 360 ml (6 vol.) of 1-butanol and the mixture heated to 80-90C to obtain a clear solution. 2.7 g Activated charcoal ( orit B) was added into the clear solution and maintained for 1 hour at 80-85C. The reaction mixture was filtered through a Celite bed at 80-85C and die Celite bed was washed with 1 volume hot 1-butanol. The combined mother liquor was slowly cooled to 25-30C and stirred for 1 hour. The product was isolated by filtration and washed with 120 ml (2 vol.) of 1-butanol. The purified edotinib base was dried at 65-75C for 8 hours, under reduced pressure (160 mm Hg) to afford 35 g as a white powder.Molar yield = 58.3%HPLC purity 99.9%
  • 9
  • [ 179688-29-0 ]
  • [ 54060-30-9 ]
  • [ 183321-74-6 ]
YieldReaction ConditionsOperation in experiment
82% With titanium tetrachloride; methoxybenzene; In 1,4-dioxane; for 4h;Inert atmosphere; Reflux; 6,7-Bis(2-methoxyethoxy)quinazolin-4(3H)-one (VI) (14.7 g, 0.05 mol) was suspended in absolute dioxane (150 ml) and 3-aminophenylacetylene (7.0 g, 0.06 mol) was added. In a dropping funnel a mixture of TiCI4 (11.4 g, 6.6 ml, 0.06 mol) and anisole (32.4 g, 33.0 ml, 0.30 mol) was prepared under argon atmosphere, and then the obtained brown solution was added dropwise with stirring and cooling of the suspension of amide (VI). During the addition of TiC14-anisole complex the clear brown solution is formed. The reaction mixture was refluxed for 4 h and then cooled to room temperature. EtOAc (300 ml) and 1120 (10 ml) were added, and the mixture was stirred for 30 mm. The formed precipitate was filtered off and washed with EtOAc (3 x 30 ml). The organic filtrate was extracted with 5% HC1 (50 ml), water phase was separated, neutralized with saturated Na2CO3 sloution (50 ml) and extracted with EtOAc (3 x 50 ml). The organic extract was dried with Na2SO4 and evaporated in vacuum. Erlotinib (I) base is obtained in a form of an yellowish oil, that crystallizes on standing. Yield 16.1 g (82%).
64% (2) Preparation of Erlotinib 6,7-bis(2-methoxyethoxy)quinazolin-4-one 16 (0.53 g, 1.80 mmol) is placed in a two-neck bottle of 50 ml, N2 is added at room temperature, toluene (5.3 ml) and triethylamine(0.39 ml=0.28 g, 2.77 mmol), phosphorus oxychloride(0.57 ml=0.94 g, 6.12 mmol) is added and stirred for 10 minutes, and at 65 C. N2 is added and reaction is carried out for 3 hours. 3-aminophenylacetylen (0.22 g, 1.84 mmol) dissolved in isopropanol (1 ml) is added to the above reaction solution to continue reaction for 2.5 hours. After the reaction is completed, Erlotinib (0.5 g, 64%) that is white solid compound is obtained by cooling, filter and solid drying (in oven at 65 C.), whose purity determined by HPLC is greater than 99.7%. 1H-NMR (DMSO) spectrum: 3.35 (s, 6H), 3.77 (brs, 4H), 4.28 (s, 1H), 4.32 (brs, 2H), 4.38 (brs, 2H), 7.41 (m, 2H), 7.49 (m, 1H), 7.78 (m, 1H), 7.87 (s, 1H), 8.44 (s, 1H), 8.85 (s, 1H), 11.56 (s, 1H).
  • 10
  • [ 183321-74-6 ]
  • N‐(3‐ethynylphenyl)‐6,7‐bis(2‐methoxyethoxy)quinazolin‐4‐amine hydrochloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
100% With hydrogenchloride; In diethyl ether; dichloromethane; at 15 - 30℃; for 3.08333h;Product distribution / selectivity; Example 4: Preparation of <strong>[183321-74-6]Erlotinib</strong> Hydrochloride Form A<strong>[183321-74-6]Erlotinib</strong> base (2.0 g) was charged into dichloromethane (40 ml) at 25C to 30C and stirred for 10 minutes at 25C to 30C to give a clear solution. The solution was cooled to 15C to 20C and 4% hydrogen chloride in ether (10 ml) was added slowly in 5 minutes at 15C to 20C. The temperature of the reaction mass was raised to 25C to 30C and stirred for 3 hours at 25C to 30C. The reaction mass was filtered, washed with dichloromethane (10 ml) and dried under vacuum for 6 hours at 40C to 45C.Yield: 2.18 g (100%)
97.2% With hydrogenchloride; In 1,4-dioxane; isopropyl alcohol; at 0 - 70℃; for 1.5h; 10.0 g crystal form IV of <strong>[183321-74-6]erlotinib</strong> base was added to 200 ml 1,4-dioxane, heated to dissolve until being clarified, 6.4 g isopropanol saturated with HCl gas was added dropwise at 60-70 C., after dripping, stirred for 30 minutes while maintaining the temperature, stirred for 1 hour at 0-15 C. before filtration, dried at 50 C. to obtain 10.6 g sample of crystal form A. The yield was 97.2% and the purity was 99.8% (by HPLC).
93.13% With hydrogenchloride; In water; butanone; at 30 - 35℃; <strong>[183321-74-6]Erlotinib</strong> hydrochloride (crystalline form B) was prepared in accordance with the process described in U.S. Patent Publication No. 2009-0131665, which is incorporated in its entirety here by reference.[100] 20.00 g (50.83 mmol) of <strong>[183321-74-6]erlotinib</strong> was added to 440 of a mixture of methyl ethyl ketone and distilled water (10:1, v/v) and heated to 30 to 35 to give a complete solution. 5.15 (61.00 mmol) of conc. HCl was added dropwise, and the reaction solution was stirred strongly.[101] The light yellow crystalline solid formed was filtered and dried under vacuum at 60 for 20 hours to give 20.35 g of the target compound. The yield was 93.13%.
30.0 g With hydrogenchloride; In isopropyl alcohol; at 20 - 65℃; for 1h; Charge mixture of 1.5 lit MIBK:IPA (50:50) in a clean three necked round bottom flask and stir for about 10 minutes. Add 30.0gm <strong>[183321-74-6]Erlotinib</strong> (free base) at room temperature under stirring. Raise the temperature of reaction mixture up to 60-65C and stir for about 30 mm. and ensure the solution to become clear. Filter this solution through membrane filter. Collected clear filtrate taken into clean three necked round bottom flask and temperature is raised to again at 60-65C under stirring to maintain the clear solution. Start adding slowly added IPA:HCI solution (about 14 % v/w) at 60-65C under stirring.Cool the reaction solution to room temperature naturally and stir for about 30 minutes at roomtemperature.Filter the separated solid and subject it to drying at about 60-70C under vacuum for nearly 12 hrs.Yield: 30.0gH. Individual Impurity =0.04%; Total impurities=0.2%; Water content =0.2%Purity: 99.8% (By HPLC purity)
90 mg With hydrogenchloride; In diethyl ether; chloroform; 3-Ethynylaniline (37 mg, 0.32 mmol.), and 4-chloro-6,7-bis-(2-methoxy-ethoxy)-quinazoline (90 mg, 0.29 mmol)were added to isopropanol (1.5 mL) containing pyridine (25 mL, 0.32 mmol) and the mixture was refluxed 4 hours underan atomospher of dry nitrogen. The solvent was removed , in vacuo, and the residue partitioned between 10% methanolin CHCl3 and saturated aqueous NaHCO3. The organic phase was dried over Na2SO4, filtered and concentrated invacuo. The residue was flash chromatographed on silica using 30% acetone in hexanes to afford 81 mg of the free baseof the title product as a pale yellow solid. The free-base was dissolved in a minimum volume of CHCl3, diluted withseveral volumes of ether, and titrated with 1 M HCl in ether to precipitate the title product as its hydrochloride salt; 90mg; 71%; mp 228-230 C.

  • 11
  • [ 6482-24-2 ]
  • [ 183321-74-6 ]
  • N-[(3-ethynylphenyl)-(2-methoxyethyl)]-6,7-bis(2-methoxyethoxy)-4-quinazolinamine [ No CAS ]
  • C25H29N3O5 [ No CAS ]
  • C25H29N3O5 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 24h;Product distribution / selectivity; In order to determine whether the <strong>[183321-74-6]erlotinib</strong> prepared by the process of the present invention contains the impurity mentioned in WO 2009/007984, namely N-[(3-ethynylphenyl)-2-methoxyethyl)]-6,7-bis(2-methoxyethoxy)-4- quinazolinamine (of which, as stated in this document, it is difficult to purify <strong>[183321-74-6]erlotinib</strong>), this impurity was prepared and was identified following the methods described in this patent application. Thus, this impurity was prepared by alkylation of eriotinib. The alkylation was carried out in DMF at 80 C for 24 h using bromoethyl methyl ether as alkylating agent. The reaction gave a mixture of starting material (60%) and three products (25%, 7.7% and 6.0%) having the same mass (m/z = 452). Based on the HPLC-MS results and on NMR spectroscopy, this could be a mixture of the three possible isomers, C, D and E, drawn below.
  • 12
  • [ 183322-18-1 ]
  • [ 183321-74-6 ]
  • 13
  • [ 1312937-41-9 ]
  • [ 54060-30-9 ]
  • [ 183321-74-6 ]
YieldReaction ConditionsOperation in experiment
70% In a 100 mL flask, a solution of 3-ethynylaniline (1 .46 mL, 12.97 mmol, 2 eq.) in anhydrous THF (10 mL) was cooled to 0 C under N2. n-BuLi (2.35 M in toluene, 1 1 .04 mL, 25.9 mmol, 4 eq.) was added slowly at 0 C and the mixture was stirred at 0 C for 30 min. A solution of 6,7-bis(2-methoxyethoxy)- 4-methoxyquinazoline (2.00 g, 6.48 mmol) in anhydrous tetrahydrofuran (THF) (15 mL) was added over 10 min and the reaction mixture was stirred at room temperature for 4 h. The reaction was quenched with H2O (5 mL). THF was removed under reduced pressure and H2O (20 mL) was added. The aqueous layer was extracted with AcOEt (3 x 20 mL). The combined organic layers were dried over MgSO4 and were evaporated under reduced pressure to give a brown oil (3.1 1 g). The crude was purified by flash chromatography on silica gel (eluent: CH2CI2 to CH2CI2/MeOH 95/5) to give erlotinib as a yellow solid (1 .78 g, 70%). 1H NMR (CDCI3, ppm): delta 8.66 (s, 1 H), 7.86 (s, 1 H), 7.76 (m, 1 H), 7.35 (m, 1 H), 7.28 (s, 1 H), 7.22 (s, 1 H), 7.21 (s, 1 H), 4.36-4.25 (m, 4H), 3.85-3.81 (m, 4H), 3.48 (s, 3H), 3.46 (s, 3H), 3.10 (s, 1 H).
70% Example 4: Preparation of erlotinib from 6,7-bis(2-methoxvethoxy)-4-methoxyquinazoline using n-BuLi In a 100 mL flask, a solution of 3-ethynylaniline (1.46 mL, 12.97 mmol, 2 eq.) in anhydrous THF (10 mL) was cooled to 0 C under N2. n-BuLi (2.35 M in toluene, 11.04 mL, 25.9 mmol, 4 eq.) was added slowly at 0 C and the mixture was stirred at 0 C for 30 min. A solution of 6,7-bis(2-methoxyethoxy)-4-methoxyquinazoline (2.00 g, 6.48 mmol) in anhydrous tetrahydrofuran (THF) (15 mL) was added over 10 min and the reaction mixture was stirred at room temperature for 4 h. The reaction was quenched with H2O (5 mL). THF was removed under reduced pressure and H2O (20 mL) was added. The aqueous layer was extracted with AcOEt (3 x 20 mL). The combined organic layers were dried over MgSO4 and were evaporated under reduced pressure to give a brown oil (3.11 g). The crude was purified by flash chromatography on silica gel (eluent: CH2Cl2 to CH2Cl2/MeOH 95/5) to give erlotinib as a yellow solid (1.78 g, 70%). 1H NMR (CDCl3, ppm): delta 8.66 (s, 1 H), 7.86 (s, 1 H), 7.76 (m, 1 H), 7.35 (m, 1 H), 7.28 (s, 1 H), 7.22 (s, 1 H), 7.21 (s, 1 H), 4.36-4.25 (m, 4H), 3.85-3.81 (m, 4H), 3.48 (s, 3H), 3.46 (s, 3H), 3.10 (s, 1 H).
  • 15
  • [ 4101-33-1 ]
  • [ 183321-74-6 ]
  • 16
  • [ 16064-15-6 ]
  • [ 183321-74-6 ]
  • 17
  • [ 1312937-40-8 ]
  • [ 183321-74-6 ]
  • 18
  • [ 6482-24-2 ]
  • [ 183321-74-6 ]
  • N-[(3-ethynylphenyl)-(2-methoxyethyl)]-6,7-bis(2-methoxyethoxy)-4-quinazolinamine [ No CAS ]
  • C25H31N3O5 [ No CAS ]
  • C25H31N3O5 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 24h; Example 18: Determination of the amount of the impurity described in WO2009/007984 in the <strong>[183321-74-6]erlotinib</strong>/<strong>[183321-74-6]erlotinib</strong> hydrochloride prepared by the process of the present invention. In order to determine whether the <strong>[183321-74-6]erlotinib</strong> prepared by the process of the present invention contains the impurity mentioned in WO 2009/007984, namely N-[(3-ethynylphenyl)-2-methoxyethyl)]-6,7-bis(2-methoxyethoxy)-4-quinazolinamine (of which, as stated in this document, it is difficult to purify <strong>[183321-74-6]erlotinib</strong>, this impurity was prepared and was identified following the methods described in this patent application. Thus, this impurity was prepared by alkylation of <strong>[183321-74-6]erlotinib</strong>. The alkylation was carried out in DMF at 80 C for 24 h using bromoethyl methyl ether as alkylating agent. The reaction gave a mixture of starting material (60%) and three products (25%, 7.7% and 6.0%) having the same mass (m/z = 452). Based on the HPLC-MS results and on NMR spectroscopy, this could be a mixture of the three possible isomers, C, D and E, drawn below.
  • 21
  • C24H30N4O4 [ No CAS ]
  • [ 183321-74-6 ]
  • 22
  • methoxyethoxy 3,4-bis(2-methoxyethoxy)-benzoate [ No CAS ]
  • [ 183321-74-6 ]
  • 26
  • [ 950596-59-5 ]
  • [ 183321-74-6 ]
  • 28
  • [ 79-43-6 ]
  • [ 183321-74-6 ]
  • [ 1355242-84-0 ]
YieldReaction ConditionsOperation in experiment
95.43% In isopropyl alcohol; at 20 - 25℃; for 0.0416667h;Product distribution / selectivity; 3.94 g (10.01 mmol) of <strong>[183321-74-6]erlotinib</strong> was suspended in 10 of isopropanol, and 0.83 ml (10.01 mmol) of dichloroacetic acid was added dropwise. Then, the reaction solution was stirred for 30 minutes at 20 to 25 . After the compounds were completely dissolved in the reaction solution and a solid began to be formed, 65 of isopropanol was added and the reaction solution was further stirred for 2 hours at 20 to 25 .[85] The light yellow crystalline solid formed was filtered, washed with 10 of isopropanol and dried under vacuum at 60 for 20 hours to give 4.99 g of the target compound. The yield was 95.43%. The obtained crystalline <strong>[183321-74-6]erlotinib</strong> dichloroacetate was subjected to X-ray powder diffraction (XRPD) and differential scanning calorimeter (DSC) analyses, and the results are shown in Figs. 3 and 4, respectively.[86] M.P.: 140-142
  • 29
  • [ 183321-74-6 ]
  • [ 1415223-74-3 ]
  • [ 1415223-75-4 ]
  • [ 1415223-76-5 ]
  • [ 1415223-77-6 ]
  • [ 1415223-78-7 ]
  • [ 1415223-79-8 ]
  • N-(5-ethynyl-2-fluorophenyl)-5-chloro-6,7-bis(2-methoxyethoxy)quinazolin-4-amine [ No CAS ]
  • 2-fluoro-4-(3-ethynylanilino)-6,7-bis(2-methoxyethoxy)quinazoline [ No CAS ]
  • C22H22FN3O4 [ No CAS ]
  • [ 776274-03-4 ]
  • [ 1415223-68-5 ]
  • [ 1415223-69-6 ]
  • [ 1415223-70-9 ]
  • [ 1415223-71-0 ]
  • [ 1415223-72-1 ]
  • [ 1415223-73-2 ]
YieldReaction ConditionsOperation in experiment
With dichloromethane; fluorine; at -78℃; for 0.5h; Example 1 N-(3-ethynyl-5-fluorophenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine [0064] [0065] 300 mg <strong>[183321-74-6]erlotinib</strong> was dissolved in 200 mL CH2Cl2 at -78 C. cooled by dry-ice/acetone bath. A mixture of F2 and N2 gas containing 20% F2/80% N2 was passed through the reaction vessel continuously at a flow rate of 2 L/min. Reaction was stopped after 30 min and the solvent was removed under vacuum. Dried reaction products were dissolved in 3 mL acetonitrile and was separated on an Agilent Zorbax C8 250×4.6 mm column, gradient elution from 30% MeOH/70% 0.1% formic acid in dd-H2O to 90% MeOH/10% 0.1% formic acid in dd-H2O, 1 ml/min total flow rate. Each fraction was analyzed by mass spectrometry. Fractions containing reaction products without excess amount of the starting material <strong>[183321-74-6]erlotinib</strong>, were mixed to form the modified <strong>[183321-74-6]erlotinib</strong> mixture compound library for drug property screening to identify components with improved properties over <strong>[183321-74-6]erlotinib</strong>. A component with m/z value corresponding to mono-fluorinated <strong>[183321-74-6]erlotinib</strong> was isolated and purified by successive preparative HPLC separations. The purified compound was analyzed by LC-MS/MS and NMR to provide the structure of the title compound. The observed m/z value 412.1665 (Thermo Finnigan LTQ Orbitrap, positive ion mode), is consistent with calculated m/z of protonated mono-fluorinated <strong>[183321-74-6]erlotinib</strong> (m/z(calc)=412.1667), molecular formula: C22H23FN3O4+. High resolution MSn (n=2-4) experiments on LTQ orbitrap indicate the fluorine substitution is on the 3-ethynylphenyl ring of <strong>[183321-74-6]erlotinib</strong> (fragment at m/z 136.0555, calc: 136.0557 for C8H7FN+). 1H-NMR spectra data indicate the fluorine substitution is at the 5-position of the 3-ethynylphenyl ring of <strong>[183321-74-6]erlotinib</strong>. 1H-NMR (400 MHz, DMSO-d6) delta ppm 3.42 (s, 3H), 3.45 (s, 3H), 3.83 (m, 4H), 4.2-4.4 (m, 5H), 7.06 (dt, J=8.1, 1.7, 1H), 7.49 (s, 1H), 7.74 (dt, J=8.0, 1.5, 1H), 8.01 (t, 1.6, 1H), 8.21 (s, 1H), 9.02 (s, 1H). Example 2 N-(5-ethynyl-2-fluorophenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine [0066] [0067] 300 mg <strong>[183321-74-6]erlotinib</strong> was dissolved in 200 mL CH2Cl2 at -78 C. cooled by dry-ice/acetone bath. A mixture of F2 and N2 gas containing 20% F2/80% N2 was passed through the reaction vessel continuously at a flow rate of 2 L/min. Reaction was stopped after 30 min and the solvent was removed under vacuum. Dried reaction products were dissolved in 3 mL acetonitrile and was separated on an Agilent Zorbax C8 250×4.6 mm column, gradient elution from 30% MeOH/70% 0.1% formic acid in dd-H2O to 90% MeOH/10% 0.1% formic acid in dd-H2O, 1 ml/min total flow rate. Each fraction was analyzed by mass spectrometry. Fractions containing reaction products without excess amount of the starting material <strong>[183321-74-6]erlotinib</strong>, were mixed to form the modified <strong>[183321-74-6]erlotinib</strong> mixture compound library for drug property screening to identify components with improved properties over <strong>[183321-74-6]erlotinib</strong>. A component with m/z value corresponding to mono-fluorinated <strong>[183321-74-6]erlotinib</strong> was isolated and purified by successive preparative HPLC separations. The purified compound was analyzed by LC-MS/MS and NMR to provide the structure of the title compound. The observed m/z value 412.1664 (Thermo Finnigan LTQ Orbitrap, positive ion mode), is consistent with calculated m/z of protonated mono-fluorinated <strong>[183321-74-6]erlotinib</strong> (m/z(calc)=412.1667), molecular formula: C22H23FN3O4+. High resolution MSn (n=2-4) experiments on LTQ orbitrap indicate the fluorine substitution is on the 3-ethynylphenyl ring of <strong>[183321-74-6]erlotinib</strong> (fragment at m/z 136.0556, calc: 136.0557 for C8H7FN+). 1H-NMR spectra data indicate the fluorine substitution is at the 6-position of the 3-ethynylphenyl ring of <strong>[183321-74-6]erlotinib</strong>. 1H-NMR (400 MHz, DMSO-d6) delta ppm 3.43 (s, 3H), 3.46 (s, 3H), 3.8 (m, 4H), 4.4 (m, 5H), 7.29 (s, 1H), 7.42 (dd, J=8.4, 1.9, 1H), 7.56 (dd, 8.4, 8.0, 1H), 8.36 (dd, J=4.8, 1.9, 1H), 8.49 (s, 1H), 8.84 (s, 1H). Example 3 N-(5-ethynyl-2-chlorophenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine [0068] [0069] 300 mg <strong>[183321-74-6]erlotinib</strong> was dissolved in 200 mL CH2Cl2 at -78 C. cooled by dry-ice/acetone bath. A mixture of F2 and N2 gas containing 20% F2/80% N2 was passed through the reaction vessel continuously at a flow rate of 2 L/min. Reaction was stopped after 30 min and the solvent was removed under vacuum. Dried reaction products were dissolved in 3 mL acetonitrile and was separated on an Agilent Zorbax C8 250×4.6 mm column, gradient elution from 30% MeOH/70% 0.1% formic acid in dd-H2O to 90% MeOH/10% 0.1% formic acid in dd-H2O, 1 ml/min total flow rate. Each fraction was analyzed by mass spectrometry. Fractions containing reaction products without excess amount of the starting material <strong>[183321-74-6]erlotinib</strong>, were mixed to form the modified <strong>[183321-74-6]erlotinib</strong> mixture compound library for drug property screening to identify components with improved properties over <strong>[183321-74-6]erlotinib</strong>. A component with m/z value corresponding to mono-chlorinated <strong>[183321-74-6]erlotinib</strong> was isolated and purified by successive preparative HPLC separations. The purified compound was analyzed by LC-MS/MS and NM...
  • 30
  • [ 110-16-7 ]
  • [ 183321-74-6 ]
  • [6,7-bis(2-methoxyethoxy)-4-chinazolinyl](3-ethynylphenyl)amine maleate [ No CAS ]
YieldReaction ConditionsOperation in experiment
0.41 g In ethanol;Reflux; Into an apparatus 10 ml of ethanol are weighed in whereupon 0.496 g /l .26 millimoles/ of <strong>[183321-74-6]erlotinib</strong> base is dissolved therein under intensive stirring and under reflux. To the reaction mixture a solution of 0.146 g /L26 millimoles/ of maleic acid is added at this temperature under stirring. After some seconds the precipitation of crystals begins. Stirring is continued until the reaction mixture cools to room temperature. The precipitated crystalline product is filtered and washed with tertiary butyl methyl ether. The crude product is dried at 50C under a pressure of 160 mbar for 10 hours.Yield: 0.63 g (98 %)Mp.: 164.5-167C b) 0.48 g of the crude product thus obtained is recrystallized from 27 ml of methanol. The mixture is allowed to stand in a refrigerator overnight, the precipitated product is filtered, washed with a small amount of cold methanol and tertiary butyl methyl ether.Thus 0.41 g (85 %) of the Ml polymorph /Form Ml/ are obtained as white crystals.Mp.: 169.4-173C.Analysis for the Formula C22H23N304 · C4H404 · H20 (527,53): Calc: C: 59.20 H: 5.54 N: 7.97Found: C: 60.01 H: 5.67 N: 7.93Water content ( F method) 3.79 %.IR (KBr, cm'1): 3275, 1584, 1524, 1447, 1039.?-NMR (DMSO-^6, 500 MHz): 10.1 1 (b, 1H), 8.66 (s, 1H), 7.93 (m, 1H), 7.92 (s, 1H),7.82 (m, lH), 7.46 (m, 1H), 7.32 (m, 1H), 7.22 (s, 1H), 6.19 (s, 2H), 4,30 (m, 4H), 4.17 (s, 1H), 3.80 (m, 2H), 3.77 (m, 2H), 3.37 (s, 3H), 3.37 (s, 3H).13C-NMR (DMSO-i/6, 125 MHz) 167.07, 157.11, 154.80, 151.20, 148.90, 141.96, 138.74, 132.80, 129.21, 127.90, 126.15, 123.84, 122.11, 108.26, 105.03, 103.84, 83.35, 81.02, 70.1 1, 68.71, 68.57, 58.55. c) 3.0 g (5.9 millimoles) of the crude product obtained according to par. a) are recrystallized from 90 ml of a 80:20 mixture of methanol and water whereupon the reaction mixture is cooled to 20-25C within an hour under stirring. The precipitate is filtered and washed with a 80:20 mixture of methanol and water. The wet solid is dried at room temperature in vacuo until constant weight.Yield: 2.67 g (89%), A pale fluffy precipitate of the M2 polymorph /Form M2/.Mp. 167.9-171.5C.The ?-NMR and 13C-NMR data of the product are identical with the values disclosed in point b).
0.602 g In methanol; at 50℃; for 18h; Methanol (1 mL) was added to a mixture of <strong>[183321-74-6]erlotinib</strong> free base (0.4 g) and maleic acid (0.232 g) and then slurried for 18 hours at 50C. The solvent was evaporated at 25C to 30C and the solid obtained was dried at 55C in a vacuum tray drier for 6 hours to obtain the title compound. Yield: 0.602 g
  • 31
  • [ 69-72-7 ]
  • [ 183321-74-6 ]
  • [ 1429636-51-0 ]
YieldReaction ConditionsOperation in experiment
0.85 g In ethanol;Reflux; Into an apparatus 25 ml of ethanol are weighed in whereupon 1.3 g (3.3 millimoles) of <strong>[183321-74-6]erlotinib</strong> base are dissolved therein under stirring and reflux. To the reaction mixture at this temperature 0.454 g (3.3 millimoles) of salicylic acid are added under stirring; the colour of the solution becomes yellow. The reaction mixture is allowed to cool to room temperature while the precipitation of crystals begins. The precipitated crystalline product is filtered, washed with tert.butyl methyl ether and washed on the air at room temperature for a day. Yield: 1.51 g (86 %). The crude product thus obtained is recrystallized from 30 ml of isopropanol. The precipitate is filtered and washed with a small amount of cold isopropanol and tertiary butyl methyl ether. Yield :0.85 g (57 %), a pale yellow substance.Mp.: 138.8-142.4C.Analysis for the Formula C22H23N304 C7H603 (531.57):Calc: C: 65.53 H: 5.50 N: 7.90Found: C: 64.47 H: 5.72 N: 7.70IR (KBr, cm4): 3266, 3063, 1642, 1588, 1459, 1127.1H-NMR (DMSO-i¾, 500 MHz): 9.66 (b, 1H), 8.56 (s, 1H), 8.00 (m, 1H), 7.90 (m, 1H), 7.89 (s, 1H), 7.81 (m, 1H), 7.48 (m, 1H), 7.42 (m, 1H), 7.25 (s, 1H), 6.93 (m, 1H), 6.90 (m, 1H), 4.30 (m, 4H), 4.19 (s, 1H), 3.79 (m, 2H), 3.77 (m, 2H), 3.39 (s, 3H), 3.37 (s, 3H).13C-NMR (DMSO-d6, 125 MHz) 172.13, 161.43, 156.50, 154.10, 152.44, 148.46, 145.76, 139.66, 135.28, 130.39, 129.03, 126.83, 125.22, 122.98, 121.95, 1 18.97, 1 17.07, 113.90, 108.88, 107.50, 103.55, 83.58, 80.69, 70.19, 68.60, 68.30, 58.50.
  • 32
  • [ 17199-29-0 ]
  • [ 183321-74-6 ]
  • [ 1429636-52-1 ]
YieldReaction ConditionsOperation in experiment
0.29 g In ethanol;Reflux; Into an apparatus 10 ml of ethanol are weighed in under intensive stirring, whereupon 0.537 g /l .36 millimoles/ of <strong>[183321-74-6]erlotinib</strong> base are dissolved therein under intensive stirring and reflux. To the reaction mixture at this temperature 0.207 g /1.36 millimoles/ of L-mandelic acid are added, whereby the colour of the solution becomes yellow. The reaction mixture is allowed to stand overnight at room temperature under stirring whereby the slow precipitation of crystals begins. The reaction mixture is allowed to stand at room temperature overnight. The precipitated crystalline product is filtered and washed with a small amount of ethanol and tertiary butyl methyl ether.Yield 0.54 g (72% ).0.325 g of the crude product thus obtained is recrystallized from 25 ml of isopropanol. The suspension is allowed to stand overnight, then filtered and washed with a small amount of cold isopropanol and tertiary butyl methyl ether. Yield: 0.29 g (89 %).Mp.: 140.4-141.1C.Analysis for the Formula a C22H23N304 · C8H803 (545.60):Calc: C: 66.04 H: 5.73 N: 7.70Found: C: 66.26 H: 5.72 N: 7.65IR (KBr, cm ): 3231, 2927, 1636, 1583, 1515, 1448, 1365, 1327, 1278.?-NMR (DMSC 500 MHz): 9.48 (b, 1H), 8.02 (m, 1H), 7.92 (m, 1H), 7.87 (s, 1H), 7.42(m, 2H), 7.41 (m, 1H), 7.35 (m, 2H), 7.29 (m, 1H), 7.24 (s, 1H), 7.23 (m, 1H), 5.05 (s, 1H),4.30 (m, 4H), 4.18 (s, 1H), 3.80 (m, 2H), 3.76 (m, 2H), 3.39 (s, 3H), 3.36 (s, 3H).13C-NMR (DMSO- 6, 125 MHz) 174.26, 156.32, 153.90, 152.90, 148.34, 147.05, 140.43,139.97, 129.03, 128.26, 127.77, 126.79, 126.53, 124.95, 122.74, 121.93, 109.10, 108.33,103.46, 83.68, 80.62, 72.60, 70.30, 70.23, 68.60, 68.24, 58.56.
  • 33
  • [ 124-04-9 ]
  • [ 183321-74-6 ]
  • [ 1429636-54-3 ]
YieldReaction ConditionsOperation in experiment
0.55 g In ethanol;Reflux; Into an apparatus 10 ml of ethanol are weighed in under intensive stirring whereupon 0.604 g /l .54 millimoles/ of <strong>[183321-74-6]erlotinib</strong> base are dissolved therein under reflux. To the reaction mixture at this temperature a solution of 0.225 g l .54 millimoles/ of adipinic acid in 5 ml of ethanol is added under stirring. The reaction mixture is allowed to cool to room temperature under stirring while the precipitation of crystals begins already in the warm solution, The precipitated product is filtered and washed with tertiary butyl methyl ether. The product is dried at room temperature on the air for a day.Yield: 0.70 g (84 %).The crude product thus obtained is recrystallized from 25 ml of isopropanol. The precipitate is filtered and washed with a small amount of cold isopropanol and tertiary butyl methyl ether. Thus 0.55 g (78 %) of a white crystalline product is obtained.Mp.: 150.3-154.0CAnalysis for the Formula C22H23N304 · C6Hi0N3O4 (539.59):Calc: C: 62.33 H: 6.16 N: 7.79Found: C: 62.63 H: 6.29 N: 7.69 IR (KBr, cm-1): 3254, 2929, 2456, 1606, 1574, 1515, 1446, 1327, 1286, 1128, 1073, 1035. ?-NMR 400 MHz): 12.00 (b, 2H), 9.46 (b, 1H), 8.51 (s, 1H), 8.01 (m, 1H), 7.92 (m, 1H), 7.87 (s, 1H), 7.41 (m, 1H), 7,23 (s, 1H), 7.22 (m, 1H), 4.30 (m, 4H), 3.80 (m, 2H), 3.76 (m, 2H), 3.39 (s, 3H), 3.37 (s, 3H), 2.21 (m, 4H), 1.52 (m, 4H).,3C-NMR (DMSO- , 100 MHz): 174.46, 156.29, 153.88, 152.93, 148.33, 147.17, 139.98, 129.02, 126.49, 124.91, 122.70, 121.92, 109.1 1, 108.40, 103.45, 83.67, 80.61, 70.31, 70.24, 68.59, 68.23, 58.56, 33.56, 24.21.
  • 34
  • [ 81-04-9 ]
  • [ 183321-74-6 ]
  • [6,7-bis(2-methoxyethoxy)-4-chinazolinyl](3-ethynylphenyl)amine 1,5-naphthalenedisulfonate [ No CAS ]
YieldReaction ConditionsOperation in experiment
0.85 g In ethanol;Reflux; Into an apparatus 10 ml of ethanol are weighed in under vigorous stirring whereupon 0.730 g /l .86 millimoles/ of <strong>[183321-74-6]erlotinib</strong> base are dissolved therein under stirring and reflux. To the reaction mixture 0.335 g /0.93 millimoles/ of 1 ,5-naphthalene-disulfonic acid is added under stirring and the reaction mixture is stirred overnight without heating. The precipitated crystalline product is filtered, washed with a small amount of cold ethanol and tert.butyl methyl ether.Yield 0.83 g (78 %) white crystals.1,06 g of the crude product thus obtained are recrystallized from 20 ml of dimethyl sulfoxide. The precipitate is filtered, washed with a small amount of cold dimethyl sulfoxide and tertiary butyl methyl ether.Yield: 0.85 g (80 %), ochre colored substance.Mp.: >290C (decomposition)Analysis for the Formula (C22H23N304)2 · C10H8S2O6 (1075.59):Calc: C: 60.32 H: 5.06 N: 7.82 S: 5.96Found: C: 59.96 H: 4.96 N: 7.82 S: 5.89IR (KBr, cm-1): 3269, 1637, 1575, 1451, 1165, 1029, 607.?-NMR (DMSO- g, 500 MHz): 14.53 (b), 8.88 (m, 1H), 8.86 (s, 1H), 8.06 (s, 1H), 7.95 (m, 1H), 7.83 (m, 1H), 7.71 (m, 1H), 7.51 (m, 1H), 7.43 (m, 1H), 7.39 (m, 1H), 7.29 (s, 1H), 4.31 (m, 4H), 4.27 (s, 1H), 3.76 (m, 2H), 3.36 (s, 3H), 3.35 (s, 3H). 13C-NMR (DMSO-£¾, 125 MHz): 158.26, 156.01, 149.66, 149.25, 143.95, 137.26, 135.81, 129.66, 129.63, 129.50, 129.16, 127.69, 125.27, 124.15, 123.98, 122.35, 107.34, 104.56, 101.12, 82.94, 81.57, 69.98, 69.96, 69.01, 68.92, 58.56.
  • 35
  • [ 98-79-3 ]
  • [ 183321-74-6 ]
  • [ 1429636-56-5 ]
YieldReaction ConditionsOperation in experiment
0.51 g In ethanol;Reflux; Into an apparatus 20 ml of ethanol are weighed in under intensive stirring whereupon 1.000 g (2.54 millimoles) of <strong>[183321-74-6]erlotinib</strong> base are dissolved therein under stirring and reflux. To the reaction mixture at this temperature 0.328 g /2.54 millimoles/ of L-pyroglutamic acid is added under stirring. The reaction mixture is allowed to cool to room temperature under stirring whereby the slow precipitation of crystals begins. The reaction mixture is allowed to stand at room temperature for an hour, the precipitated crystalline product is filtered and washed with a small amount of cold ethanol and thereafter with tertiary butyl methyl ether.Yield 0.87 g (65 %)0.717 g of the crude product is recrystallized from 25 ml of isopropanol. The suspension obtained is allowed to stand in a refrigerator overnight, filtered and washed with a small amount of cold isopropanol and thereafter with tertiary butyl methyl ether.Yield: 0.51 g (72 %).Mp.: 158.3-160.7C.Analysis for the Formula C22H23N304 · C5H7N03 (522.56):Calc: C: 62.06 H: 5.79 N: 10.72Found: C: 60.97 H: 6.08 N: 10.65IR (KBr, cm"1): 3319, 1691, 1628, 1520, 1447, 1279, 1 129.1H-NMR (DMSO-i/e, 500 MHz): 12.74 (b), 9.47 (b, 1H), 8.35 (s, 1H), 8.01 (m, 1H), 7.92 (m, 1H), 7.90 (b, 1H), 7.87 (s, 1H), 7.41 (m, 1H), 7.23 (s, 1H), 7.22 (m, 1H), 4.30 (m, 4H), 4.18 (s, 1H), 4.09 (m, 1H), 3.80 (m, 2H), 3.76 (m, 2H), 3.39 (s, 3H), 3.38 (s, 3H), 2.34 (m, 1H), 2.14 (m, 2H), 1.99 (m, 1H).13C-NMR (DMSO-
  • 36
  • [ 183321-74-6 ]
  • [ 86-48-6 ]
  • [ 1429636-57-6 ]
YieldReaction ConditionsOperation in experiment
0.47 g In ethanol;Reflux; Into an apparatus 15 ml of ethanol are weighed in under vigorous stirring, whereupon 0.704 g /l .79 millimoles/ of <strong>[183321-74-6]erlotinib</strong> base are dissolved therein under stirring and reflux. To the reaction mixture at this temperature 0.336 g /l .79 millimoles/ of l-hydroxy-2 -naphthoic acid are added under stirring. A dark yellow solution is obtained. The reaction mixture is allowed to cool to room temperature under stirring whereby a slow precipitation of crystals can begin. The reaction mixture is allowed to stand in a refrigerator overnight the precipitated product is filtered and washed with a small amount of cold ethanol and thereafter with tertiary butyl methyl ether.Yield: 0.77 g (74 %)0.700 g of the crude product thus obtained is recrystallized from 10 ml of ethanol. The suspension obtained is allowed to stand in a refrigerator overnight and washed with a small amount of cold isopropanol and thereafter with tertiary butyl methyl ether.Yield: 0.47 g (67 %)Mp.:144.2-147C.Analysis for the Formula C22H23N304 CuH803 (581.63):Calc: C: 68.15 H: 5.37 N: 7.22Found: C: 67.39 H: 5.46 N: 7.22IR (KBr, cm"1): 3258, 1648, 1583, 1439, 1403, 775.?-NMR (DMSO-</6, 500 MHz): 12-10 (b), 9.74 (b, 1H), 8.58 (s, 1H), 8.29 (m, 1H), 8.00 (m, 1H), 7.89 (m, 3H), 7.78 (d, J=8.7 Hz, 1H), 7.65 (m, 1H9, 7.56 (m, 1H), 7.43 (m, 1H), 7.34 (d, J=8.7 Hz, 1H), 7.27 (m, lH), 7.25 (s, 1H), 4.30 (m, 4H), 4.21 (s, 1H), 3.78 (m, 4H), 3.39 (s, 2H), 3.37 (s,3H).13C-NMR (DMSO- e, 125 MHz) 173.06, 160.68, 156.54, 154.14, 152.36, 148.49, 145.53, 139.60, 129.22, 129.05, 127.69, 126.91 , 125.80, 125.28, 125.23, 124.43, 123.22, 123.04, 121.96, 117.88, 108.84, 107.35, 106.93, 103.57, 83.56, 80.73, 70.24, 70.18, 68.60, 68.31 , 58.53, 58.49.
  • 37
  • [ 611-71-2 ]
  • [ 183321-74-6 ]
  • [ 1399540-91-0 ]
YieldReaction ConditionsOperation in experiment
0.60 g In ethanol;Reflux; Into an apparatus 20 ml of ethanol are weighed in whereupon 1.00 g /2.54 millimoles/ of <strong>[183321-74-6]erlotinib</strong> base are dissolved therein under intensive stirring and reflux. To the reaction mixture at this temperature 0.387 g /2.54 millimoles/ of DL-mandelic acid are added. The colour of the solution becomes yellow. The reaction mixture is allowed to cool to room temperature whereby a slow precipitation of crystals begins on rubbing. The reaction mixture is allowed to stand at room temperature overnight the precipitated product is filtered and washed with a small amount of cold ethanol and tertiary butyl methyl ether.Yield.: 0.80 g (80 %)The crude product thus obtained is recrystallized from 10 ml of isopropanol. The suspension obtained is allowed to stand in a refrigerator, filtered and washed with a small amount of cold isopropanol and thereafter with tertiary butyl methyl ether.Yield: 0.60 g (75 %)Mp.: 138.6-140.9C.Analysis for the Formula C22H23N304 C8H803 (545.60):Calc: C: 66.04 H: 5.73 N: 7.70Found: C: 65.24 H: 5.73 N: 7.73IR (KBr, cm'1): 3284, 2933, 1583, 1513, 1448, 1 128, 946, 861, 731 , 699.?-NMR (DMSO-i/6, 500 MHz): 9.48 (b, 1H), 8.02 (m, 1H), 7.92 (m, 1H), 7.87 (s, 1H), 7.42(m, 2H), 7.41 (m, 1H), 7.35 (m, 2H), 7.29 (m, 1H), 7.24 (s, 1H), 7.23 (m, 1H), 5.05 (s, 1H),4.30 (m, 4H), 4.18 (s, 1H), 3.80 (m, 2H), 3.76 (m, 2H), 3.39 (s, 3H), 3.36 (s, 3H).13C-NMR (DMS0-i 125 MHz) 174.26, 156.32, 153.90, 152.90, 148.34, 147.05, 140.43,139.97, 129.03, 128.26, 127.77, 126.79, 126.53, 124.95, 122.74, 121.93, 109.10, 108.33,103.46, 83.68, 80.62, 72.60, 70.30, 70.23, 68.60, 68.24, 58.56.
  • 38
  • [ 86520-52-7 ]
  • [ 183321-74-6 ]
  • [ 1454772-95-2 ]
YieldReaction ConditionsOperation in experiment
93% With copper(ll) sulfate pentahydrate; sodium L-ascorbate; In ethanol; water; at 20℃; for 24h; <strong>[183321-74-6]Erlotinib</strong> (0.944mg, 2.4mmol) and 2-(2-(2-azidoethoxy) ethoxy) ethan-1-ol (420mg, 2.4mmol) was dissolved in THF (10ml). The mixture of CuSO4?5H2O (120mg) and sodium ascorbate (240mg) were added in EtOH (1.0ml) and water (1.0ml). The reaction mixture was stirred for 24hat room temperature. After the reaction was completed, it was extracted with CH2Cl2 and H2O three times and the organic layer was evaporatd under reduced pressure. The residue was further purified by silica gel column chromatography using CH2Cl2: MeOH=10:1(v/v) as mobile phase. The product was isolated as yellow oily substance. Yield: 1.268g, 93.0%.1H NMR (400MHz, CDCl3) delta 8.56 (s, 1H), 8.16 (s, 1H), 7.97 (d, J=8.2Hz, 1H), 7.92 (s, 1H), 7.66 (d, J=7.6Hz, 1H), 7.54 (s, 1H), 7.42 (d, J=7.9Hz, 1H), 7.22 (s, 1H), 4.59 (t, J=4.4Hz, 2H), 4.38-4.33 (m, 2H), 4.28-4.23 (m, 2H), 3.89 (d, J=4.1Hz, 2H), 3.84 (s, 4H), 3.81-3.77 (m, 2H), 3.66 (d, J=1.7Hz, 4H), 3.64-3.59 (m, 2H), 3.50-3.45 (m, 6H).
93% With copper(ll) sulfate pentahydrate; sodium L-ascorbate; In tetrahydrofuran; ethanol; water; at 20℃; for 24h; First, <strong>[183321-74-6]erlotinib</strong> (0.944 mg, 2.4 mmol)And 2- (2- (2-azidoethoxy) ethoxy) eth-1-ol (420 mg, 2.4 mmol) were dissolved in 10 ml of THF. CuSO 4 · 5H2O (120 mg)With sodium ascorbate (240mg) with EtOH (1.0 ml)And water (1.0 ml) were added to the reaction system. The reaction mixture was stirred at room temperature for 24 hours. After the reaction was completed, it was extracted three times with dichloromethane and water. The organic layers were combined.Dry and evaporate the solvent under reduced pressure. Finally, take CH2Cl2: MeOH = 10: 1The eluent was further separated and purified by silica gel column chromatography to obtain 1.268 g of a yellow oily substance. Yield: 93.0%.
  • 39
  • [ 86520-52-7 ]
  • [ 183321-74-6 ]
  • [ 1454772-96-3 ]
  • 40
  • 2-[2-[2-[2-(2-azidoethoxy)ethoxy]ethoxy]ethoxy]ethanol [ No CAS ]
  • [ 183321-74-6 ]
  • [ 1454772-97-4 ]
  • 41
  • [ 81-07-2 ]
  • [ 183321-74-6 ]
  • N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine saccharinate [ No CAS ]
YieldReaction ConditionsOperation in experiment
0.706 g In methanol; at 50℃; for 18h; Methanol (1 mL) was added to a mixture of <strong>[183321-74-6]erlotinib</strong> free base (0.4 g) and saccharin (0.366 g) and slurried for 18 hours at 50C. The solvent was evaporated at 25C to 30C and the solid obtained was dried at 55C in a vacuum tray drier for 6 hours to obtain the title compound. Yield: 0.706 g
  • 42
  • [ 10041-19-7 ]
  • [ 183321-74-6 ]
  • erlotinib 1,4-bis(2-ethylhexoxy)-1 ,4-dioxobutane-2-sulfonate [ No CAS ]
YieldReaction ConditionsOperation in experiment
In tetrahydrofuran; A 0.226 g sample of sodium 1 ,4-bis(2-ethylhexoxy)-1 ,4-dioxobutane-2-sulfonate was placed in a 20 mL glass vessel with 10 mL tetrahydrofuran (THF) and stirred with a magnetic stir bar until completely dissolved. A 0.41 mL sample of 1 .25 M HCL in methanol was added with stirring yielding a white precipitate. The mixture was chilled to about 0C to ensure complete precipitation of sodium chloride. The mixture was then filtered through a 0.2 micron filter to remove sodium chloride followed by an additional rinse of 10 mL THF to extract all of the 1 ,4-bis(2-ethylhexoxy)-1 ,4-dioxobutane-2-sulfonate. The solution was placed on a rotoevaporator and solvents were removed resulting in a clear film of 1 ,4-bis(2-ethylhexoxy)- 1 ,4-dioxobutane-2-sulfonate in its protonated (non-ionized) form. The entire sample of the protonated 1 ,4-bis(2-ethylhexoxy)-1 ,4-dioxobutane-2-sulfonate was dissolved in 10 mL of THF and added quantitatively to a separate solution containing 200.1 mg of eriotinib free base in 10 mL THF. The resulting clear solution was stirred for several minutes. Solvent was removed by rotoevaporation. The residue was placed on a vacuum line overnight to remove residual solvent. The sample was dissolved in 10 mL of acetone and then rotoevapo rated to remove solvent. The sample was dissolved a second time in 10 mL of acetone followed by rotoevaporation and was then dried overnight under vacuum. The product, <strong>[183321-74-6]erlotinib</strong> 1 ,4-bis(2- ethylhexoxy)-1 ,4-dioxobutane-2-sulfonate, was a clear syrup/glass at room temperature, and did not exhibit a melting point when analyzed by mDSC.
  • 43
  • [ 183321-74-6 ]
  • C38H42N8O8 [ No CAS ]
  • 44
  • [ 183321-74-6 ]
  • C56H42N14O5Zn [ No CAS ]
  • 45
  • [ 183321-74-6 ]
  • C56H42N14O5Zn [ No CAS ]
  • 46
  • [ 183321-74-6 ]
  • C60H50N14O7Zn [ No CAS ]
  • 47
  • [ 183321-74-6 ]
  • C32H30N8O5 [ No CAS ]
  • 48
  • [ 183321-74-6 ]
  • C38H42N8O8 [ No CAS ]
  • 49
  • [ 183321-74-6 ]
  • C32H30N8O5 [ No CAS ]
  • 50
  • [ 183321-74-6 ]
  • C36H38N8O7 [ No CAS ]
  • 51
  • [ 1517-05-1 ]
  • [ 183321-74-6 ]
  • C24H28N6O5 [ No CAS ]
  • 52
  • [ 86770-67-4 ]
  • [ 183321-74-6 ]
  • C30H40N6O8 [ No CAS ]
  • 53
  • 2-[2-[2-[2-(2-azidoethoxy)ethoxy]ethoxy]ethoxy]ethanol [ No CAS ]
  • [ 183321-74-6 ]
  • C40H46N8O9 [ No CAS ]
  • 56
  • C13H17ClO5 [ No CAS ]
  • [ 183321-74-6 ]
  • 57
  • C15H23NO6 [ No CAS ]
  • [ 183321-74-6 ]
  • 58
  • 2-(3,4-bis(2-methoxyethoxy)phenyl)-4,5-dihydro-oxazole [ No CAS ]
  • [ 183321-74-6 ]
  • 59
  • C17H21F3N2O6 [ No CAS ]
  • [ 183321-74-6 ]
  • 60
  • 2-(4,5-dihydro-1,3-oxazol-2-yl)-4,5-bis(2-methoxyethoxy)aniline [ No CAS ]
  • [ 183321-74-6 ]
  • 61
  • 2-((6,7-bis(2-methoxyethoxy))-4-quinazolinylamino)-ethanol [ No CAS ]
  • [ 183321-74-6 ]
  • 62
  • C22H29NO8S [ No CAS ]
  • [ 183321-74-6 ]
  • 63
  • [ 7585-39-9 ]
  • [ 183321-74-6 ]
  • C42H70O35*C22H23N3O4 [ No CAS ]
YieldReaction ConditionsOperation in experiment
In water; at 25℃; UV spectroscopic measurements were carried out on aJasco V-550 diode-array spectrometer with 10-mm quartzcuvettes at 25 C. Stoichiometry of ERL-CD complex wasobtained by continuous variation Job?s plot. Total molarconcentration of the aqueous mixture of ERL and differentCDs were kept constant at 2.5 × 10-5 M, while varying themolar ratio from 0 to 1 and measuring the absorbances ateach molar ratio.
  • 65
  • 6,7-bis(2-methoxyethoxy)quinazolone [ No CAS ]
  • [ 183321-74-6 ]
  • 67
  • ethyl 2-amino-4,5-bis-(2-methoxyethoxy)benzoate hydrochloride [ No CAS ]
  • [ 183321-74-6 ]
  • 68
  • C54H55BF2I2N8O7 [ No CAS ]
  • [ 183321-74-6 ]
  • C76H78BF2I2N11O11 [ No CAS ]
YieldReaction ConditionsOperation in experiment
89% With copper(ll) sulfate pentahydrate; sodium L-ascorbate; In ethanol; chloroform; water; for 24h;Darkness; The compound 0.1mmol) and the compound (39mg, 0.1mmol) at a molar ratio of 1: 1, was added to 7mLCHCl3, A mixture of ethanol and water, wherein CHCl3-EtOH-H2O (12: 1: 1, v / v / v, 7mL), added to stir crushed CuSO4·5H2O (15mg, 0.06mmol) and sodium ascorbate (24mg, 0.12mmol) powder, dark reaction was stirred 24h; the reaction was treated with CH2Cl2And water extraction; the organic layer was washed with Na2SO4After drying under reduced pressure to spin dry; then dichloromethane - methanol 15: 1 as the eluent and silica gel column chromatography to give a green solid product single <strong>[183321-74-6]erlotinib</strong> modified two fluorine boron azole derivatives:
  • 69
  • C46H49BF2I2N8O7 [ No CAS ]
  • [ 183321-74-6 ]
  • C90H95BF2I2N14O15 [ No CAS ]
YieldReaction ConditionsOperation in experiment
82% With copper(ll) sulfate pentahydrate; sodium L-ascorbate; In ethanol; chloroform; water; for 24h;Darkness; Compound 2 (98mg, 0.25mmol) and (113mg, 0.1mmol) molar ratio of 1: 2.5, was added to 7mLCHCl3, A mixture of ethanol and water, wherein CHCl3-EtOH-H2O (12: 1: 1, v / v / v, 7mL), added to stir crushed CuSO4·5H2O (15mg, 0.06mmol) and sodium ascorbate (24mg, 0.12mmol) powder, dark reaction was stirred 24h; the reaction was treated with CH2Cl2And water extraction; the organic layer was dried over anhydrous Na2SO4After drying under reduced pressure to spin dry; then dichloromethane - methanol 15: 1 as eluent, silica gel column chromatography to give a green solid product i.e. bis <strong>[183321-74-6]erlotinib</strong> fluoroboric two modified pyrrole derivative:
  • 70
  • [ 183321-74-6 ]
  • [ 13992-25-1 ]
  • N-(3-(1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-1H-1,2,3-triazol-4-yl)phenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine [ No CAS ]
  • 71
  • [ 131603-21-9 ]
  • [ 183321-74-6 ]
  • N-(3-(1-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyl)-1H-1,2,3-triazol-4-yl)phenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine [ No CAS ]
  • 72
  • [ 183321-74-6 ]
  • [ 69266-15-5 ]
  • N-(3-(1-(2, 3, 4-tri-O-acetyl-α-L-arabinopyranosyl)-1H-1,2,3-triazol-4-yl)phenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine [ No CAS ]
  • 73
  • [ 6205-69-2 ]
  • [ 183321-74-6 ]
  • C36H43N7O12 [ No CAS ]
  • 74
  • [ 183321-74-6 ]
  • N-(4-aminobenzyl)-N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine [ No CAS ]
  • 75
  • [ 183321-74-6 ]
  • (1-methyl-2-nitro-1H-imidazol-5-yl)methyl (4-(((6,7-bis(2-methoxyethoxy)quinazolin-4-yl) (3-ethynylphenyl)amino)methyl)phenyl)carbamate [ No CAS ]
  • 76
  • [ 100-11-8 ]
  • [ 183321-74-6 ]
  • N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-N-(4-nitrobenzyl)quinazolin-4-amine [ No CAS ]
  • 77
  • [ 239074-27-2 ]
  • [ 183321-74-6 ]
  • tert-butyl (4-(((6,7-bis(2-methoxyethoxy)quinazolin-4-yl)(3-ethynylphenyl)amino)methyl)phenyl)carbamate [ No CAS ]
  • 78
  • [ 1355254-25-9 ]
  • [ 183321-74-6 ]
  • 4-{3-{1-[3-(2-methyl-1,2-dicarba-closododecaboran-1-yl)propyl]-1H-[1,2,3]triazol-4-yl}phenyl}amino-6,7-bis(2-methyloxyethyloxy)quinazoline [ No CAS ]
  • 79
  • 1-(3-azidopropyl)-1,7-dicarba-closododecaborane [ No CAS ]
  • [ 183321-74-6 ]
  • 4-{3-{1-[3-(1,7-dicarba-closododecaboran-1-yl)propyl]-1H-[1,2,3]triazol-4-yl}phenyl}amino-6,7-bis(2-methyloxyethyloxy)quinazoline [ No CAS ]
  • 80
  • 1-(3-azidopropyl)-7-methyl-1,7-dicarbacloso-dodecaborane [ No CAS ]
  • [ 183321-74-6 ]
  • 4-{3-{1-[3-(7-methyl-1,7-dicarba-closododecaboran-1-yl)propyl]-1H-[1,2,3]triazol-4-yl}phenyl}amino-6,7-bis(2-methyloxyethyloxy)quinazoline [ No CAS ]
  • 81
  • 1-(4-iodophenylmethyl)-1,2-dicarba-closododecaborane [ No CAS ]
  • [ 183321-74-6 ]
  • 4-{3-{2-[4-(1,2-dicarba-closododecaboran-1-ylmethyl)phenyl]ethynyl}phenyl}amino-6,7-bis(2-methyloxyethyloxy)quinazoline [ No CAS ]
  • 82
  • [ 920317-31-3 ]
  • [ 183321-74-6 ]
  • 4-{3-{2-[4-(2-methyl-1,2-dicarba-closododecaboran-1-ylmethyl)phenyl]ethynyl}phenyl}amino-6,7-bis(2-methyloxyethyloxy)quinazoline [ No CAS ]
  • 83
  • 1-(4-iodophenylmethyl)-1,7-dicarba-closododecaborane [ No CAS ]
  • [ 183321-74-6 ]
  • 4-{3-{2-[4-(1,7-dicarba-closododecaboran-1-ylmethyl)phenyl]ethynyl}phenyl}amino-6,7-bis(2-methyloxyethyloxy)quinazoline [ No CAS ]
  • 84
  • 1-(4-iodophenylmethyl)-7-methyl-1,7-dicarba-closo-dodecaborane [ No CAS ]
  • [ 183321-74-6 ]
  • 4-{3-{2-[4-(7-methyl-1,7-dicarba-closododecaboran-1-ylmethyl)phenyl]ethynyl}phenyl}amino-6,7-bis(2-methyloxyethyloxy)quinazoline [ No CAS ]
  • 85
  • C2H16B9(2-)*Co(3+)*C6H23B9N3O2(2-)*Na(1+) [ No CAS ]
  • [ 183321-74-6 ]
  • 4-{3-{1-[(1’,2’-dicarba-closoundecaborane)-3’,3-cobalt-(-1)(1,2-dicarba-closo-undecaborane)]-8-oxy-3-oxa-pentyl}-1H-[1,2,3]triazol-4-yl}phenyl}amino-6,7-bis(2-methyloxyethyloxy)quinazoline sodiumsalt [ No CAS ]
  • 86
  • bis(tetra-n-butylammonium) 1-(5-azido-3-oxapentoxy)-closo-dodecaborate [ No CAS ]
  • [ 183321-74-6 ]
  • C26H42B12N6O6(2-)*2C16H36N(1+) [ No CAS ]
  • 87
  • [ 27126-20-1 ]
  • [ 183321-74-6 ]
  • 4-{3-[1-(phenylpropyl)-1H-[1,2,3]triazol-4-yl]phenyl}amino-6,7-bis(2-methyloxyethyloxy)quinazoline [ No CAS ]
  • 88
  • [ 1200693-88-4 ]
  • [ 183321-74-6 ]
  • 4-{3-{1-[3-(1,2-dicarba-closododecaboran-1-yl)propyl]-1H-[1,2,3]triazol-4-yl}phenyl}amino-6,7-bis(2-methyloxyethyloxy)quinazoline [ No CAS ]
  • 89
  • 6,7-bis(2-methoxyethoxy)quinazolin-4-one hydrochloride [ No CAS ]
  • [ 183321-74-6 ]
  • 90
  • [ 129392-84-3 ]
  • [ 183321-74-6 ]
  • tert-butyl-3-(4-(3-(6,7-bis(2-methoxyethoxy)quinazolin-4-ylamino)phenyl)-1H-1,2,3-triazol-1-yl)propylcarbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
90% With copper(ll) sulfate pentahydrate; sodium L-ascorbate; In water; tert-butyl alcohol; at 60℃;Inert atmosphere; To a solution of <strong>[183321-74-6]Erlotinib</strong> (50 mg,0.13 mmol) and Compound 1 (25 mg, 0.13 mmol) in a 1:1 mixture of water and tert-BuOH (6 mL), sodium ascorbate (12 mg, 0.06 mmol) and copper sulphate pentahydrate (3 mg, 0.01 mmol) were added. The reaction mixture was stirred at 60 C for 4-5 h under nitrogen atmosphere. Progress of the reaction was monitored by TLC (5% MeOH:CHCl3). After completion of the reaction, solvent was evaporated and the reaction mixture was diluted with chloroform (50 mL) and washed with water (3 * 50 mL). Organic layer wascollected and purified by column chromatography affording a yellow solid:Rf = 0.3 (in 5% MeOH in CHCl3). The purified product was characterized by IR,1H NMR, 13C NMR and ESI-MS. Yield: 68 mg (90%) IR (mmax, cm1): 3403m(NAH), 2928s (CAH), 1692s (CO amide), 1623s, 1582s, 1511m, 1449m, 1367s,1244s, 1166s, 1126s, 930s, 865s1H NMR (500 MHz, CDCl3) d ppm: 8.64 (s, 1H,quinazoline-NC(H)NCA), 8.12 (s, 1H, triazole-CH), 7.92-7.90 (m, 3H, quinazoline-CC(H)C(N)CA, ACC(H)C(C)CA, Aryl-C(H)C(H)C(H)CC(H)A), 7.54-7.53 (d, 1H,Aryl-C(H)C(H)C(H)CC(H)A), 7.46-7.43 (t, 1H, Aryl-C(H)C(H)C(H)CC(H)A), 7.37(s, 1H, Aryl-C(H)C(H)C(H)CC(H)A), 4.49-4.46 (t, 4H, CH3OCH2CH2OA), 4.32-4.29 (m, 6H, CH3OCH2CH2OA, NCH2CH2CH2NHA), 3.49 (s, 6H,CH3OCH2CH2OA), 3.2-3.19 (m, 2H, NCH2CH2CH2NHA), 2.16-2.13 (m, 2H,NCH2CH2CH2NHA), 1.28 (s, 9H, AC(CH3)3)13C NMR (125 MHz, CDCl3) d ppm:156.4 (quinazoline-N(H)C(N)CA), 156.2(-C(O)OC(CH3)3), 154.3, 153.2, 148.8,147.4, 146.8 (quinazoline-C8N2H3A), 139.3 (triazole quarternary CA), 131.0,129.4, 121.5, 121.1, 120.3 (Aryl C6H4A), 118.7 (triazoleACH), 79.6 (AC(CH3)3),70.8,70.3, 68.9, 68.18 (AOCH2CH2OA), 59.2 (AOCH3), 47.61(ANCH2CH2CH2NHA), 37.3 (ANCH2CH2CH2NHA), 30.6 (ANCH2CH2CH2NHA),28.3 (A(CH3)3).MS (ESI, +ve mode): Mass (calculated) [C30H39N7O6] 593.3; m/z(observed) 594 (M+H+), 616 (M+Na+)
  • 91
  • [ 108-24-7 ]
  • [ 183321-74-6 ]
  • N-(6,7-bis(2-methoxyethoxy)quinazolin-4-yl)-N-(3-ethynylphenyl)acetamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
88% for 72h;Heating; Inert atmosphere; To a solid of eriotinib (165 mg, 0.4194 mmol) was added acetic anhydride (5.0 mL). After being heated at 90 C (bath temperature) with stirring for 3 d, the reaction mixture was cooled to room temperature and neutralized with saturated aqueous NaHCCb (20 mL), and diluted with EtOAc (20 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (2 x 30 mL). The combined organic layers were washed successively with H2O and saturated brine, dried over anhydrous MgS04, filtered, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, hexanes/EtOAc, 1/1 to 1/3) to give JGK002 (161 mg, 88% isolated yield); NMR (400 MHz, CDCh) delta 9.06 (s, 1H,), 7.45 (t, J = 1.6 Hz, 1H,), 7.37-7.39 (m, 2 H), 7.36 (s, 1H), 7.30-7.34 (m, 1H), 7.15 (s, 1H), 4.32 (t, J = 4.8 Hz, 2 H), 4.16 (t, J = 4.8 Hz, 2 H), 3.86 (t, J = 4.8 Hz, 2 H), 3.79 (t, J = 4.8 Hz, 2 H), 3.46 (s, 3 H), 3.45 (s, 3 H), 3.06 (s, 1H), 2.14 (s, 3 H); 13C NMR (100 MHz, CDCh) delta 170.5, 158.8, 156.1, 153.5, 151.1, 150.8, 141.0, 130.9, 130.3, 129.3, 127.5, 123.4, 117.2, 107.9, 103.1, 82.4, 78.4, 70.6, 70.3, 68.9, 68.7, 59.3, 59.3, 23.7; HRMS-ESI [M+H]+ found 436.1811 [calcd for C24H25N3O5 435.1788].
  • 92
  • [ 5653-40-7 ]
  • [ 183321-74-6 ]
  • 93
  • [ 13794-72-4 ]
  • [ 183321-74-6 ]
  • 94
  • [ 13790-39-1 ]
  • [ 183321-74-6 ]
  • 95
  • N-(3-ethynylphenyl)-6,7-dimethoxyquinazolin-4-amine [ No CAS ]
  • [ 183321-74-6 ]
  • 96
  • [ 938185-06-9 ]
  • [ 6482-24-2 ]
  • [ 183321-74-6 ]
YieldReaction ConditionsOperation in experiment
27 g With potassium carbonate; In acetone;Reflux; In a 500 mL flask equipped with a stirrer, 28 g of 4-aminophenylene-6,7-dihydroxyquinazoline and 28-40 g of methoxyethyl bromide was added to 200 mL of acetone, 20 g of potassium carbonate was added,Heated to reflux reaction, TLC monitoring of raw materials after the reaction completely, the solvent solvent acetone, then add 85mL of methanol and water 15mL, cooled to 0 C stirring solidification, pumping dryingTo 4-aminophenylacetylene-6,7-bis (2-methoxyethoxy) quinazoline27g.
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