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CAS No. : | 183319-69-9 | MDL No. : | MFCD07781272 |
Formula : | C22H24ClN3O4 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | GTTBEUCJPZQMDZ-UHFFFAOYSA-N |
M.W : | 429.90 | Pubchem ID : | 176871 |
Synonyms : |
CP-358774 hydrochloride;NSC 718781 hydrochloride;OSI-774;NSC 718781;CP 358,774;Erlotinib (hydrochloride);Erlotinib HCl;OSI-774 hydrochloride
|
Num. heavy atoms : | 30 |
Num. arom. heavy atoms : | 16 |
Fraction Csp3 : | 0.27 |
Num. rotatable bonds : | 10 |
Num. H-bond acceptors : | 6.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 117.25 |
TPSA : | 74.73 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | Yes |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | Yes |
CYP3A4 inhibitor : | Yes |
Log Kp (skin permeation) : | -6.0 cm/s |
Log Po/w (iLOGP) : | 0.0 |
Log Po/w (XLOGP3) : | 4.11 |
Log Po/w (WLOGP) : | 0.6 |
Log Po/w (MLOGP) : | 1.83 |
Log Po/w (SILICOS-IT) : | 4.06 |
Consensus Log Po/w : | 2.12 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -4.83 |
Solubility : | 0.00637 mg/ml ; 0.0000148 mol/l |
Class : | Moderately soluble |
Log S (Ali) : | -5.39 |
Solubility : | 0.00177 mg/ml ; 0.00000412 mol/l |
Class : | Moderately soluble |
Log S (SILICOS-IT) : | -7.26 |
Solubility : | 0.0000235 mg/ml ; 0.0000000546 mol/l |
Class : | Poorly soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 3.0 |
Synthetic accessibility : | 3.27 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P273-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335-H412 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | The hydrochloride salt of N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine (12.0 g, 27.91 mmol), ethyl acetate (200 mL) and water (50 mL) were mixed together using mechanical agitation and then warmed to 60-70 C. The stirred mixture was treated portionwise with 50% aqueous sodium hydroxide (14 mL) so that the pH of the aqueous phase was in the range 10-11. The mixture was allowed to settle and separate into two clear liquid phases. The aqueous phase was removed and the residual clear organic layer was heated to reflux in a Dean and Stark apparatus to azeotropically remove residual water. The volume of the organic layer was reduced by about 60 mL during this procedure. The hot organic solution was stirred and treated slowly with methanesulfonic acid (2.2 mL, 33.49 mmol) to give a hazy solution which on cooling to room temperature gave a crystal slurry. The crystal slurry was granulated for 1 hour in the temperature range 0-5 C., the crystals were isolated by filtration, washed with cold ethyl acetate (2×50 mL) and dried under vacuum at 35 C. to give the monohydrate 14.2 g, yield 100%, as a white crystalline solid mp 96-100 C. The monohydrate is characterized by the powder X-ray diffraction pattern noted above. | |
93% | The hydrochloride salt of N-(3-ethynylphenyl)-6,7bis(2-methoxyethoxy)-4-quinazolinamine (100.0 g, 0.223 mole), ethyl acetate (2000 mL) and water (500 mL) were mixed together using mechanical agitation and thenwarmed to 40-45 C. The stirred mixture was treated portionwise with 50% aqueous sodium hydroxide (40 mL) so that the pH of the aqueous phase was in the range 8-9. The mixture was allowed to settle and separate into two clear liquid phases. The aqueous phase was removed and organic phase washed with water (300 mL). The resultant pale yellow organic solution was filtered to obtain a clear solution which was concentrated by distillation at atmospheric pressure to remove 1L of solvent. Isopropanol (2L) was added to the concentrate and a further 1L of solvents were removed by distillation at atmospheric pressure. The resultant concentrate was cooled to 40 C. and treated with methanesulfonic acid (15.1 mL, 0.233 mole) and allowed to crystallize. The crystal slurry was warmed to 62 C. for 18 hours. Monitoring with near-infrared spectroscopy after the method of Norris, Aldridge and Sekulic, Analyst, 1997 ,122, 549, indicated that no conversion to polymorph C had occurred. The temperature was raised to 70 C., after a period of 16 hours, near-infrared monitoring as described indicated the conversion was complete. The heat source was removed and the mixture cooled to 0-5 C. and granulated for a period of 1 hour. The crystalline product was isolated by filtration, washed with isopropanol (50 mL) and dried under vacuum at 33 C. to give polymorph C, 105.63 g, yield 93%, as a white crystalline solid mp 153-156 C. Polymorph C is characterized by the powder X-ray diffraction pattern noted above. | |
69% | The hydrochloride salt of N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine (30.0 g, 69.79 mmol), dichloromethane (1125 mL) and water (300 mL) were mixed together using mechanical agitation and then treated with saturated sodium bicarbonate solution (300 mL). The mixture was allowed to settle and separate into two cloudy liquid phases. The aqueous phase was removed and further extracted with dichloromethane (300 mL) The organic layers were combined and washed with saturated sodium bicarbonate solution (300 mL), separated and dried by treatment with dried magnesium sulfate (50 g) and then filtered to give a clear organic layer which was concentrated by evaporation to a volume of about 300 mL. The resultant solution was treated with isopropanol (450 mL) and concentrated by evaporation to 300 mL giving a slurry mixture. The slurry mixture was treated slowly with methanesulfonic acid (4.5 mL, 69.79 mmol) to give a pale yellow solution which on cooling to room temperature gave a gum. Addition of seed crystals of polymorph B as prepared in example 4 eventually resulted in formation of a crystal slurry. The crystal slurry was granulated for 24 hours at ambient temperature overnight, the crystals were isolated by filtration, washed with isopropanol (50 mL) and dried under vacuum at 45 C. to give polymorph B, 23.43 g, yield 69%, as a white crystalline solid mp 142-144 C. Polymorph B is characterized by the powder X-ray diffraction pattern noted above. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | In iso-propanol (IPA); for 0.5h;Heating / reflux;Product distribution / selectivity; | A suspension of CMEQ (48.Og; 153 mmol) and 3-EBA (19.7g; 168 mmol) in IPA (100OmL) was mechanically stirred under reflux for 30 min. The resulting <n="14"/>thick suspension was diluted with IPA (500 mL) and the precipitate was collected, washed with IPA and dried under vacuum at 40 0C to give ERL HCl Form A as a colorless solid (63.8g; 97% yield). |
97.6% | The purified compound I was 5.0 g (HPLC purity was 99.76%,Impurity 3 and impurity 4 (0.11%) were added to 42 ml of acetonitrile and 8 ml of DMF.Add 2.2g of 3-aminophenylacetylene,Heated to 90 C for 7 h in the dark,Cool down to 30 C,Add 8ml 2mol/L hydrochloric acid,Continue to cool down to 15 C, a large amount of solids precipitated,Filtering,The filter cake was washed with acetonitrile.50 C blastDrying to obtain pure erlotinib hydrochloride,The yield was 97.6%, and the HPLC purity was 99.85%.Impurity 1 and impurity 2 total 0.06%. | |
96.2% | In methanol; at 70℃; for 2h; | Compound 2 was added to a 3 L reaction flask, 120 g of a 95% aqueous methanol solution, and the mixture was heated to 70 C Dissolved, slowly dropping between acetylene aniline 52. 5g, 70 C reaction 2 hours, the reaction is complete, the gradient temperature to 20 C or so, stir Mixed crystallization crystallization 2h, filtration, 95% methanol aqueous solution, blast drying 4h, get erlotinib hydrochloride 158. 6g, yield 96. 2%, the content of 99.6%, spectral data consistent with the literature. |
90% | In N,N-dimethyl-formamide; at 80℃; for 1h;Product distribution / selectivity; | In a 50 mL flask, 3-ethynylaniline (360 mu, 3.20 mmol, 1 eq.) was added to a solution of 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline (1 .00 g, 3.20 mmol, prepared according to Heterocvcles, 2007, vol.71 , pp. 39-48, namely from henceforth compound A) in anhydrous DMF (10 mL). The mixture was stirred at 80 C for 1 h. The mixture was cooled to 10 C and the resulting solid was filtered and was washed with cold DMF to give the title compound as a white solid (1 .238 g, 90% yield, 100.0% HPLC). |
90% | In N,N-dimethyl-formamide; at 80℃; for 1h; | Comparative Example 14: Reproduction of the process described in Heterocycles, 2007, vol.71, pp. 39-48 for the preparation of erlotinib hydrochloride from 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline In a 50 mL flask, 3-ethynylaniline (360 muL, 3.20 mmol, 1 eq.) was added to a solution of 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline (1.00 g, 3.20 mmol, prepared according to Heterocycles, 2007, vol.71, pp. 39-48, namely from henceforth compound A) in anhydrous DMF (10 mL). The mixture was stirred at 80 C for 1 h. The mixture was cooled to 10 C and the resulting solid was filtered and was washed with cold DMF to give the title compound as a white solid (1.238 g, 90% yield, 100.0% HPLC). |
88% | In toluene; acetonitrile; at 25℃;Inert atmosphere; Reflux; | Example 8 - Synthesis of Erlotinib hydrochloride of formula (I) - exemplifying the invention.; Synthesis scheme [Show Image] Literature reference: US 2006/0188498. In a 250 ml flask provided with a thermometer there are introduced - in succession at 25C and under nitrogen atmosphere - 1 0 g of 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline of formula (III), 80 mL of acetonitrile and a solution made up of 3.75 g of 3-ethynylanyline of formula (IV-a) (1 mol. equiv.) and 50 mL of toluene. The mixture is heated at the reflux temperature and controlled by means of TLC. Upon completing the reaction it is cooled to 25C and it is stirred for 2 hours. The reaction mixture is filtered and the solid is washed using 5 ml of acetonitrile. The product is dried under vacuum at 40 C. 12.1 g corresponding to an 88.0 % molar yield are obtained. 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline of formula (III) is a substance available in the market. |
88% | In toluene; acetonitrile;Inert atmosphere; Reflux; | Example 8 Synthesis of Erlotinib Hydrochloride of Formula (I)-Exemplifying the Invention Literature reference: US 2006/0188498. In a 250 ml flask provided with a thermometer there are introduced-in succession at 25 C. and under nitrogen atmosphere-10 g of 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline of formula (III), 80 mL of acetonitrile and a solution made up of 3.75 g of 3-ethynylanyline of formula (IV-a) (1 mol. equiv.) and 50 mL of toluene. The mixture is heated at the reflux temperature and controlled by means of TLC. Upon completing the reaction it is cooled to 25 C. and it is stirred for 2 hours. The reaction mixture is filtered and the solid is washed using 5 ml of acetonitrile. The product is dried under vacuum at 40 C. 12.1 g corresponding to an 88.0% molar yield are obtained. 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline of formula (III) is a substance available in the market. |
81.3% | In ethanol; isopropyl alcohol; for 5h;Reflux; | 12.5 g (0.040 mol) of 4-chloro-6,7-bis- (2-methoxyethoxy) quinazoline was dissolved in 80 ml of ethanol,Then, 20 ml of an isopropanol solution of 5.7 g (0.049 mol) of aminophenylacetylene was added dropwise,Heating reaction reflux 5h, TLC detection reaction end,Cooling, suction filtration, filter cake washed with ethyl acetate 3 times,Dried to give erlotinib 12.8 g, yield 81.3%Content ?99%. |
With hydrogenchloride; In (alpha,alpha,alpha)-trifluorotoluene; at 20℃;Heating / reflux; | A 500 mL jacketed reactor is purged at room temperature with nitrogen and charged with 30 g OF 4-CHLORO-6, 7-bis (2-methoxyethoxy) quinazoline and 130 g of (A, a, a)-trifluorotoluene. To the white suspension 12.55 g 3-ETHYNYLANILINE dissolved in 180 g (a, a, A)-TRIFLUOROTOLUENE are added. After adding 0.18 g HCl (37%), the reaction mixture is stirred for another 15 min at room temperature and then heated to reflux temperature. After completion of the reaction, the suspension is cooled to room temperature and filtered. The isolated crystals of [6,7-Bis (2-methoxy-ethoxy) -quinazolin- 4-YL]- (3-ETHYNYL-PHENYL) amine hydrochloride are washed with ethanol and dried at 60 C/ 10 mbar overnight. The dry final product is characterized by means of X-ray powder diffraction and IR-SPECTROSCOPY as modification E. The crystals melt around 213 C (TONSET, measured by differential scanning calorimetry). | |
In toluene; acetonitrile;Heating / reflux; | 61.1 kg of formula 5 compound, 4.5 kg sodium hydroxide pellets and 489 L toluene were charged to a clean, dry, reaction vessel under nitrogen atmosphere and the reaction temperature is adjusted to between 105 to 108 C. Acetone was removed over four hours by atmospheric distillation while toluene is added to maintain a minimum volume of 6 L of solvent per kg of formula 5 compound. The reaction mixture was then heated at reflux temperature, returning distillates to pot, until the reaction was complete. The mixture was then cooled to between 20 to 25 C., at which time a slurry of 40.0 L toluene and 0.5 kg filteraid was charged to the reaction mixture and the mixture was agitated for ten to fifteen minutes. The resultant material was filtered to remove filteraid, and the cake is washed with 30 L toluene (compound of formula 6). The filtrate (compound of formula 6) was placed in a clean, dry reaction vessel under nitrogen atmosphere, and 90.8 kg of the compound of formula 4 was charged into the reaction vessel together with 732 L acetonitrile. The reaction vessel was heated to reflux temperature and well agitated. Agitator speed was lowered when heavy solids appear. When the reaction was complete, the contents of reaction vessel were cooled to between to 25 C. over three to four hours and the contents were agitated for at least one hour at a temperature between 20 and 25 C. The solids (compound of formula 2, polymorph A form, or mixture of polymorph A and B) were then isolated by filtration and the filter cake was washed with two portions of 50 L acetonitrile and dried under vacuum at a temperature between 40 and 45 C. | |
With pyridine; hydrogenchloride; In chloroform; isopropyl alcohol; acetone; | EXAMPLE 20 [6-,7-Bis-(2-methoxyethoxy)-quinazolin-4-yl]-(3-ethynylphenyl)amine Hydrochloride 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 muL, 0.32 mmol) and the mixture was refluxed 4 hours under an atomospher of dry nitrogen. The solvent was removed, in vacuo, and the residue partitioned between 10% methanol in CHCl3 and saturated aqueous NaHCO3. The organic phase was dried over Na2 SO4, filtered and concentrated in vacuo. The residue was flash chromatographed on silica using 30% acetone in hexanes to afford 81 mg of the free base of the title product as a pale yellow solid. The free-base was dissolved in a 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; 90 mg; 71%; mp 228-230 C. | |
With pyridine; In CHCl3and; chloroform; isopropyl alcohol; acetone; | EXAMPLE 20 [6-,7-Bis-(2-methoxyethoxy)-quinazolin-4-yl]-(3-ethynylphenyl)amine hydrochloride 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 muL, 0.32 mmol) and the mixture was refluxed 4 hours under an atomospher of dry nitrogen. The solvent was removed, in vacuo, and the residue partitioned between 10% methanol in CHCl3and saturated aqueous NaHCO3. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The residue was flash chromatographed on silica using 30% acetone in hexanes to afford 81 mg of the free base of the title product as a pale yellow solid. The free-base was dissolved in a minimum volume of CHCl3, diluted with several volumes of ether, and titrated with 1M HCI in ether to precipitate the title product as its hydrochloride salt; 90 mg; 71%; mp 228-230 C. | |
In acetonitrile;Heating / reflux; | 61.1 kg of formula 5 compound, 4.5 kg sodium hydroxide pellets and 489 L toluene were charged to a clean, dry, reaction vessel under nitrogen atmosphere and the reaction temperature is adjusted to between 105 to 108 C. Acetone was removed over four hours by atmospheric distillation while toluene is added to maintain a minimum volume of 6 L of solvent per kg of formula 5 compound. The reaction mixture was then heated at reflux temperature, returning distillates to pot, until the reaction was complete. The mixture was then cooled to between 20 to 25 C., at which time a slurry of 40.0 L toluene and 0.5 kg filteraid was charged to the reaction mixture and the mixture was agitated for ten to fifteen minutes. The resultant material was filtered to remove filteraid, and the cake is washed with 30 L toluene (compound of formula 6). | |
With hydrogenchloride; In water; at 25 - 40℃; for 1 - 2h;Product distribution / selectivity; | 5.0 g of 4-chloro-6,7-bis (2-methoxyethoxy) quinazoline was suspended in 75 ml water and 2.55 g of 3-aminophenyl acetylene was charged at 25 - 300C. Further 1.0 ml 50 % hydrochloric acid was added. The reaction mass was stirred at 25 - 300C for 2 hours. The solid obtained was filtered and washed with water. The product was dried at 40 - 45C to obtain 6.1 g of erlotinib hydrochloride.; Example - 2a:Preparation of Erlotinib Hydrochloride :5.0 g of 4-chloro-6,7-bis(2-methoxyethoxy) quinazoline was suspended in 75 ml of water and 2.55 g of 3-aminophenyl acetylene was added at 25 - 300C followed by 1.0 ml of 50 % hydrochloric acid. The reaction mass was heated at 35 - 400C for 1 hour. The solid obtained was filtered and washed with water. The product was dried at 40 - 45C to obtain 5.8 g of erlotinib hydrochloride. | |
With hydrogenchloride; In water; ethyl acetate; acetonitrile; at 25 - 40℃; for 1h;Product distribution / selectivity; | 5.0 g of 4-chloro-6,7-bis(2-methoxyethoxy) quinazoline was suspended in 75 ml of water and 2.55 g of 3-aminophenyl acetylene was added at 25 - 300C followed by 1.0 ml of 50 % hydrochloric acid. The reaction mass was heated at 35 - 400C for 1 hour. The solid obtained was filtered and washed with water. The product was dried at 40 - 45C to obtain 5.8 g of erlotinib hydrochloride. In a similar manner, different solvents were used for preparing erlotinib hydrochloride under acidic conditions as given in table 1 below: | |
With hydrogenchloride; In water; isopropyl alcohol; at 25 - 30℃; for 0.5h;Product distribution / selectivity; | 5.0 g of 4-chloro-6,7-bis (2-methoxyethoxy) quinazoline was suspended in 75 ml water and 2.55 g of 3-aminophenyl acetylene was charged at 25 - 300C. Further 1.0 ml 50 % hydrochloric acid was added. The reaction mass was stirred at 25 - 300C for 2 hours. The solid obtained was filtered and washed with water. The product was dried at 40 - 45C to obtain 6.1 g of erlotinib hydrochloride. In a similar manner, different solvents were used for preparing erlotinib hydrochloride under acidic conditions as given in table 1 below: | |
With hydrogenchloride; In water; toluene; acetonitrile; at 25 - 40℃; for 1h;Product distribution / selectivity; | 5.0 g of 4-chloro-6,7-bis(2-methoxyethoxy) quinazoline was suspended in 75 ml of water and 2.55 g of 3-aminophenyl acetylene was added at 25 - 300C followed by 1.0 ml of 50 % hydrochloric acid. The reaction mass was heated at 35 - 400C for 1 hour. The solid obtained was filtered and washed with water. The product was dried at 40 - 45C to obtain 5.8 g of erlotinib hydrochloride. In a similar manner, different solvents were used for preparing erlotinib hydrochloride under acidic conditions as given in table 1 below: | |
With hydrogenchloride; In water; toluene; acetonitrile; at 25 - 40℃; for 6h;Industry scale;Product distribution / selectivity; | 1.98 Kg of 4-chloro-6,7-bis (2-methoxyethoxy) quinazoline was suspended in 30 litres of acetonitrile and 10 litres of toluene and 1.0 Kg of 3-aminophenyl acetylene was charged at 25 - 300C and hydrochloric acid was added. The reaction mass was heated and stirred at 35 - 400C for 6 hours. The solid obtained was filtered and washed with a mixture of acetonitrile and toluene. The product was dried at 38 - 4O0C to obtain 2.5 Kg of erlotinib hydrochloride. | |
With hydrogenchloride; In water; carbonic acid dimethyl ester; at 25 - 30℃; for 1.5h;Product distribution / selectivity; | 5.0 g of 4-chloro-6,7-bis (2-methoxyethoxy) quinazoline was suspended in 75 ml water and 2.55 g of 3-aminophenyl acetylene was charged at 25 - 300C. Further 1.0 ml 50 % hydrochloric acid was added. The reaction mass was stirred at 25 - 300C for 2 hours. The solid obtained was filtered and washed with water. The product was dried at 40 - 45C to obtain 6.1 g of erlotinib hydrochloride. In a similar manner, different solvents were used for preparing erlotinib hydrochloride under acidic conditions as given in table 1 below: | |
With hydrogenchloride; In water; acetonitrile; at 25 - 40℃; for 0.5 - 1h;Product distribution / selectivity; | 5.0 g of 4-chloro-6,7-bis (2-methoxyethoxy) quinazoline was suspended in 75 ml water and 2.55 g of 3-aminophenyl acetylene was charged at 25 - 300C. Further 1.0 ml 50 % hydrochloric acid was added. The reaction mass was stirred at 25 - 300C for 2 hours. The solid obtained was filtered and washed with water. The product was dried at 40 - 45C to obtain 6.1 g of erlotinib hydrochloride.; Example - 2a:Preparation of Erlotinib Hydrochloride :5.0 g of 4-chloro-6,7-bis(2-methoxyethoxy) quinazoline was suspended in 75 ml of water and 2.55 g of 3-aminophenyl acetylene was added at 25 - 300C followed by 1.0 ml of 50 % hydrochloric acid. The reaction mass was heated at 35 - 400C for 1 hour. The solid obtained was filtered and washed with water. The product was dried at 40 - 45C to obtain 5.8 g of erlotinib hydrochloride. In a similar manner, different solvents were used for preparing erlotinib hydrochloride under acidic conditions as given in table 1 below: | |
With hydrogenchloride; In tetrahydrofuran; water; at 25 - 40℃; for 1h;Product distribution / selectivity; | 5.0 g of 4-chloro-6,7-bis(2-methoxyethoxy) quinazoline was suspended in 75 ml of water and 2.55 g of 3-aminophenyl acetylene was added at 25 - 300C followed by 1.0 ml of 50 % hydrochloric acid. The reaction mass was heated at 35 - 400C for 1 hour. The solid obtained was filtered and washed with water. The product was dried at 40 - 45C to obtain 5.8 g of erlotinib hydrochloride. In a similar manner, different solvents were used for preparing erlotinib hydrochloride under acidic conditions as given in table 1 below: | |
With hydrogenchloride; In denaturated spirit; water; at 25 - 40℃; for 0.5 - 1h;Product distribution / selectivity; | 5.0 g of 4-chloro-6,7-bis (2-methoxyethoxy) quinazoline was suspended in 75 ml water and 2.55 g of 3-aminophenyl acetylene was charged at 25 - 300C. Further 1.0 ml 50 % hydrochloric acid was added. The reaction mass was stirred at 25 - 300C for 2 hours. The solid obtained was filtered and washed with water. The product was dried at 40 - 45C to obtain 6.1 g of erlotinib hydrochloride.; Example - 2a:Preparation of Erlotinib Hydrochloride :5.0 g of 4-chloro-6,7-bis(2-methoxyethoxy) quinazoline was suspended in 75 ml of water and 2.55 g of 3-aminophenyl acetylene was added at 25 - 300C followed by 1.0 ml of 50 % hydrochloric acid. The reaction mass was heated at 35 - 400C for 1 hour. The solid obtained was filtered and washed with water. The product was dried at 40 - 45C to obtain 5.8 g of erlotinib hydrochloride. In a similar manner, different solvents were used for preparing erlotinib hydrochloride under acidic conditions as given in table 1 below: | |
With hydrogenchloride; In water; acetone; at 25 - 40℃; for 0.5 - 1h;Product distribution / selectivity; | 5.0 g of 4-chloro-6,7-bis (2-methoxyethoxy) quinazoline was suspended in 75 ml water and 2.55 g of 3-aminophenyl acetylene was charged at 25 - 300C. Further 1.0 ml 50 % hydrochloric acid was added. The reaction mass was stirred at 25 - 300C for 2 hours. The solid obtained was filtered and washed with water. The product was dried at 40 - 45C to obtain 6.1 g of erlotinib hydrochloride.; Example - 2a:Preparation of Erlotinib Hydrochloride :5.0 g of 4-chloro-6,7-bis(2-methoxyethoxy) quinazoline was suspended in 75 ml of water and 2.55 g of 3-aminophenyl acetylene was added at 25 - 300C followed by 1.0 ml of 50 % hydrochloric acid. The reaction mass was heated at 35 - 400C for 1 hour. The solid obtained was filtered and washed with water. The product was dried at 40 - 45C to obtain 5.8 g of erlotinib hydrochloride. In a similar manner, different solvents were used for preparing erlotinib hydrochloride under acidic conditions as given in table 1 below: | |
With hydrogenchloride; In water; acetone; at 25 - 40℃; for 1h;Product distribution / selectivity; | 5.0 g of 4-chloro-6,7-bis(2-methoxyethoxy) quinazoline was suspended in 75 ml of water and 2.55 g of 3-aminophenyl acetylene was added at 25 - 300C followed by 1.0 ml of 50 % hydrochloric acid. The reaction mass was heated at 35 - 400C for 1 hour. The solid obtained was filtered and washed with water. The product was dried at 40 - 45C to obtain 5.8 g of erlotinib hydrochloride. In a similar manner, different solvents were used for preparing erlotinib hydrochloride under acidic conditions as given in table 1 below: | |
In dichloromethane; N,N-dimethyl-formamide; isopropyl alcohol; at 40℃; for 8h;Reflux;Product distribution / selectivity; | Example 3Preparation of Crystalline Erlotinib Base Form G26,7-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. | |
In toluene; acetonitrile;Heating / reflux; | Example 4 Preparation of Compound of Formula 2 The following procedure is exemplary of the procedure to follow in the synthesis of the formula 2 compound and intermediate compound of formula 6: 61.1 kg of formula 5 compound, 4.5 kg sodium hydroxide pellets and 489 L-toluene were charged to a clean, dry, reaction vessel under nitrogen atmosphere and the reaction temperature is adjusted to between 105 to 108 C. Acetone was removed over four hours by atmospheric distillation while toluene is added to maintain a minimum volume of 6 L of solvent per kg of formula 5 compound. The reaction mixture was then heated at reflux temperature, returning distillates to pot, until the reaction was complete. The mixture was then cooled to between 20 to 25 C., at which time a slurry of 40.0 L toluene and 0.5 kg filteraid was charged to the reaction mixture and the mixture was agitated for ten to fifteen minutes. The resultant material was filtered to remove filteraid, and the cake is washed with 30 L toluene (compound of formula 6). The filtrate (compound of formula 6) was placed in a clean, dry reaction vessel under nitrogen atmosphere, and 90.8 kg of the compound of formula 4 was charged into the reaction vessel together with 732 L acetonitrile. The reaction vessel was heated to reflux temperature and well agitated. Agitator speed was lowered when heavy solids appear. When the reaction was complete, the contents of reaction vessel were cooled to between 19 to 25 C. over three to four hours and the contents were agitated for at least one hour at a temperature between 20 and 25 C. The solids (compound of formula 2, polymorph A form, or mixture of polymorph A and B) were then isolated by filtration and the filter cake was washed with two portions of 50 L acetonitrile and dried under vacuum at a temperature between 40 and 45 C. It has been discovered that the production of the A polymorph is favored by the reduction of the amount of acetonitrile relative to toluene, and particularly favored if isopropanol is used in place of acetonitrile. However, the use of isopropanol or other alcohols as cosolvents is disfavored because of the propensity to form an ether linkage between the alcoholic oxygen and the 4-carbon of the quinazoline, instead of the desired ethynyl phenyl amino moiety. It has been further discovered that adjusting the pH of the reaction to between pH 1 and pH 7, preferably between pH 2 and pH 5, more preferably between pH 2.5 and pH 4, most preferably pH 3, will improve the rate of the reaction. | |
In methanol; dimethyl sulfoxide; at 25 - 85℃;Heating / reflux;Product distribution / selectivity; | 4-Chloro-6,7-bis-(2-methoxyethoxy)-quinazoline (50 gm) and dimethyl sulfoxide (250 ml) are added to methanol (500 ml) under stirring at 25 - 300C, 3- ethynylaniline (20.5 gm) is added to the reaction mixture at 25 - 300C and then <n="12"/>the contents are heated to 850C. The reaction mass is stirred for 2 hours at 80 - 850C, cooled the mass to 25 - 300C and then stirred for 1 hour. Filtered the material, washed with a mixture of dimethyl sulfoxide (50 ml) and methanol (100 ml), and then dried at 600C under vacuum for 4 hours to give 60 gm of erlotinib hydrochloride [HPLC purity. 99.65%; Content of N-methoxyethyl impurity: 0.09% (at 1.14 RRT)]. | |
In isopropyl alcohol; at 25 - 30℃; for 2 - 2.5h;Heating / reflux;Product distribution / selectivity; | 4-Chloro-6,7-bis-(2-methoxyethoxy)-quinazoline (63 gm) and isopropyl alcohol (990 ml) are added to 3-ethynylaniline (23.6 gm) at 25 - 300C under stirring, the contents are heated to reflux and then refluxed for 1 hour 30 minutes to 2 hours. The reaction mass is cooled to 25 - 300C and stirred for 30 minutes.Filtered the material, washed with chilled isopropyl alcohol (400 ml) followed by n-hexane (300 ml) and then dried the material at 50 - 600C under vacuum for 6 hours to give 75 gm of crude erlotinib hydrochloride in polymorph form A [HPLC purity: 97%; Mean particle size (D50): 3.42 mum and 90 volume-% of the particles(D90): 4.53 mum]. | |
In ethanol; at 25 - 30℃; for 2 - 2.5h;Heating / reflux; | 4-Chloro-6,7-bis-(2-methoxyethoxy)-quinazoline (2.5 gm) and ethanol (40 ml) are added to 3-ethynylaniline (1.25 gm) at 25 - 300C under stirring, the contents are heated to reflux and then refluxed for 1 hour 30 minutes to 2 hours.The reaction mass is cooled to 25 - 300C and stirred for 30 minutes. Filtered the material, washed with chilled isopropyl alcohol (20 ml) followed by n-hexane (20 ml) and then dried the material at 50 - 550C under vacuum to give 3.5 gm of crude erlotinib hydrochloride in polymorph form B [HPLC purity: 99.1%; Mean particle size (D50): 2.30 mum and 90 volume-% of the particles (D90): 7.74 mum]. |
Yield | Reaction Conditions | Operation 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. |
Yield | Reaction Conditions | Operation in experiment |
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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]. |
Yield | Reaction Conditions | Operation in experiment |
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88% | In a 50 mL-volume glass vessel equipped with a stirrer, a thermometer and a reflux condenser were placed4.08 g (13.9 mmol) of 6,7-bis(2-methoxy)quinazolin-4-one, 2.55 g (16.7 mmol) of phosphorus oxychloride, 3.37 g (33.4mmol) of triethylamine and 12 mL of toluene in a nitrogen atmosphere. The resulting mixture was heated at 70 - 80Cfor 3 hours. Subsequently the mixture was cooled to room temperature, and 1.94 g (16.7 mmol) of 3-ethynylanilinewas added. The resulting mixture was then stirred at 70 - 80C for 2 hours. Subsequently, the mixture was stirred atroom temperature after addition of 16 mL of acetonitrile. After the reaction was complete, the precipitated crystallineproduct was collected by filtration, washed with 8 mL of cooled acetonitrile, and dried under reduced pressure, to give6.75 g (isolated yield: 88%, purity 78.1% in terms of area percentage determined by high performance liquid chromatography)of 6,7-bis(2-methoxyethoxy)-4-(3-ethynylanilino)quinazoline hydrochloride as yellow solid.6,7-Bis(2-methoxyethoxy)-4-(3-ethynylanilino)-quinazoline hydrochloride had the following physical properties.1H-NMR (DMSO-d6, d (ppm)): 3.63 (2H, s), 3.78-3.80 (4H, m), 4.28 (1H, s), 4.33-4.41 (4H, m), 7.39-7.52 (3H,m), 7.80 (1H, d, J=8.1Hz), 7.89 (1H, s), 8.46 (1H, s), 8.85 (1H, brs), 11.60 (1H, s), 14.9 (1H, brs)CI-MS (m/e): 394 (M+1) |
Yield | Reaction Conditions | Operation in experiment |
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94 - 95% | In methanol; at 20 - 87℃;Product distribution / selectivity; | Example 4; Preparation of Amorphous Erlotinib Hydrochloride: Spray Drying Method; Example A; Crystalline erlotinib hydrochloride (3.2 g, obtained by the procedure described in Example 20 of WO 96/30347) was dissolved in methanol (320 ml) at 48-52 C. to obtain a clear solution. The solution was cooled to 30 C., and then subjected to spray drying in a Mini-Spray Dryer (e.g., Buchi Model-190) at an inlet temperature 85-87 C. and outlet temperature 50-40 C. sing nitrogen gas. The light-white fine powder of erlotinib hydrochloride in an amorphous form was obtained. The product was further dried under vacuum at about 40 C. for about 12 hour to afford 3.0 g of the desired product (yield, 94%). The powder X-ray diffractogram of the solid (FIG. 1) showed that the resulting substance was in amorphous form.; Example 4; Preparation of Amorphous Erlotinib Hydrochloride: Spray Drying Method; Example A; Crystalline erlotinib hydrochloride (3.2 g, obtained by the procedure described in Example 20 of WO 96/30347) was dissolved in methanol (320 ml) at 48-52 C. to obtain a clear solution. The solution was cooled to 30 C., and then subjected to spray drying in a Mini-Spray Dryer (e.g., Buchi Model-190) at an inlet temperature 85-87 C. and outlet temperature 50-40 C. sing nitrogen gas. The light-white fine powder of erlotinib hydrochloride in an amorphous form was obtained. The product was further dried under vacuum at about 40 C. for about 12 hour to afford 3.0 g of the desired product (yield, 94%). The powder X-ray diffractogram of the solid (FIG. 1) showed that the resulting substance was in amorphous form. |
91% | In ethanol; water; at 20 - 90℃;Product distribution / selectivity; | Example 3; Preparation of Solid Amorphous Dispersion of Erlotinib Hydrochloride and PVP (K 30): Spray Drying Method; Crystalline erlotinib hydrochloride (2.0 g, 1.6 g, obtained by the procedure described in Example 20 of WO 96/30347) and 10.0 g polyvinylpyrrolidone (PVP, K=30) was dissolved in 200 ml of ethanol and water (ethanol/water, 80:20, v/v) at ambient temperature in a round bottom flask, with the aid of magnetic stirring and sonication. The suspension mixture was heated to 60 C. to obtain a clear solution. The solution was cooled to 35 C., and then subjected to spray drying in a Mini-Spray Dryer (e.g., Buchi Model-190) at an inlet temperature 145-175 C. and outlet temperature 70-90 C. using nitrogen gas. The light-white fine powder of erlotinib hydrochloride and PVP in an amorphous form was obtained. The product was further dried under vacuum at about 40 C. for about 12 hour to afford 10.5 g of the desired solid amorphous product, as characterized by powder X-ray diffractogram or DSC.; Example B; Crystalline erlotinib hydrochloride (3.2 g, obtained by the procedure described in Example 4 and 5 of WO 01/34574) was dissolved in 320 ml of ethanol and water (ethanol/water, 80:20, v/v) at 48-52 C. to obtain a clear solution. The solution was cooled to 30 C., and then subjected to spray drying in a Mini-Spray Dryer (e.g., Buchi Model-190) at an inlet temperature 85-90 C. and outlet temperature 50-40 C. sing nitrogen gas. The light-white fine powder of erlotinib hydrochloride in an amorphous form was obtained. The product was further dried under vacuum at about 40 C. for about 12 hour to afford 2.9 g of the desired product (yield, 91%). The powder X-ray diffractogram of the solid (FIG. 1) showed that the resulting substance was in amorphous form. |
91% | In ethanol; at 20 - 70℃;Heating / reflux;Product distribution / selectivity; | Example B; Crystalline erlotinib hydrochloride (1.6 g, obtained by the procedure described in Example 20 of WO 96/30347) was dissolved in ethanol (160 ml) at ambient temperature, and suspension mixture was heated to 70 C. to obtain a clear solution. The solution was then heated at reflux temperature. The solvent was evaporated through distillation under vacuum (30-80 mm Hg) at about 60 C. to about 70 C. The product was then isolated (1.46 g, yield 91%) when no visible liquid was remained, and drying was continued under vacuum at about 40 C. for about 12 hour to remove the solvent. The powder X-ray diffractogram of the solid (FIG. 1) showed that the resulting substance was in amorphous form. |
72% | EXAMPLE 4 Preparation of N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine, monohydrochloride A slurry of the silyl compound, 6,7-bis(2-methoxyethoxy)-N-[3-[(trimethylsilyl)ethynyl]phenyl]-4-quinazolinamine monohydrochloride, prepared above (1.22 g, 2.43 mmol) in tetrahydrofuran (6.1 mL) was treated with a 1M solution of tetra-n-butylammonium fluoride in tetrahydrofuran (2.6 mL, 2.55 mmol) and stirred at room temperature for 1 hour. The solution was treated with 2-propanol (12.2 mL) and concentrated by evaporation. The oil in 2-propanol (20 mL) was treated with concentrated hydrochloric acid (0.2 mL) giving a precipitate. The mixture was stirred at room temperature for 1 hour. The solid was collected by filtration, washed with 2-propanol (2 mL) and dried in vacuo to afford the title product (747 mg, 72%) as an off white solid (mp 226-229 C.). deltaH (300 MHz; d6-DMSO) 3.36 (6H, s), 3.77-3.80 (4H, m), 4.30 (1H, s), 7.39 (1H, s), 7.41 (1H, d, J=7.8), 7.50 (1H, t, J=7.9), 7.79 (1H, d, J=8.1), 7.88 (1H, s), 8.40 (1H, s), 8.86 (1H, s), 11.48 (1H, bs); deltaC (100 MHz; d6-DMSO) 58.4, 58.5, 68.7, 69.2, 69.7, 67.0, 81.3, 83.0, 100.3, 105.2, 107.2, 121.9, 125.4, 127.6, 128.9, 129.2, 135.2, 137.7, 148.3, 149.2, 155.4, 158.0; m/e 394 (M+H)+ | |
EXAMPLE 10 Preparation of N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine, monohydrochloride 4-[3-[[6,7-Bis(2-methoxyethoxy]-4-quinazolinyl]amino]phenyl]-2-methyl-3-butyn-2-ol, prepared above (20.0 g, 44.3 mmol), anhydrous solid sodium hydroxide (260 mg, 6.5 mmol) and propan-2-ol (200 mL) were stirred together and heated in a pressure vessel at 135-140 C. for 23 hours. The reaction mixture was cooled to 60-65 C. and concentrated hydrochloric acid (4.8 mL) was added. The resultant mixture was granulated overnight at 20-25 C. to establish crystallization. The mixture was treated with water (10 mL) and stirred at 58-60 C. for 21 hours, cooled to 15-20 C. and granulated for 2 hours. The title product crystals were isolated by filtration, washed with propan-2-ol (2*30 mL) and dried under vacuum at 45-50 C. to remove propan-2-ol. Yield (17.6 g, 92%). | ||
EXAMPLE 11 Preparation of N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine, monohydrochloride 4-[3-[[6,7-Bis(2-methoxyethoxy]-4-quinazolinyl]amino]phenyl]-2-methyl-3-butyn-2-ol, prepared above (5.0 g, 11 mmol), anhydrous solid sodium hydroxide (44 mg, 11 mmol) and 2-methoxyethanol (50 mL) were stirred together and heated at reflux for 47 hours. The reaction mixture was cooled to 20-25 C. and concentrated hydrochloric acid (1.1 mL) was added. The resultant mixture was granulated at 20-25 C. for 1 hour to establish crystallization. The title product crystals were isolated by filtration, washed with 2-methoxyethanol (10 mL) and dried under vacuum at 45-50 C. to remove 2-methoxyethanol. Yield (3.73 g, 78%). | ||
EXAMPLE 7 Preparation of N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine, monohydrochloride 4-[3-[[6,7-Bis(2-methoxyethoxy]-4-quinazolinyl]amino]phenyl]-2-methyl-3-butyn-2-ol, monohydrochloride, prepared as described above (32.34 g, 66.3 mmol), water (300 mL) and butan-1-ol (600 mL) were stirred together at room temperature to form a mixture. The pH of the mixture was adjusted to pH 10-12 with 50% aqueous sodium hydroxide solution to give two clear layers. The organic layer was separated from the aqueous layer and concentrated under atmospheric pressure, so that water was azeotropically removed from the butan-1-ol solution. The final volume of butan-1-ol solution was ~300 mL. Anhydrous solid sodium hydroxide (0.13 g, 3.3 mmol) was added to the azeotropically dried butan-1-ol solution and the resultant mixture was heated under reflux at 115-120 C. for 24 hours. Butan-1-ol (150 mL) was removed by distillation and the concentrated reaction mixture cooled to 15-25 C. Concentrated hydrochloric acid (6.1 mL) and butan-1-ol (60 mL) were added to the cooled concentrate and the mixture was granulated overnight at 20-25 C. to establish crystallization. The title product crystals were isolated by filtration and dried under vacuum at 45-50 C. to remove butan-1-ol. Yield (21.0 g, 73.7%). Purity by HPLC 96.5%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With water; at 4℃; for 672h;Heating / reflux; Unstirred; | Hemihydrate Form I[0040] 0.5 g of anhydrous <strong>[183319-69-9]erlotinib hydrochloride</strong> was dissolved in 50 ml of demi-water at reflux. The hot solution was left unagitated at 4 C for 28 days, during which slow crystallisation occurred. The solid was isolated by careful filtration over aP3-glass filter (reduced pressure) and air dried overnight at ambient conditions. Off-white to pale beige bunches of fibre-like crystals were obtained. The yield was 170 mg. | |
With water; at 4℃; for 96h;Heating / reflux; Unstirred; | Hemihydrate Form II[0041] 0.3 g of anhydrous <strong>[183319-69-9]erlotinib hydrochloride</strong> was dissolved in 50 ml of demi-water at reflux. To the hot solution, a few mg of <strong>[183319-69-9]erlotinib hydrochloride</strong> hemihydrate Form I was added as seed. Subsequently, the solution was placed at 4 C and left unagitated at 4 C for 4 days, during which slow crystallisation occurred (crystals stuck at the wall of the flask). The crystals were scratched from the wall using a spatula, resulting in some additional nucleation. The suspension was left at 4 C for an additional 2 hours. The solid was isolated by filtration over a P3-glass filter (reduced pressure, rapid) and air dried at R.T. and under ambient conditions for about 4 days. Pale yellow lumps of sticky powder were obtained. The yield was 300 mg. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In isopropyl alcohol; for 1.5 - 2h;Heating / reflux;Product distribution / selectivity; | 4-Chloro-6,7-bis-(2-methoxyethoxy)-quinazoline (63 gm) and isopropyl. alcohol (990 ml) are added to 3-ethynylaniline (23.6 gm) at 25 - 300C under stirring, the contents are heated to reflux and then refluxed for.1 hour 30 minutes <n="11"/>to 2 hours. The reaction mass is cooled to 25 - 300C and stirred for 30 minutes. Filtered the material, washed with chilled isopropyl alcohol (400 ml) followed by n-hexane (300 ml) and then dried the material at 50 - 600C under vacuum for 6 hours to give 75 gm of crude erlotinib hydrochloride [HPLC purity. 97%; Content of N-methoxyethyl impurity: 0.24% (at 1.14 RRT)]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 1 : Preparation of Erlotinib HydrochlorideTo a solution of 2-amino-4,5-bis(2-methoxyethoxy)benzonitrile (5.0 g) in isopropanol (25.0 ml) was added drop-wise a solution of triethyl orthoformate (4.0 g); 3-ethnylphenylamine (3.45 g) and acetic acid (0.2 ml). The mixture was stirred and heated at reflux for 4 hours. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mass was cooled to room temperature and the pH was adjusted to 3.0 to 4.0 with isopropanolic hydrochloride (3.0 ml). The reaction mixture was stirred for 2 hours at room temperature. The solid was filtered, washed with isopropyl alcohol and dried on the air oven to obtain the titleCompound.Yield: 3.0 g |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In isopropyl alcohol; at 25 - 30℃;Product distribution / selectivity; | Example 5: Preparation of Erlotinib Hydrochloride from Erlotinib TrifluoroacetateErlotinib trifluoroacetate salt (10 g) was charged in to isopropyl alcohol (60 ml) at 250C to 300C. 7.5% isopropanolic hydrochloride (13 ml) was added slowly to the reaction mixture at 25C to 300C and stirred for about 2 hours at 25C to 300C. The solid obtained was filtered, washed with DI water (2 x 15 ml), suck dried and dried under vacuum for about 18 hours at 400C to 450C to give erlotinib hydrochloride.Yield: 8.08 g |
Yield | Reaction Conditions | Operation 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. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In isopropyl alcohol; for 15h;Reflux; | In a 50 mL flask, 3-ethynylaniline (410 mu, 3.64 mmol, 1 .18 eq.) and 3- ethynylaniline hydrochloride (559 mg, 3.64 mmol, 1 .18 eq.) were added to a solution of 4-(methylthio)-6,7-bis-(2-methoxyethoxy)quinazoline (1 .00 g, 3.08 mmol, prepared according to Synthetic Communications, 2007, vol. 37, pp.3409-3415, namely from henceforth compound B) in anhydrousisopropanol (IPA) (1 1 mL). The mixture was refluxed for 15 h. The mixture was cooled to 10 C and the resulting solid was filtered and was washed with cold IPA to give the title compound as a white solid (1 .098 g, 83% yield, 93.4% HPLC, impurity 4.1 %, impurity i2: 1 .2%). | |
In isopropyl alcohol; for 15h;Reflux; | Comparative Example 15: Reproduction of the process described in Synthetic Communications, 2007, vol.37 , pp. 3409-3415 for the preparation of erlotinib hydrochloride from 4-(methylthio)-6,7-bis-(2-methoxyethoxy) quinazoline In a 50 mL flask, 3-ethynylaniline (410 muL, 3.64 mmol, 1.18 eq.) and 3-ethynylaniline hydrochloride (559 mg, 3.64 mmol, 1.18 eq.) were added to a solution of 4-(methylthio)-6,7-bis-(2-methoxyethoxy)quinazoline (1.00 g, 3.08 mmol, prepared according to Synthetic Communications, 2007, vol. 37, pp.3409-3415, namely from henceforth compound B) in anhydrous isopropanol (IPA) (11 mL). The mixture was refluxed for 15 h. The mixture was cooled to 10 C and the resulting solid was filtered and was washed with cold IPA to give the title compound as a white solid (1.098 g, 83% yield, 93.4% HPLC, impurity i1 4.1%, impurity i2: 1.2%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | In a 50 mL flask, a solution of 3-ethynylaniline hydrochloride (697 mg, 4.54 mmol, 1 .4 eq.) in anhydrous THF (10 mL) was cooled to 0 C under N2. sec- BuLi (1 .3 M in cydohexane, 10.72 mL, 13.95 mmol, 4.3 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 (1 .00 g, 3.24 mmol) in anhydrous THF (7.5 mL) was added slowly and the reaction mixture was stirred at room temperature for 15 h (100% conversion, 95.5% HPLC). The resulting suspension was quenched with H2O (5 mL) and 6 M HCI (1 .2 mL) was added slowly until the suspension dissolved and a new precipitation began. Further 6 M HCI (0.6 mL, 3.6 mmol, 1 .1 eq.) was added and the mixture was stirred for 1 h at room temperature. The resulting solid was filtered and was washed with THF (3 mL) to give the title compound as an off-white solid (1 .40 g, 100% yield, 97.1 % HPLC). | |
100% | Example 10: Preparation of erlotinib hydrochloride from 6,7-bis(2-methoxyethoxy)-4-methoxyauinazoline using sec-BuLi and 3-ethynylaniline hydrochloride In a 50 mL flask, a solution of 3-ethynylaniline hydrochloride (697 mg, 4.54 mmol, 1.4 eq.) in anhydrous THF (10 mL) was cooled to 0 C under N2. sec-BuLi (1.3 M in cyclohexane, 10.72 mL, 13.95 mmol, 4.3 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 (1.00 g, 3.24 mmol) in anhydrous THF (7.5 mL) was added slowly and the reaction mixture was stirred at room temperature for 15 h (100% conversion, 95.5% HPLC). The resulting suspension was quenched with H2O (5 mL) and 6 M HCl (1.2 mL) was added slowly until the suspension dissolved and a new precipitation began. Further 6 M HCl (0.6 mL, 3.6 mmol, 1.1 eq.) was added and the mixture was stirred for 1 h at room temperature. The resulting solid was filtered and was washed with THF (3 mL) to give the title compound as an off-white solid (1.40 g, 100% yield, 97.1 % HPLC). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In water; N,N-dimethyl-formamide; | Reaction of 3,4-dihydroxybenzaldehyde (i) with 2-chloroethyl methyl ether gives 3,4-bis(2-methoxyethoxy)benzaldehyde (ii),Then ii is treated with hydroxylamine hydrochloride and acetic anhydride to give 3,4-bis(2-methoxyethoxy)benzonitrile (iii).3,4-bis(2-methoxyethoxy)benzonitrile (iii) Nitration with concentrated nitric acid in acetic acid to give 2-nitro-3,4-bis(2-methoxyethoxy)benzonitrile(iv).2-Nitro-3,4-bis(2-methoxyethoxy)benzonitrile (iv) is oxidized with hydrogen peroxide to give 2-nitro-4,5-bis(2-methoxyethoxy)benzeneFormamide (v), then v-reduced with ammonium formate under Pd/C catalysis to give 2-amino-4,5-bis(2-methoxyethoxy)benzamide (vi). 2-amino-4,5-bis(2-methoxyethoxy)benzamide (vi) according to the actualThe description of Example 1 can be converted to 6,7-bis[(2-methoxy)-ethoxy]-quinazolinone (vii).6,7-bis [(2-methoxy)(Ethyl)-ethoxy]-quinazolinone (vii) is reacted with phosphorus oxychloride in triethylamine to give 4-chloro-6,7-bis(2-methoxyethoxy)Base) quinazoline (viii).4-chloro-6,7-bis(2-methoxyethoxy)quinazoline (viii) with HCl as initiator in DMFReaction with 3-ethynylaniline can give erlotinib hydrochloride. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In a 50 mL flask, 3-ethynylaniline (421 mu, 3.74 mmol, 1 .1 eq.) and anhydrous pyridine (302 mu, 3.74 mmol, 1 .1 eq.) were added to a solution of 4-chloro- 6,7-bis(2-methoxyethoxy)quinazoline (1 .06 g, 3.40 mmol, prepared according to US 5747498) in anhydrous IPA (15 mL). The mixture was stirred at 80 C for 1 h. The solvents were removed under vacuum and the residue was suspended in a mixture of CH2CI2 (18 mL) and MeOH (2 mL). The organic layer was washed with 1 M NaHCO3 (10 mL), was dried over MgSO4 and was evaporated under reduced pressure to give erlotinib as a yellow solid (1 .234 g, 92% conversion, 87.6% HPLC). The solid was dissolved in a minimum ofCHCIs (2.4 mL, 2 mL/g) and Et2O (7.4 mL, 6 mL/g) was added. HCI (4 M solution in dioxane, 0.85 mL, 3.36 mmol, 1 .1 eq.) was added slowly and the mixture was stirred at RT for 1 h. The resulting solid was filtered and was washed with Et2O (2 mL) to give the title compound as a white solid (1 .186 g, 81 % yield from 6,7-bis(2-methoxyethoxy)quinazolinone, 82.4% HPLC, impurity ia: 1 1 .4% (hydrolisis product of 4-chloro-6,7-bis(2- methoxyethoxy)quinazoline, i.e. 6,7-bis(2-methoxyethoxy)quinazolinone), impurity ib: 4.4%, impurity ic:1 .9%). | ||
Comparative Example 16: Reproduction of the process described in US5747498 for the preparation of erlotinib hydrochloride from 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline In a 50 mL flask, 3-ethynylaniline (421 muL, 3.74 mmol, 1.1 eq.) and anhydrous pyridine (302 muL, 3.74 mmol, 1.1 eq.) were added to a solution of 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline (1.06 g, 3.40 mmol, prepared according to US 5747498) in anhydrous IPA (15 mL). The mixture was stirred at 80 C for 1 h. The solvents were removed under vacuum and the residue was suspended in a mixture of CH2Cl2 (18 mL) and MeOH (2 mL). The organic layer was washed with 1 M NaHCO3 (10 mL), was dried over MgSO4 and was evaporated under reduced pressure to give erlotinib as a yellow solid (1.234 g, 92% conversion, 87.6% HPLC). The solid was dissolved in a minimum of CHCl3 (2.4 mL, 2 mL/g) and Et2O (7.4 mL, 6 mL/g) was added. HCl (4 M solution in dioxane, 0.85 mL, 3.36 mmol, 1.1 eq.) was added slowly and the mixture was stirred at RT for 1 h. The resulting solid was filtered and was washed with Et2O (2 mL) to give the title compound as a white solid (1.186 g, 81 % yield from 6,7-bis(2-methoxyethoxy)quinazolinone, 82.4% HPLC, impurity ia: 11.4% (hydrolisis product of 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline, i.e. 6,7-bis(2-methoxyethoxy)quinazolinone), impurity ib: 4.4%, impurity ic:1.9%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | In a 50 mL flask, a solution of 3-ethynylaniline (51 1 mu, 4.54 mmol, 1 .4 eq.) in anhydrous THF (10 mL) was cooled to 0 C under N2. LDA (1 .49 M inTHF/heptane/ethylbenzene, 6.26 mL, 9.40 mmol, 2.9 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 (1 .00 g, 3.24 mmol) in anhydrous THF (7.5 mL) was added slowly and the reaction mixture was stirred at room temperature for 15 h (100% conversion, 88.8% HPLC). The reaction was quenched with H2O (5 mL) and 6 M HCI (3.6 mL) was added slowly until the precipitation of a solid began. Further 6 M HCI (0.6 mL, 3.6 mmol, 1 .1 eq.) was added and the mixture was stirred for 3 h at room temperature. The resulting solid was filtered and was washed with THF (3 mL) to give the title compound as an orange solid (1 .353 g, 97% yield, 98.0% HPLC). | |
97% | Example 7: Preparation of erlotinib hydrochloride from 6,7-bis(2-methoxvethoxy)-4-methoxyguinazoline using LDA In a 50 mL flask, a solution of 3-ethynylaniline (511 muL, 4.54 mmol, 1.4 eq.) in anhydrous THF (10 mL) was cooled to 0 C under N2. LDA (1.49 M in THF/heptane/ethylbenzene, 6.26 mL, 9.40 mmol, 2.9 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 (1.00 g, 3.24 mmol) in anhydrous THF (7.5 mL) was added slowly and the reaction mixture was stirred at room temperature for 15 h (100% conversion, 88.8% HPLC). The reaction was quenched with H2O (5 mL) and 6 M HCl (3.6 mL) was added slowly until the precipitation of a solid began. Further 6 M HCl (0.6 mL, 3.6 mmol, 1.1 eq.) was added and the mixture was stirred for 3 h at room temperature. The resulting solid was filtered and was washed with THF (3 mL) to give the title compound as an orange solid (1.353 g, 97% yield, 98.0% HPLC). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | Example 10 - Synthesis of Erlotinib hydrochloride of formula (I) - exemplifying the invention.; Synthesis scheme [Show Image] In a 500 ml flask provided with a thermometer there are introduced - in succession at 25C and under nitrogen atmosphere - 32.3 g of 3-Butyn-2-ol, 4-[3-[[6,7-bis(2-methoxyethoxy)-4-quinazolinyl]amine] phenyl]-2-methyl-, hydrochloride (1:1) of formula (II), 300 mL of purified water and 600 mL of n-butanol. It is stirred at ambient temperature for 30 minutes. 50% aqueous NaOH is added up to a 10-12 pH. A limpid two-phase system is obtained. The phases are separated and the organic phase is concentrated at atmospheric pressure (thus azeotropically removing water) up to a residual volume of 300 mL. Thus 0.13 g of anhydrous solid NaOH are added and the resulting mixture is heated at reflux to 115-120C for 24 hours. Thus 150 mL of n-butanol are removed and the concentrated mixture is cooled to 15-25C. A solution of 6.1 mL of concentrated HCl and 60 mL of n-butanol are thus dripped maintaining the temperature below 25C. The obtained suspension is left under stirring over the whole night at 20-25C. The suspension is filtered and the solid is washed using 25 mL of n-butanol. The solid is dried under vacuum at 45-50C. 21 g of Erlotinib hydrochloride are obtained for a molar yield equivalent to 74%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 10 Synthesis of Erlotinib Hydrochloride of Formula (I)-Exemplifying the Invention In a 500 ml flask provided with a thermometer there are introduced-in succession at 25 C. and under nitrogen atmosphere-32.3 g of 3-Butyn-2-ol, 4-[3-[[6,7-bis(2-methoxyethoxy)-4-quinazolinyl]amine]phenyl]-2-methyl-, hydrochloride (1:1) of formula (II), 300 mL of purified water and 600 mL of n-butanol. It is stirred at ambient temperature for 30 minutes. 50% aqueous NaOH is added up to a 10-12 pH. A limpid two-phase system is obtained. The phases are separated and the organic phase is concentrated at atmospheric pressure (thus azeotropically removing water) up to a residual volume of 300 mL. Thus 0.13 g of anhydrous solid NaOH are added and the resulting mixture is heated at reflux to 115-120 C. for 24 hours. Thus 150 mL of n-butanol are removed and the concentrated mixture is cooled to 15-25 C. A solution of 6.1 mL of concentrated HCl and 60 mL of n-butanol are thus dripped maintaining the temperature below 25 C. The obtained suspension is left under stirring over the whole night at 20-25 C. The suspension is filtered and the solid is washed using 25 mL of n-butanol. The solid is dried under vacuum at 45-50 C. 21 g of Erlotinib hydrochloride are obtained for a molar yield equivalent to 740. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | 3.0 g 16.9 millimoles/ of <strong>[183319-69-9]erlotinib hydrochloride</strong> are intensively stirred in the mixture of 100 ml of ethyl acetate, 60 ml of water and 30 ml of a concentrated ammonium hydroxide solution for 30 minutes /Heidolph MR 3001 , 1000 rpm/ at 50C. The phases are separated and the strongly alkaline aqueous layer is washed twice with 80 ml of ethyl acetate each and thereafter with 50 ml ethyl acetate at 50C the solution layers are well separated and are completely clear. The united ethyl acetate phases are washed four times with 100 ml of water each at the above temperature /the duration of each washing step is 15 minutes/. After each washing step clear well-separated phases are obtained. Finally the ethyl acetate phase is washed with 100 ml of a saturated sodium chloride solution, which is then dried over sodium sulfate and the drying agent is filtered off. Thus 310 ml /total volume/ of a solution are obtained which can be used in the salt forming reactions. a) Salt formation with maleic acid /preparation of the compound of the Formula 2/To the 310 ml of the ethyl acetate solution thus obtained a solution of 0.81 g (6.98 millimoles) of maleic acid and 10 ml of ethanol is added under intensive stirring /Heidolph MR 3001 , 1000 rpm/ at room temperature. The precipitation of crystals begins, whereupon the mixture is stirred for a further period of 24 hours, the precipitated crystals are filtered, washed with 20 ml of tert. butyl methyl ether and dried at 50C under a pressure of 160 mbar for 20 hours. Yield: 3.17 g (89 %). b) Salt formation with adipinic acid /preparation of the compound of the Formula 5/One proceeds according to point a) except that to the ethyl acetate solution 1.02 g (6.98 millimoles) of adipinic acid in 20 ml of ethanol is added. Crystallization is started by using a seeding crystals and external ice-water cooling. After the beginning of the crystal precipitation the mixture is stirred for a further period of 24 hours. The precipitated crystals are filtered, washed with 20 ml of tert. butyl methyl ether and dried at 50C under a pressure of 160 mbar for 20 hours.Yield 2.71 g (72 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | 3.0 g 16.9 millimoles/ of <strong>[183319-69-9]erlotinib hydrochloride</strong> are intensively stirred in the mixture of 100 ml of ethyl acetate, 60 ml of water and 30 ml of a concentrated ammonium hydroxide solution for 30 minutes /Heidolph MR 3001 , 1000 rpm/ at 50C. The phases are separated and the strongly alkaline aqueous layer is washed twice with 80 ml of ethyl acetate each and thereafter with 50 ml ethyl acetate at 50C the solution layers are well separated and are completely clear. The united ethyl acetate phases are washed four times with 100 ml of water each at the above temperature /the duration of each washing step is 15 minutes/. After each washing step clear well-separated phases are obtained. Finally the ethyl acetate phase is washed with 100 ml of a saturated sodium chloride solution, which is then dried over sodium sulfate and the drying agent is filtered off. Thus 310 ml /total volume/ of a solution are obtained which can be used in the salt forming reactions. a) Salt formation with maleic acid /preparation of the compound of the Formula 2/To the 310 ml of the ethyl acetate solution thus obtained a solution of 0.81 g (6.98 millimoles) of maleic acid and 10 ml of ethanol is added under intensive stirring /Heidolph MR 3001 , 1000 rpm/ at room temperature. The precipitation of crystals begins, whereupon the mixture is stirred for a further period of 24 hours, the precipitated crystals are filtered, washed with 20 ml of tert. butyl methyl ether and dried at 50C under a pressure of 160 mbar for 20 hours. Yield: 3.17 g (89 %). b) Salt formation with adipinic acid /preparation of the compound of the Formula 5/One proceeds according to point a) except that to the ethyl acetate solution 1.02 g (6.98 millimoles) of adipinic acid in 20 ml of ethanol is added. Crystallization is started by using a seeding crystals and external ice-water cooling. After the beginning of the crystal precipitation the mixture is stirred for a further period of 24 hours. The precipitated crystals are filtered, washed with 20 ml of tert. butyl methyl ether and dried at 50C under a pressure of 160 mbar for 20 hours.Yield 2.71 g (72 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In isopropyl alcohol; at 25 - 45℃; for 4h;Inert atmosphere; | 4-chloro-6, 7-bis (2-methoxyethox.y) quinazoline (100 g; 0.319 mol) as prepared from process cited in Example No.3 in Isopropanol (2000mL), stirred under nitrogen at atemperature about 25-35C.To the above solution, 3-ethynyl aniline hydrochloride (54g; 0.35 mumol) was added and the reaction mass temperature was raised to 40-45C.The reaction was maintained at 40-45C for a period about 4 hours. The completion of the reaction was monitored by HPLC. After the completion of reaction, the reaction mass was allowed to cool to 25-3 SC and solids thus obtained after stirring, were filtered and washedwith isopropanol (500mL). The resultant compound was suck dried and dried under vacuum over a period of 6-8 hrs at 50-5 5C to obtain crude erlotinib hydrochloride. (130g; 94%). EXAMPLE 5: Preparation of Erlotinib hydrochloride Form A. The crude erlotinib hydrochloride (100g; 0.232 mol) in methanol (10 L) was heated to reflux, to obtain the clear solution. This reaction mass was filtered at the same temperature without any prior cooling and then washed with 50 mL of hot (-60C) methanol. The filtrate temperature was maintained at 60-65C.This reaction mass was slowly added to aprecooled solution (less than 30C) of isopropanol (10 L) seeded with Erlotinib hydrochloride Form A crystal under stirring. The reaction mass was allowed to crystallize under stirring at a temperature about 0-5C.The reaction mass was filtered off over a stipulated period of time and the wet cake was washed with mixture of chilled isopropanol and methanol (1:1 ; 100 mL). The resultant compound was suck dried and dried under vacuum over a period of 6-8 hrs at 50-55C to obtain pure erlotinib hydrochloride Form A (yield: ~80%; purity by HPLC: 99.5 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | With triethylamine; In N,N-dimethyl-formamide; at 65℃; for 17h; | Dichloro(ethylenediamine)platinum(II) (Pt(en)Cl2); 300 mg, 1.76 mmol, dissolved in 30 ml dimethylformamide (DMF)) was converted into Pt(en)(N03)Cl (LCL-chloride) by adding 1 molar equivalent of AgN03 (520 mg, 1.76 mmol, dissolved in 52 ml of DMF) divided in 4 equal portions. Each addition was separated by 2 h and the mixture was stirred in the absence of light, at ambient temperature. The grey precipitated silver chloride was removed by filtration over a 0.2 mupiiota membrane filter 16 h after the last addition. The resulting pale yellow solution was stored at 4C. The identity and purity of the product was confirmed by 195Pt- MR (DMF-d6): delta -2075 ppm. Erlotinib.HCl (125 mg, 0.3 mmol) and triethyl amine (88 mg, 0.9 mmol) were dissolved in 37.5 ml of DMF and reacted with LCL-chloride (176 mg, 0.5 mmol, dissolved in 22.5 ml of DMF) at 65C for 17 h. To this mixture dilute HCl (65 ml, 0.1 mM) was added and subsequently the solvents were removed under reduced pressure. The crude product was redissolved in milliQ and purified by preparative FIPLC (Phenomenex (P/NO: 00G-4253-P0), Luna 2, 10mu, C18 column, 250 x 21.20 mm. EluentA: 90% NaCl (20mM)/10% isopropanol, Eluent B: 30% NaCl (20mM)/70%> isopropanol, gradient elution (0% B from 0-17.7 min; 0-30% B from 17.7-35.3; 30- 80%B from 35.3-79.4 min; 80-100% B from 79.4-88.2 min; 100% B from 88.2-114.7 min; 100-0% B from 114.7-123.6 min; 0% B from 123.6-158.8 min, flow 5.0 mL/min). Elution buffers were subsequently removed by co-evaporation in vacuo (yield 22 %). Erlotinib-LCL-chloride was stored at 4C until further use. The identity and purity of the final product erlotinib-LCL-chloride was confirmed by HPLC (>95%), 195Pt- MR (DMF-d6): delta -2543 ppm and mass spectroscopy (calculated mass: 684 (m/z); detected: 684 [M+]). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29% | Erlotinib.HCl (125 mg, 0.291 mmol) was converted in its free base form by adding a 3 times molar excess of triethyl amine (88 mg, 0.87 mmol) in 12.5 ml of DMF. The mixture was stirred for 2 h at room temperature after which the solvent was removed under reduced pressure. The product was washed 3 times with 5 ml milliQ and redissolved in 12.5 ml DMF. Subsequently, 3 ml of this solution was reacted with LCL-nitrate (46 mg, 0.12 mmol, dissolved in 9 ml of DMF) at 65C for 17 h. To this mixture 40 ml of milliQ was added and subsequently the solvent was removed under reduced pressure. The crude product was redissolved in milliQ and purified by preparative HPLC (Phenomenex (P/NO: 00G-4253-P0), Luna 2, 10 mu, C18 column, 250 x 21.20 mm. Eluent A: 90% NaCl (20mM)/10%> isopropanol, EluentB: 30% NaCl (20mM)/70% isopropanol, gradient elution (0% B from 0-17.7 min; 0-30% B from 17. 7-35.3; 30-80%B from 35.3-79.4 min; 80-100% B from 79.4-88.2 min; 100% B from 88.2-114.7 min; 100-0% B from 114.7-123.6 min; 0% B from 123.6-158.8 min, flow 5.0 mL/min). Elution buffers were subsequently removed by co-evaporation in vacuo (yield 29%). Erlotinib-LCL-nitrate was stored at 4C until further use. The identity and purity of the final product erlotinib-LCL-nitrate was confirmed by HPLC (>95%), 195Pt- MR (DMF-d6): delta -2525 ppm and mass spectroscopy (calculated mass: 683 (m/z); detected: 683 [M+]). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36.02 g | In the reaction flask was charged with 2-amino-4,5-bis (2-methoxyethoxy) - benzonitrile (37.01g, 0.139mol) and acetonitrile (185ml); added 3-ethynyl aniline salt acid (30.00g, 0.195mol), trifluoroacetic acid (17.43g, 0.152mol) and formamidine acetate (15.19g, 0.145mol) in the resultant mixture.The reaction mixture temperature was adjusted to reflux temperature of the solvent, and maintained in this condition for about 15 hours.At the end of the reaction, the temperature was adjusted to about 25 , the solvent was removed by vacuum distillation, and methyl ethyl ketone (430ml).(2 × 100ml) and water (2 × 100ml) the organic phase was washed with saturated sodium bicarbonate solution.The organic phase was collected and concentrated by vacuum distillation to a residue.The resulting crude product was suspended in ethyl acetate (450ml), and adding 37% hydrochloric acid solution (14.38g, 0.145mol), maintained at a temperature of 15 for about 30 minutes.The resulting solid was filtered, washed under vacuum at 45 C oven dried to obtain 36.02g erlotinib hydrochloride. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | A process for the preparation of erlotinib hydrochloride, characterized in that the specific preparation steps are as follows:A 3 L four-necked flask was charged with 88 g (0.751 mol) of m-aminophenylacetylene,4- (dimethoxymethylene) -morpholine 169. 5 g (1.05 mol),Toluene 1. 32 L,Acetic acid 2.5mL began to heat reflux 2-3h,To the system was added 352 mL of a toluene solution of 200 g (0.751 mol) of 2N-amino _4,5-bis (2-methoxyethoxy) benzonitrile dissolved therein,Acetic acid 352mL continue to join the reflux 3 ~ 4 hours,After the reaction was completed, the temperature was lowered to 5-15 C,The pH was adjusted to 9 with aqueous ammonia,A large number of solid precipitation,filter,The filter cake was dried and recrystallized from a mixed solvent of 400 mL of ethyl acetate and 200 mL of methanol,The resulting solid was dissolved in 880 mL of methanol,A solution of hydrochloric acid in methanol (containing 0.68 mol of HC1) was slowly added dropwise with stirring,After completion of the dropwise addition, the mixture is stirred at 15 to 20 C for 15 to 20 minutes,The filter cake was washed with 100 mL of methanol,After drying, 203.5 g of erlotinib hydrochloride was obtained,Yield 63%HPLC purity 99.7%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With hydrogenchloride; In methanol; at 20℃; for 1h; | (Erlotinib hydrochloride, ): A mixture of Compound 1f (R = SiMe, R = H, the compound is f N- (3- trimethylsilyl-ethynyl-phenyl) -6 1,7-bis (2-methoxyethoxy) -4-quinolyl-amine) 1 g (2.15 mmol) was dissolved in 20 ml of methanol. Methanol solution of hydrochloric acid gas under stirring at room temperature leads to saturation compound 1f of hydrochloric acid until the (hydrochloric acid bubbles emerge). The solution was stirred at room temperature for one hour, the methanol solvent was evaporated to dryness. The resulting solid was recrystallized from acetonitrile to give N- (3- ethynyl-phenyl) -6,7-bis (2-methoxyethoxy) -4-quinolyl-amine hydrochloride (erlotinib hydrochloride , ) needle crystals 0.85 g, yield 90%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95.1% | for 3h;Reflux; Large scale; | (3) in the filtrate by adding 11.9Kg 3-aminophenyl acetylene, heated to reflux for 3h, the reaction liquid .(4) the reaction solution to 10 , stirring 1h after the centrifuge centrifuge, with methanol leaching filter cake.(5) control the hot water tank temperature 55 ~ 65 , vacuum ?-0.09MPa, the obtained centrifugal wet product drying 8h,package,That is, hydrochloric acid productsRobutyne, The yield was 95.1%. The purity of the product was above 99.0% by HPLC. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.5% | In dimethyl sulfoxide; at 45℃; | Take 20 mg of <strong>[183319-69-9]erlotinib hydrochloride</strong> in a reaction flask and add 2000 ml of a mixed solution of dimethylsulfoxide and water (1: 2 in volume ratio of dimethylsulfoxide and water), heated to 45 C, stirred and stirred, Hot filter; While stirring, while cooling to 30 (cooling rate of 20 every 20 minutes)To the solution at a flow rate of 2 mL / min, a pre-cooled mixed solvent B (volume ratio of water and acetone of 1: 4) was added to 4000 ml, Continue to cool to -5 (cooling rate of 20 every 20 minutes), stirring 2h. The filter cake was vacuum dried at 50 C for 5 h to give 37.0 g of crystals in a yield of 92.5%. The X-ray powder diffraction spectrum of the prepared erlotinibine crystal using Cu-Kalpha ray was similar to that of Example 1, Differential thermal scanning spectrumAnd thermogravimetric analysis is basically shown in Figure 2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With sulfuric acid; at 50℃;Cooling with ice; | 1.5g erlotinib was added to 10mL of 50% sulfuric acid solution under ice bath conditions.Slowly warm to 50 C to continue the reaction, TLC monitoring reaction progress. After the reaction was completed, the reaction solution was slowly dropped into a 10% sodium hydroxide solution, extracted with ethyl acetate, and the organic layer was concentrated.The residue was purified by column chromatography to give a white solid, about 1.32 g, yield: 84%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95.29% | 10mmol of compound 2,13mmol-iodoethyl methyl ether, tetra-n-propyl ammonium iodide 4mmol,15mmol pyridine was dissolved in 60mL N-methylpyrrolidone,React for 1h at room temperature,After the reaction, the reaction solution was added with 30mL water and 60mL ethyl acetate,Stir, separate layers, extract the aqueous phase once with ethyl acetate, combine ethyl acetate,Wash with 50mL saturated sodium chloride, add activated carbon and stir for 30min,Decolorize and filter, add 5g of anhydrous sodium sulfate to the filtrate, and concentrate ethyl acetate under reduced pressure.To obtain an oily substance, add the oily substance to 100 mL of acetone-methyl tert-butyl ether (1 / 3v / v),Stir and dissolve, then add 10mL of 16% hydrochloric acid solution, after a large number of crystals are precipitated,After filtration, the crystals were washed repeatedly with cold acetone-methyl tert-butyl ether and drained,To give a white solid which was dried in vacuo 40 ,Obtained erlotinib hydrochloride 3.755g,The yield is 95.29% and the purity is 99.94%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With copper(II) sulfate; sodium L-ascorbate In water at 40℃; for 6h; | 1 Then the compound of formula IV (N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-quinazolin-4-amine hydrochloride, 77.4mg, was added to the reaction solution, 0.18mmol) and a catalyst formed by mixing 0.2ml CuSO4 aqueous solution (0.1mol/L, 0.02mmol) and 0.2ml sodium ascorbate aqueous solution (2mol/L, 0.4mmol), make the reaction system evenly mixed and then keep stirring at 40 Reaction for 6 hours;After finishing the reaction, first extract with ethyl acetate, then wash the extract with saturated brine, and then dry the washed organic phase with anhydrous sodium sulfate, concentrate and column chromatography to obtain the compound of formula I (126.4mg, yield Rate 92%). |
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P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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