CN103396371B - A kind of preparation method of Erlotinib hydrochloride crystal form A - Google Patents
A kind of preparation method of Erlotinib hydrochloride crystal form A Download PDFInfo
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Abstract
The invention provides a kind of preparation method of Erlotinib hydrochloride crystal form A, belong to the preparing technical field of medical compounds.The method comprises: by 2-amino-4,5-bis-(2-methoxy ethoxy) cyanophenyl and N, dinethylformamide dimethylacetal reacts, gained Schiff base intermediate is after recrystallization purifying, synthesize with 3-aminophenylacetylene and obtain erlotinib free base, finally add hydrochloric acid soln, recrystallization obtains Erlotinib hydrochloride crystal form A.The present invention program's operational path is short, and product purity is high, and favorable reproducibility is easy to operation, is suitable for large-scale industrial production.
Description
Technical field
The present invention relates to medicinal chemistry art, be specifically related to a kind of preparation method of Erlotinib hydrochloride crystal form A.
Background technology
Erlotinib hydrochloride (ErlotinibHydrochloride, formula I), it is the original new drug being used for the treatment of Locally Advanced to the failure of at least one chemotherapy regimen or Metastatic Nsclc (NSCLC), by Genetech, OSI, Roche tri-company's joint development, by Roche(Roche Holding Ag) produce.Obtain U.S. FDA approval in November, 2004, obtain European Union's approval listing in September, 2005, in April, 2006 is in Discussion on Chinese Listed.FDA in 2005 also have approved erlotinib and combines treatment for advanced pancreatic cancer with gemcitabine, and this becomes first approved advanced pancreatic cancer medicine over nearly 10 years.Erlotinib hydrochloride is epidermal growth factor recipient tyrosine kinase inhibitor (EGFR-TK).Its by cell with the intracellular region catalysed partial of Triphosaden competition binding receptor tyrosine kinase, suppress phosphorylation reaction, thus retardance is conducted to downstream proliferation signal, the activity of the HER-1/EG-FR that inhibition tumor cell ligand-dependent or part rely on outward, reaches the effect of anticancer propagation.
In existing erlotinib synthetic method, the chlorination that the committed step of first kind method relates to intermediate A or its analogue (is shown below, see patent US5747498, US6900221, WO2007/060691, US2009/0306377 and US2010/0094004), agents useful for same mainly contains phosphorus pentachloride, phosphorus oxychloride, thionyl chloride, oxalyl chloride etc., severe reaction conditions and productive rate is lower is simultaneously very large to the pollution of environment.Obtain product B after intermediate A chlorination, react with 3-aminophenylacetylene or derivatives thereof in the basic conditions, obtain required product.
Equations of The Second Kind synthetic method is with patent WO2007/138612 and WO2007/138613 and OrganicProcessResearch & Development2007,11:813-816 is representative, conventional dimethylformamide dimethyl acetal (DMF-DMA) forms Schiff base intermediate, forms erlotinib through resetting.
According to the literature, Erlotinib hydrochloride has A crystal formation, B crystal form, crystal form E, M crystal formation, N crystal form, P crystal formation and unformed.The document prepared about A crystal formation is more, that erlotinib free base is dissolved in chloroform by US Patent No. 5747498 the earliest, then drip ether solution of hydrogen chloride and obtain erlotinib hydrochloride, but it is A and Type B mixing crystal formation that US690021 discloses it what repeat to obtain when testing.WO2010040212 and EP185108 also refer at a lower temperature, erlotinib free base is dissolved in organic solvent, then adds hydrogen chloride gas organic solution and produces hydrochloride A crystal formation.Erlotinib free base crystallization in ethyl formate, butylacetate or isopropyl acetate solvent is obtained free alkali FormIV by Huahai medicine company patent WO2012022240A1, then obtains hydrochloride A crystal formation with hydrochloric acid soln process.A kind of A crystal formation preparation method patent CN200910097966 of Zhejiang in April, 2009 nine divisions of China in remote antiquity medicine company application, is dissolved in organic solvent by erlotinib, then drips hydrogenchloride ethers solution.But need to carry out (less than 20 DEG C) at lesser temps, this patent emphasizes that, if exceed this temperature, A crystal formation is then easy to be transformed into other crystal formations.First sign medicine company is on the basis that it is studied, the temperature condition forming crystal form A is improved, it provides a kind of preparation method of Erlotinib hydrochloride crystal form A in patent CN201010274216.9, describe within the scope of comparative high temperature, erlotinib free base is mixed with organic solvent, then drip chlorination hydrogen ester class solution, obtain Erlotinib hydrochloride crystal form A.
Summary of the invention
The object of this invention is to provide a kind of with low cost, easy and simple to handle, product purity be high, good product quality can stablize the method preparing Erlotinib hydrochloride crystal form A, there is higher industrial using value.The present invention, at document OrganicProcessResearch & Development2007, the basis of 11:813-816 improves and optimizates.By increasing re-crystallization step and optimized choice crystallization solvent, obtaining highly purified erlotinib free base easy to operately, being finally dissolved in appropriate solvent, adding hydrochloric acid soln, stably obtain Erlotinib hydrochloride crystal form A at ambient temperature.
The present invention is achieved by the following technical solutions (reaction scheme is as follows), and a kind of preparation method of Erlotinib hydrochloride crystal form A, comprises the steps:
(1) by 2-amino-4,5-bis-(2-methoxy ethoxy) cyanophenyl (formula II compound) and N, dinethylformamide dimethylacetal (DMF-DMA) reaction under toluene solvant and acetate catalyst exist, react complete, reclaim reaction solvent, residue oily matter recrystallization purifying in solvent orange 2 A obtains Schiff's base (formula III compound) solid, and described solvent orange 2 A is selected from the mixed solvent of isopropyl ether and tetrahydrofuran (THF), or the mixed solvent of methyl tertiary butyl ether and ethyl acetate;
(2) Schiff's base (formula III compound) of purifying and 3-aminophenylacetylene are reacted in acetate solvate, react complete, slow cooling, to interior temperature 60 DEG C, adds the mixed solvent of water and solvent B in reaction solution, continue to be cooled to 20-25 DEG C, stirring and crystallizing, obtains the white solid of erlotinib free base (formula IV compound), wherein, described solvent B is selected from acetone, tetrahydrofuran (THF), the one in Isosorbide-5-Nitrae-dioxane;
(3), under certain temperature, erlotinib free base is dissolved in the mixed solvent of Virahol and acetone, or in the mixed solvent of Virahol and methyl ethyl ketone, filtered while hot, filtrate cooling down is to 15-20 DEG C;
(4) with step (3) mixed solvent dilution used concentrated hydrochloric acid, the hydrochloric acid soln obtained walks in filtrate on being added drop-wise in 0.5h-2h, and in maintaining, temperature is at 15-20 DEG C, drips off and continues insulation reaction 3-4h, collect the white crystal of separating out, obtain Erlotinib hydrochloride crystal form A (formula I).
Further, the solvent orange 2 A of step (1) is selected from: the mixed solvent (25:1, v/v) of isopropyl ether/tetrahydrofuran (THF) mixed solvent (20:1, v/v) or methyl tertiary butyl ether/ethyl acetate, mixed solvent volume is 8-10 times (v/w, unit L/Kg) of described residue oily matter weight.
Further, acetate solvate volume is 5 times (v/w, unit is L/kg) of Schiff's base weight, and in step (2), the volume ratio of water and solvent B is 4-6:1, and added mixed solvent volume is 6 times (v/w, unit is L/kg) of Schiff's base weight; Preferably, the volume ratio of water and solvent B is 5:1; More preferably, solvent B is selected from Isosorbide-5-Nitrae-dioxane.
Further, step (1) formula compound of formula H is 1:1.1 in the mol ratio of DMF-DMA, and the mol ratio of step (2) compound of formula III and 3-aminophenylacetylene is 1:1.1, and step (3) described certain temperature refers to 40-45 DEG C.
Further, the mixed solvent of step (3) is selected from: the mixed solvent (1:5, v/v) of Virahol/acetone, or the mixed solvent (1:4, v/v) of Virahol and methyl ethyl ketone.
Further, described mixed solvent volume is 6-8 times (v/w, unit is L/kg) of erlotinib free base weight.
Further, concentrated hydrochloric acid in step (4) is selected from about 37% commercially available concentrated hydrochloric acid aqueous solution, required concentrated hydrochloric acid volume is 0.3 times (v/w, unit L/Kg) of erlotinib free base weight, and the mixed solvent volume being used for diluting this concentrated hydrochloric acid is 2 times (v/v) of concentrated hydrochloric acid.
Further, after completion of the reaction with methyl tertiary butyl ether washing, dry temperature is preferably 30-40 DEG C, and vacuum tightness is greater than 0.09Mpa, and time of drying is 8-10h.
In the Erlotinib hydrochloride synthetic route of prior art, if adopt first method (chlorination method), then relate to the chlorination reagent using big for environment pollution and national forbidding, as thionyl chloride and oxalyl chloride etc.; If adopt second method (rearrangement), then prior art also there is (1) aftertreatment need with ammoniacal liquor adjust pH and with the troublesome operations such as a large amount of solvent extractions; (2) gained free alkali purity is not high, needs further recrystallization to make the defects such as hydrochloride again.
In the processing method preparing Erlotinib hydrochloride crystal form A, what prior art adopted mostly is the ester class not miscible with water, ethers, or alkane solvents, and " the hydrochloric acid source " that adopt is all almost the organic solution of hydrogen chloride gas, and this hydrogenchloride organic solution needs to be prepared separately by a locking equipment and step in suitability for industrialized production, and hydrogen chloride gas is more prone to loss along with the volatilization of organic solvent, strength of solution is inaccurate, and then preparation circulation ratio is poor.
For the defect of above-mentioned prior art, the technical program achieves technique effect useful as follows:
(1) prior art is often after preparation schiff base reaction liquid, direct steaming desolventizes and obtains oily matter, not purified, walk ring closure reaction under direct input, reaction terminates, and pours in frozen water, use ammoniacal liquor adjust ph, be extracted with ethyl acetate, concentrated, the oily matter obtained uses ethyl acetate equal solvent recrystallization again.This protocol step is loaded down with trivial details, process trouble.Technical solution of the present invention is combined and screening and optimizing by solvent, carries out recrystallization operation, obtain the Schiff base intermediate of white solid state to Schiff base intermediate (formula III compound), than prior art report oily matter advantageously.After this highly purified Schiff's base solid is carried out ring closure reaction, directly add the mixed solvent of water and specific organic solvent, the higher erlotinib free base solid of purity can be settled out by crystallization.The recrystallization of Schiff's base and the crystallization of erlotinib free base reaction soln are two last handling processes be closely connected, the troublesome operation avoiding adjust pH, extraction and recrystallization is optimized by these, substantially increase conventional efficient, be extremely of value to industrialized production.
(2) prior art is being prepared in Erlotinib hydrochloride crystal form A process, is erlotinib free base and organic solvent " mixing " to be stirred.The present inventor found through experiments, and the organic solvent overwhelming majority selected by it can not dissolve free alkali, causes the mechanical impurity in free alkali to be removed, and this requirement carries out extra recrystallization process to free alkali.The technical program is hot a little by the mixed solution of Virahol and ketones solvent, can obtain dissolving clear liquor, filtered while hot, is convenient to remove mechanical impurity, is beneficial to acid adjustment crystallization operation below.
(3) " the hydrochloric acid source " of bibliographical information is nearly all the organic solution of hydrogen chloride gas, and this just needs to be imported in organic solvent by hydrogen chloride gas separately to prepare.Due to the volatility of hydrogen chloride gas, storage and metering are used also inconvenient.Commercially available concentrated hydrochloric acid (about 37% aqueous solution) can drip with after suitable organic solvent dilution by the present invention.
Preparing in Erlotinib hydrochloride crystal form A process, owing to dissolving clarification and dripping hydrochloric acid soln crystallization again after filtering, making the technical program system while preparing crystal form A, greatly can also improve content and the purity of product, reduce related substance.
Accompanying drawing explanation
The nucleus magnetic hydrogen spectrum of Fig. 1 Erlotinib hydrochloride crystal form A;
The nuclear-magnetism carbon spectrum of Fig. 2 Erlotinib hydrochloride crystal form A;
The DSC spectrum of Fig. 3 Erlotinib hydrochloride crystal form A;
The TG spectrum of Fig. 4 Erlotinib hydrochloride crystal form A;
The X-ray powder diffraction spectrum of Fig. 5 Erlotinib hydrochloride crystal form A.
Embodiment
Below in conjunction with embodiment, the present invention is further elaborated, but do not constitute any limitation content of the present invention.
Embodiment 1
By amino for 2--4,5-bis-(2-methoxy ethoxy) cyanophenyl (formula II compound, 1Kg, 3.76mol), toluene 5L, acetic acid 20mL and DMF-DMA(492g, 4.13mol, 1.1 times of molar weights of formula II compound) mix and blend, oil bath back flow reaction, be incubated 80-90 DEG C of backflow 3h, reaction terminates, 60-65 DEG C of concentrating under reduced pressure, obtains intermediate Schiff's base oily matter and is about 1.3Kg.By oily matter isopropyl ether/tetrahydrofuran (THF) (20:1) (about 10.5L, 8 times of volumes of oily matter weight) dissolve clarification at 35-40 DEG C, slow cooling is to 10-15 DEG C, and crystallization obtains white solid 1.09Kg, Schiff's base yield 91%, HPLC purity 99.5%.
By formula III compound (1.09Kg, 3.39mol) 3-aminophenylacetylene (438g, 3.73mol, 1.1 times of molar weights of formula III compound), acetic acid 5L, mix and blend, starts heating, and in controlling, temperature is at 95-100 DEG C, reaction 2.5-3h, launch by chromatographic sheet (DCM:MeOH=15:1), react completely, slow cooling is to interior temperature 60 DEG C, add water and 1,4-dioxane mixed solvent 6L(5:1, v/v), continue to be cooled to 20-25 DEG C, stirring and crystallizing 3h, obtain white solid 1.08Kg, HPLC purity 99.3%, free alkali yield 82%.
At 40-45 DEG C, erlotinib free base 1.08Kg is dissolved in the mixed solvent 7.4L of Virahol/acetone (1:5, v/v), filtered while hot, filtrate cooling down is to 15-20 DEG C; Be about 0.64L with above-mentioned mixed solvent and add in concentrated hydrochloric acid 0.32L the hydrochloric acid soln obtaining diluting, insulation 15-20 DEG C, drips off the hydrochloric acid soln of preparation at 0.5h-2h, continue insulation reaction 3-4h, collect the white crystal of separating out, obtain Erlotinib hydrochloride crystal form A (formula I), with appropriate methyl tertiary butyl ether washing leaching cake, vacuum-drying 8-10h(30-40 DEG C, vacuum tightness is greater than 0.09Mpa), the Erlotinib hydrochloride crystal form A that must refine is about 1.07Kg, refining yield 91%, HPLC purity 99.9%.
Embodiment 2
By 2-amino-4,5-bis-(2-methoxy ethoxy) cyanophenyl (formula II compound, 1.3Kg, 4.88mol), toluene 6.5L, acetic acid 26mL and DMF-DMA(629g, 5.37mol) mix and blend, oil bath back flow reaction, be incubated 80-90 DEG C of backflow 3h, reaction terminates, and 60-65 DEG C of concentrating under reduced pressure, obtains intermediate Schiff's base oily matter and be about 1.6Kg.By oily matter methyl tertiary butyl ether/ethyl acetate (25:1) (about 16L, 10 times of volumes of oily matter weight) dissolve clarification at 35-40 DEG C, slow cooling is to 10-15 DEG C, and crystallization obtains white solid 1.39Kg, Schiff's base yield 89%, HPLC purity 99.4%.
By formula III compound (1.39K, 4.33mol), 3-aminophenylacetylene (558g, 4.76mol), acetic acid 7L, mix and blend, starts heating, in controlling, temperature is at 95-100 DEG C, and reaction 2.5-3h, launches by chromatographic sheet (DCM:MeOH=15:1), react completely, slow cooling, to interior temperature 60 DEG C, adds water and tetrahydrofuran (THF) mixed solvent 8.4L(4:1, v/v), continue to be cooled to 20-25 DEG C, stirring and crystallizing 3h, obtain white solid 1.35Kg, HPLC purity 99.4%, free alkali yield 81%.
At 40-45 DEG C, erlotinib free base 1.36Kg is dissolved in the mixed solvent 9.4L of Virahol/methyl ethyl ketone (1:4, v/v), filtered while hot, filtrate cooling down is to 15-20 DEG C; Be about 0.8L with above-mentioned mixed solvent and add in concentrated hydrochloric acid 0.4L the hydrochloric acid soln obtaining diluting, insulation 15-20 DEG C, drips off the hydrochloric acid soln of preparation in 0.5h-2h, continues insulation reaction 3-4h, collect the white crystal of separating out, obtain Erlotinib hydrochloride crystal form A (formula I), with appropriate methyl tertiary butyl ether washing leaching cake, vacuum-drying 8-10h(30-40 DEG C, vacuum tightness is greater than 0.09Mpa), the Erlotinib hydrochloride crystal form A that must refine is about 1.36Kg, refining yield 92%, HPLC purity 99.8%.
Embodiment 3
By 2-amino-4,5-bis-(2-methoxy ethoxy) cyanophenyl (formula II compound, 1.5Kg, 5.64mol), toluene 7.5L, acetic acid 30mL and DMF-DMA(730g, 6.3mol) mix and blend, oil bath back flow reaction, be incubated 80-90 DEG C of backflow 3h, reaction terminates, and 60-65 DEG C of concentrating under reduced pressure, obtains intermediate Schiff's base oily matter and be about 1.9Kg.By oily matter isopropyl ether/tetrahydrofuran (THF) (20:1) (about 17L, 9 times of volumes of oily matter weight) dissolve clarification at 35-40 DEG C, slow cooling is to 10-15 DEG C, and crystallization obtains white solid 1.58Kg, Schiff's base yield 88%, HPLC purity 99.5%.
By formula III compound (1.58Kg, 4.92mol), 3-aminophenylacetylene (633g, 5.41mol) acetic acid 7.9L, mix and blend, starts heating, in controlling, temperature is at 95-100 DEG C, and reaction 2.5-3h, launches by chromatographic sheet (DCM:MeOH=15:1), react completely, slow cooling, to interior temperature 60 DEG C, adds water and acetone mixed solvent 9.5L(6:1, v/v), continue to be cooled to 20-25 DEG C, stirring and crystallizing 3h, obtain white solid 1.54Kg, HPLC purity 99.3%, free alkali yield 80%.
At 40-45 DEG C, erlotinib free base 1.54Kg is dissolved in the mixed solvent 10L of Virahol/methyl ethyl ketone (1:4, v/v), filtered while hot, filtrate cooling down is to 15-20 DEG C; Be about 0.92L with above-mentioned mixed solvent and add in concentrated hydrochloric acid 0.46L the hydrochloric acid soln obtaining diluting, insulation 15-20 DEG C, the hydrochloric acid soln of preparation is dripped off in 0.5h-2h, continue insulation reaction 3-4h, collect the white crystal of separating out, obtain Erlotinib hydrochloride crystal form A (formula I), with appropriate methyl tertiary butyl ether washing leaching cake, vacuum-drying 8-10h(30-40 DEG C, vacuum tightness is greater than 0.09Mpa), the Erlotinib hydrochloride crystal form A that must refine is about 1.51Kg, refining yield 90%, HPLC purity 99.9%.
Embodiment 4
By 2-amino-4,5-bis-(2-methoxy ethoxy) cyanophenyl (formula II compound, 5Kg, 18.8mol), toluene 25L, acetic acid 100mL and DMF-DMA(2.45Kg, 21mol) mix and blend, oil bath back flow reaction, be incubated 80-90 DEG C of backflow 3h, reaction terminates, and 60-65 DEG C of concentrating under reduced pressure, obtains intermediate Schiff's base oily matter and be about 6.6Kg.By oily matter methyl tertiary butyl ether/ethyl acetate (25:1) (about 52L, 8 times of volumes of oily matter weight) dissolve clarification at 35-40 DEG C, slow cooling is to 10-15 DEG C, and crystallization obtains white solid 5.46Kg, Schiff's base yield 91%, HPLC purity 99.5%.
By formula III compound (5.46Kg, 17.00mol), 3-aminophenylacetylene (2.18Kg, 18.7mol), acetic acid 27L, mix and blend, starts heating, and in controlling, temperature is at 95-100 DEG C, reaction 2.5-3h, launch by chromatographic sheet (DCM:MeOH=15:1), react completely, slow cooling is to interior temperature 60 DEG C, add water and 1,4-dioxane mixed solvent 32L(5:1, v/v), continue to be cooled to 20-25 DEG C, stirring and crystallizing 3h, obtain white solid 5.52Kg, HPLC purity 99.4%, free alkali yield 83%.
At 40-45 DEG C, erlotinib free base 5.53Kg is dissolved in the mixed solvent 38.6L of Virahol/methyl ethyl ketone (1:4, v/v), filtered while hot, filtrate cooling down is to 15-20 DEG C; Be about 3.31L with above-mentioned mixed solvent and add in concentrated hydrochloric acid 1.65L the hydrochloric acid soln obtaining diluting, insulation 15-20 DEG C, drips off the hydrochloric acid soln of preparation at 0.5h-2h, continue insulation reaction 3-4h, collect the white crystal of separating out, obtain Erlotinib hydrochloride crystal form A (formula I), with appropriate methyl tertiary butyl ether washing leaching cake, vacuum-drying 8-10h(30-40 DEG C, vacuum tightness is greater than 0.09Mpa), the Erlotinib hydrochloride crystal form A that must refine is about 5.52Kg, refining yield 93%, HPLC purity 99.8%.
Embodiment 5
By 2-amino-4,5-bis-(2-methoxy ethoxy) cyanophenyl (formula II compound, 1Kg, 3.76mol), toluene 5L, acetic acid 20mL and DMF-DMA(500g, 4.2mol) mix and blend, oil bath back flow reaction, be incubated 80-90 DEG C of backflow 3h, reaction terminates, and 60-65 DEG C of concentrating under reduced pressure, obtains intermediate Schiff's base oily matter and be about 1.2Kg.By oily matter isopropyl ether/tetrahydrofuran (THF) (20:1) (about 10.8L, 9 times of volumes of oily matter weight) dissolve clarification at 35-40 DEG C, slow cooling is to 10-15 DEG C, and crystallization obtains white solid 1.08Kg, Schiff's base yield 90%, HPLC purity 99.4%.
By formula III compound (1.08Kg, 3.36mol), 3-aminophenylacetylene (433g, 3.70mol), acetic acid 5L, mix and blend, starts heating, in controlling, temperature is at 95-100 DEG C, and reaction 2.5-3h, launches by chromatographic sheet (DCM:MeOH=15:1), react completely, slow cooling, to interior temperature 60 DEG C, adds water and tetrahydrofuran (THF) mixed solvent 6.5L(4:1, v/v), continue to be cooled to 20-25 DEG C, stirring and crystallizing 3h, obtain white solid 1.05Kg, HPLC purity 99.4%, free alkali yield 80%.
At 40-45 DEG C, erlotinib free base 1.05Kg is dissolved in the mixed solvent 7L of Virahol/acetone (1:5, v/v), filtered while hot, filtrate cooling down is to 15-20 DEG C; Be about 0.66L with above-mentioned mixed solvent and add in concentrated hydrochloric acid 0.33L the hydrochloric acid soln obtaining diluting, insulation 15-20 DEG C, drips off the hydrochloric acid soln of preparation at 0.5h-2h, continue insulation reaction 3-4h, collect the white crystal of separating out, obtain Erlotinib hydrochloride crystal form A (formula I), with appropriate methyl tertiary butyl ether washing leaching cake, vacuum-drying 8-10h(30-40 DEG C, vacuum tightness is greater than 0.09Mpa), the Erlotinib hydrochloride crystal form A that must refine is about 1.04Kg, refining yield 91%, HPLC purity 99.8%.
Embodiment 6
By 2-amino-4,5-bis-(2-methoxy ethoxy) cyanophenyl (formula II compound, 2Kg, 7.52mol), toluene 10L, acetic acid 40mL and DMF-DMA(1Kg, 8.4mol) mix and blend, oil bath back flow reaction, be incubated 80-90 DEG C of backflow 3h, reaction terminates, and 60-65 DEG C of concentrating under reduced pressure, obtains intermediate Schiff's base oily matter and be about 2.51Kg.By oily matter methyl tertiary butyl ether/ethyl acetate (25:1) (about 20L, 8 times of volumes of oily matter weight) dissolve clarification at 35-40 DEG C, slow cooling is to 10-15 DEG C, and crystallization obtains white solid 2.1Kg, Schiff's base yield 89%, HPLC purity 99.5%.
By formula III compound (2.1Kg, 6.54mol), 3-aminophenylacetylene (843g, 7.19mol), acetic acid 10.5L, mix and blend, starts heating, in controlling, temperature is at 95-100 DEG C, and reaction 2.5-3h, launches by chromatographic sheet (DCM:MeOH=15:1), react completely, slow cooling, to interior temperature 60 DEG C, adds water and tetrahydrofuran (THF) mixed solvent 14L(6:1, v/v), continue to be cooled to 20-25 DEG C, stirring and crystallizing 3h, obtain white solid 2.02Kg, HPLC purity 99.3%, free alkali yield 79%.
At 40-45 DEG C, erlotinib free base 2.02Kg is dissolved in the mixed solvent 13L of Virahol/acetone (1:5, v/v), filtered while hot, filtrate cooling down is to 15-20 DEG C; Be about 1.2L with above-mentioned mixed solvent and add in concentrated hydrochloric acid 0.6L the hydrochloric acid soln obtaining diluting, insulation 15-20 DEG C, drips off the hydrochloric acid soln of preparation at 0.5h-2h, continue insulation reaction 3-4h, collect the white crystal of separating out, obtain Erlotinib hydrochloride crystal form A (formula I), with appropriate methyl tertiary butyl ether washing leaching cake, vacuum-drying 8-10h(30-40 DEG C, vacuum tightness is greater than 0.09Mpa), the Erlotinib hydrochloride crystal form A that must refine is about 1.98Kg, refining yield 90%, HPLC purity 99.8%.
Embodiment 7
By 2-amino-4,5-bis-(2-methoxy ethoxy) cyanophenyl (formula II compound, 1Kg, 3.76mol), toluene 5L, acetic acid 20mL and DMF-DMA(0.5Kg, 4.2mol) mix and blend, oil bath back flow reaction, be incubated 80-90 DEG C of backflow 3h, reaction terminates, and 60-65 DEG C of concentrating under reduced pressure, obtains intermediate Schiff's base oily matter and be about 1.2Kg.By oily matter isopropyl ether/tetrahydrofuran (THF) (20:1) (about 9.6L, 8 times of volumes of oily matter weight) dissolve clarification at 35-40 DEG C, slow cooling is to 10-15 DEG C, and crystallization obtains white solid 1.09Kg, Schiff's base yield 91%, HPLC purity 99.5%.
By formula III compound 1.09Kg, 3-aminophenylacetylene 432g, acetic acid 5L, mix and blend, starts heating, and in controlling, temperature is at 95-100 DEG C, reaction 2.5-3h, launches by chromatographic sheet (DCM:MeOH=15:1), reacts completely, slow cooling, to interior temperature 60 DEG C, adds water and Isosorbide-5-Nitrae-dioxane mixed solvent 6L(6:1, v/v), continue to be cooled to 20-25 DEG C, stirring and crystallizing 3h, obtain white solid 1.08Kg, HPLC purity 99.2%, free alkali yield 82%.
At 40-45 DEG C, erlotinib free base 1.08Kg is dissolved in the mixed solvent 6.4L of Virahol/methyl ethyl ketone (1:4, v/v), filtered while hot, filtrate cooling down is to 15-20 DEG C; Be about 0.64L with above-mentioned mixed solvent and add in concentrated hydrochloric acid 0.32L the hydrochloric acid soln obtaining diluting, insulation 15-20 DEG C, drips off the hydrochloric acid soln of preparation at 0.5h-2h, continue insulation reaction 3-4h, collect the white crystal of separating out, obtain Erlotinib hydrochloride crystal form A (formula I), with appropriate methyl tertiary butyl ether washing leaching cake, vacuum-drying 8-10h(30-40 DEG C, vacuum tightness is greater than 0.09Mpa), the Erlotinib hydrochloride crystal form A that must refine is about 1.07Kg, refining yield 91%, HPLC purity 99.8%.
Embodiment 8 comparative example
According to foreign language literature OrganicProcessResearch & Development2007, the related experiment step of the 815-816 page of 11:813-816 carries out simultaneous test, and process is as follows:
2-amino-4, 5-bis-(2-methoxy ethoxy) cyanophenyl (358g, 1.34mol), toluene 3.5L, acetic acid 5ml and DMF-DMA(319g, 2.68mol, 2 times of molar weights of cyanophenyl compound) mix and blend, be warming up to 105 DEG C, backflow 3h, reaction terminates, decompression steams solvent, obtain oily matter liquid, by directly not purified for the oily matter liquid obtained, acetic acid 2.5ml is added in oily matter, 3-acetylenylaniline (141g, 1.21mol) stir, oil bath temperature 125-130 DEG C, reaction 3h, react complete, be down to 25 DEG C, reaction solution is poured in 5L frozen water, pH8-9 is regulated with dense propylhomoserin, ethyl acetate (0.5L*3) point three extractions, merge organic solvent, use water and saturated common salt water washing again, dry, steam solvent, the oily matter obtained uses 1L ethyl acetate and 0.5L recrystallizing methanol again, obtain 300g off-white color solid erlotinib free base, yield 57%, HPLC purity 99.0%.
The structural identification of embodiment 9 Erlotinib hydrochloride crystal form A
Ultimate analysis (ElementaVarioELIII type elemental analyser): theoretical value C61.46%, H5.63%, N9.77%; Measured value C61.41%, H5.80%, N9.76%.
Infrared spectra IR:3275.2,3057.5,3060.0,2898.7,2820.2,1632.7,1572.1,1517.3,1447.1,1237.1,1121.4.
Nucleus magnetic hydrogen spectrum
1h-NMR: δ ppm3.4709(s, 3H); 3.4539(s, 3H); 3.4923(s, 1H); 3.8129-3.8516(dt, 4H); 4.2449-4.3037(dt, 4H); 7.1027(s, 1H); 7.2313-7.2467(d, 1H); 7.3321-7.3637(t, 1H); 7.6643(s, 1H); 7.7517-7.7700(t, 1H); 7.9049(s, 1H); 8.3992(s, 1H).
Nuclear-magnetism carbon is composed
13c-NMR59.96,60.00,70.21,70.64,72.28,72.49,79.16,84.86,104.78,108.92,111.12,124.65,124.74,127.51,129.18,130.36,141.15,148.19,150.97,154.45,156.59,158.92.
Mass spectrum ESI-MSm/z=394.2 [M-HCl+H]
+; [416.2 M-HCl+Na]
+; [428.1 M-H]
-; [392.2 M-HCl-H]
-.
high resolution mass spectrum HRMS394.1781 [M-HCl+H]
+; [428.1381 M-H]
-.
DSC measurement result is as Fig. 3, TG measurement result Fig. 4.DSC, TG figure is presented at 211.0 DEG C, 227.5 DEG C have obvious two endotherm(ic)peaks, from the TG spectrogram of correspondence, a platform is shown as at about 211.0 DEG C, namely do not have mass attenuation, but start mass attenuation occurs at 220 DEG C later, interpret sample fusing point is 211.0 DEG C, become another crystal formation at about 220 DEG C, start to decompose simultaneously.This product can be found out not containing crystal water and other solvents from TG, DSC spectrogram.
As shown in Figure 5, use Cu-Ka radiation, (be 2 θ values outside bracket with 2 θ angles of correspondence and interplanar crystal spacing d value, being interplanar crystal spacing d value in bracket) the X-ray Powder Diffraction pattern that represents exists: 5.813(15.193), and 9.891(8.935), 11.476(7.705), 19.096(4.644), 22.911(3.897), 23.801(3.735), 29.452(3.030) there is characteristic peak.
Claims (4)
1. the preparation method of an Erlotinib hydrochloride crystal, wherein said crystal uses Cu-Ka radiation, exists: 5.813(15.193) with the X-ray Powder Diffraction pattern that 2 θ angles and the interplanar crystal spacing d value of correspondence represent, 9.891(8.935), 11.476(7.705), 19.096(4.644), 22.911(3.897), 23.801(3.735), 29.452(3.030) there is characteristic peak, be 2 θ values outside bracket, be interplanar crystal spacing d value in bracket, described preparation method comprises the steps:
(1) by 2-amino-4,5-bis-(2-methoxy ethoxy) cyanophenyl (formula II compound) and N, dinethylformamide dimethylacetal (DMF-DMA) reacts under the existence of toluene solvant and acetate catalyst, react complete, recycling design, residue oily matter is in the mixed solvent of methyl tertiary butyl ether and ethyl acetate, recrystallization purifying obtains Schiff's base (formula III compound) solid, wherein, in described mixed solvent, methyl tertiary butyl ether: the volume ratio of ethyl acetate is 25:1; The volume of this mixed solvent is 8 ~ 10 times amount of described residue oily matter weight, unit L/Kg; The mol ratio of formula II compound and DMF-DMA is 1:1.1;
(2) Schiff's base (formula III compound) of purifying and 3-aminophenylacetylene are reacted in acetate solvate, react complete, slow cooling, to interior temperature 60 DEG C, adds the mixed solvent that volume ratio is the water/Isosorbide-5-Nitrae-dioxane of 5:1 in reaction solution, continue to be cooled to 20 ~ 25 DEG C, stirring and crystallizing, obtains the white solid of erlotinib free base (formula IV compound), wherein, the volume of mixed solvent is 6 times amount of Schiff's base weight, unit L/Kg; The mol ratio of formula III compound and 3-aminophenylacetylene is 1:1.1;
(3) at 40 ~ 45 DEG C, erlotinib free base is dissolved in the mixed solvent of Virahol and acetone, or in the mixed solvent of Virahol and methyl ethyl ketone, filtered while hot, filtrate cooling down to 15 ~ 20 DEG C;
(4) with the mixed solvent dilution concentrated hydrochloric acid that step (3) is used, the hydrochloric acid soln obtained walks in filtrate on being added drop-wise within 0.5h ~ 2h, holding temperature is at 15 ~ 20 DEG C, drip off and continue insulation reaction 3 ~ 4h, collect the white crystal of separating out, obtain Erlotinib hydrochloride crystal (formula I).
2. preparation method according to claim 1, is characterized in that, in the mixed solvent described in step (3), and Virahol: the volume ratio of acetone is 1:5, Virahol: the volume ratio of methyl ethyl ketone is 1:4; The volume of described mixed solvent is 6 ~ 8 times amount of erlotinib free base weight, unit L/Kg.
3. preparation method according to claim 1, is characterized in that, in step (4), concentrated hydrochloric acid is selected from about 37% commercially available concentrated hydrochloric acid aqueous solution, and required concentrated hydrochloric acid volume is 0.3 times amount of erlotinib free base weight, unit L/kg; And the mixed solvent volume being used for diluting concentrated hydrochloric acid is 2 times amount of concentrated hydrochloric acid volume.
4. preparation method according to claim 1, is characterized in that, after obtaining Erlotinib hydrochloride crystal in step (4), with methyl tertiary butyl ether washing, drying temperature 30 ~ 40 DEG C, vacuum tightness is greater than 0.09Mpa, and time of drying is 8 ~ 10h.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007138612A2 (en) * | 2006-05-25 | 2007-12-06 | Vittal Mallya Scientific Research Foundation | A process for synthesis of [6,7-bis-(2-methoxyethoxy)-quinazolin-4- yl]-(3-ethynylphenyl)amine hydrochloride |
| WO2007138613A2 (en) * | 2006-05-25 | 2007-12-06 | Vittal Mallya Scientific Research Foundation | A process for synthesis of [6,7-bis-(2-methoxyethoxy)-quinazolin-4-yl]-(3-ethynylphenyl)amine hydrochloride |
| CN101484411A (en) * | 2006-06-27 | 2009-07-15 | 桑多斯股份公司 | New method for salt preparation |
| CN102382113A (en) * | 2006-10-27 | 2012-03-21 | 西格诺药品有限公司 | Solid forms comprising 4-[9-(tetrahydro-furan-3-yl)-8-(2,4,6-trifluoro-phenylamino)-9h-purin-2-ylamino]-cyclohexan-1-ol, compositions thereof, and uses therewith |
| CN102438995A (en) * | 2009-03-26 | 2012-05-02 | 兰贝克赛实验室有限公司 | Process for the preparation of erlotinib or its pharmaceutically acceptable salts thereof |
-
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- 2013-08-26 CN CN201310375398.2A patent/CN103396371B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007138612A2 (en) * | 2006-05-25 | 2007-12-06 | Vittal Mallya Scientific Research Foundation | A process for synthesis of [6,7-bis-(2-methoxyethoxy)-quinazolin-4- yl]-(3-ethynylphenyl)amine hydrochloride |
| WO2007138613A2 (en) * | 2006-05-25 | 2007-12-06 | Vittal Mallya Scientific Research Foundation | A process for synthesis of [6,7-bis-(2-methoxyethoxy)-quinazolin-4-yl]-(3-ethynylphenyl)amine hydrochloride |
| CN101484411A (en) * | 2006-06-27 | 2009-07-15 | 桑多斯股份公司 | New method for salt preparation |
| CN102382113A (en) * | 2006-10-27 | 2012-03-21 | 西格诺药品有限公司 | Solid forms comprising 4-[9-(tetrahydro-furan-3-yl)-8-(2,4,6-trifluoro-phenylamino)-9h-purin-2-ylamino]-cyclohexan-1-ol, compositions thereof, and uses therewith |
| CN102438995A (en) * | 2009-03-26 | 2012-05-02 | 兰贝克赛实验室有限公司 | Process for the preparation of erlotinib or its pharmaceutically acceptable salts thereof |
Non-Patent Citations (1)
| Title |
|---|
| Convergent Approach for Commercial Synthesis of Gefitinib and Erlotinib;Venkateshappa Chandregowda等;《Organic Process Research & Development》;20071231;第11卷;第814页第2段 * |
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