CN105250228A - Gefitinib tablet and preparation method of raw materials of gefitinib tablet - Google Patents
Gefitinib tablet and preparation method of raw materials of gefitinib tablet Download PDFInfo
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- CN105250228A CN105250228A CN201510654609.5A CN201510654609A CN105250228A CN 105250228 A CN105250228 A CN 105250228A CN 201510654609 A CN201510654609 A CN 201510654609A CN 105250228 A CN105250228 A CN 105250228A
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Abstract
The invention belongs to the field of medicine, and relates to a gefitinib tablet and a preparation method of raw materials gefitinib. The method mainly includes the steps of making 6-acetoxyl group-4-chlorine-7-methoxyquinazoline (6) serving as initial raw materials react with 3-chlorine-4-fluoroaniline (5) with isopropanol as solvent under the existence of CuI, ethanediol and K3PO4, regulating the pH to 1 to 2 through concentrated hydrochloric acid after the reaction is finished, conducting suction filtration to obtain 6-acetoxyl group-4-(3-chlorine-4-difluoroaniline)-7-methoxy quinazoline hydrochloride (4), hydrolyzing 6-acetoxyl group-4-(3-chlorine-4-difluoroaniline)-7-methoxy quinazoline hydrochloride (4) to obtain 4-(3-chlorine-4-difluoroaniline)-6-hydroxide radical-7-methoxy group-quinazoline (3), and making 4-(3-chlorine-4-difluoroaniline)-6-hydroxide radical-7-methoxy group-quinazoline (3) react with N-(3-mesyloxy propyl) morpholine (2) under the existence of k3PO4 and K2HPO4. The route is short in synthesis step, easy to operate, economical, environmentally friendly, high in total product yield, higher in product purity and suitable for industrialized large-scale production.
Description
Technical field
The invention belongs to field of medicaments, relate to a kind of tablet of gefitinib and the preparation method of raw material N-(the chloro-4-fluorophenyl of 3-)-7-methoxyl group-6-[3-(morpholine-4-base) propoxyl group]-quinazoline-4-amine (gefitinib) thereof particularly.
Background technology
Gefitinib (gefitinib, 1), chemistry N-(the chloro-4-fluorophenyl of 3-)-7-methoxyl group-6-[3-(morpholine-4-base) propoxyl group]-quinazoline-4-amine by name, be the micromolecular inhibitor of EGF-R ELISA (EGFR) tyrosine kinase of AstraZeneca company research and development, be clinically used for the treatment of nonsmall-cell lung cancer.Within 2002, first in Japan's listing, in May, 2003 is ratified by U.S. FDA, and on February 25th, 2005 is that China national food and medicine supervision and management general bureau (CFDA) approval is in Discussion on Chinese Listed.Specification dosage form is 250mg/ sheet, is used for the treatment of and receives chemotherapy invalid in the past or be not suitable for local or the Metastatic Nsclc of chemotherapy.Gefitinib (gefitinib, 1) structural formula is as follows:
The patent document relating to gefitinib preparation method has CN1182421, WO2004024703, WO2005023738, WO2005070909, CN102153518 etc., which discloses the multiple different method preparing gefitinib.
CN1182421 reports with 6; 7-dimethoxyquinazoline-4 (3H)-one is raw material; 6-hydroxyl-7-methoxyquinazoline hydrochloride-4 (3H)-one is obtained through selectivity demethoxylation; by hydroxyl chloro after acetic anhydride protection; again through the nucleophilic substitution of arylamine; deprotection and pendant alkoxylatedly obtain gefitinib, synthetic route is as follows:
Although this highway route design is reasonable, each step reaction mechanism is clear and definite, and raw material market is in liberal supply, still has problems in suitability for industrialized production.Such as: (1) with 6-acetoxyl group-4-chloro-7-methoxyquinazoline hydrochloride for initiation material and 3-chloro-4-fluoroaniline nucleophilic displacement of fluorine time, yield only has 56%, creates a large amount of impurity, is unfavorable for Atom economy, (2) not thorough with hydrolysis during strong aqua ammonia hydrolysis 6-acetoxyl group-4-(3-chloro-4-fluoroanilino)-7-methoxyquinazoline hydrochloride, (3) 4-(the chloro-4-fluoroanilino of 3-)-6-hydroxyl-7-methoxy-quinazoline and morpholinyl propyl chloride are obtained by reacting its yield of gefitinib only has 50%, and extend accordingly along with the response time, the amplification of reaction scale, the impurity that reaction generates constantly increases, especially 6-(3-morpholine propoxyl group)-N-(the chloro-4-fluorophenyl of 3-)-7-methoxyl group-N-(3-morpholine propyl group) quinazoline-4-amine (compd A), because compd A is similar to product property, refining removal difficulty is large, this obviously can increase production cost and may produce some other problem such as issues of purification etc., be unfavorable for suitability for industrialized production.
In view of this highway route design, to there is reaction scheme long, impurity many purification difficulty that the augmenting response time along with reaction scale that preparation method exists extends accordingly, produce is large, committed step reaction yield is low, Atom economy is poor, be not suitable for the defects such as suitability for industrialized production, need to find better synthetic method.
Summary of the invention
An object of the present invention is to provide a kind of tablet of stay-in-grade gefitinib, it is characterized in that being prepared from by following composition: gefitinib, starch, dextrin and magnesium stearate.This tablet quality is reliable and stable, and formula components is few, and preparation is simple.
Although the existing various reports preparing gefitinib, in right prior art, gefitinib preparation technology yield is low, and purity is not high.For preparing Tablets, for the deficiency that prior art described above exists, another object of the present invention is to provide the preparation method of a kind of high yield, high-purity gefitinib.High-purity gefitinib of the present invention refers to product purity more than 95%.
The technical solution used in the present invention is as follows:
A preparation method for gefitinib, is characterized in that comprising the following steps:
(a) with 6-acetoxyl group-4-chloro-7-methoxyquinazoline hydrochloride (6) for initiation material and the chloro-4-fluoroaniline (5) of 3-are at Catalysts Cu I, part ethylene glycol and K
3pO
4under existence, take isopropyl alcohol as solvent reaction;
B () after completion of the reaction, regulate reactant liquor to pH=1-2 with concentrated hydrochloric acid, sucking filtration obtains 6-acetoxyl group-4-(the chloro-4-fluoroanilino of 3-)-7-methoxyquinazoline hydrochloride hydrochlorate (4);
C () 6-acetoxyl group-4-(3-chloro-4-fluoroanilino)-7-methoxyquinazoline hydrochloride hydrochlorate (4) 4mol/L sodium hydroxide hydrolysis obtains 4-(the chloro-4-fluoroanilino of 3-)-6-hydroxyl-7-methoxy-quinazoline (3);
D () 4-(the chloro-4-fluoroanilino of 3-)-6-hydroxyl-7-methoxyquinazoline hydrochloride (3) and N-(3-methanesulfonyloxypropyl) morpholine (2) are at K
3pO
4and K
2hPO
4be obtained by reacting gefitinib (1) under existence, reaction scheme is as follows:
The reaction temperature of step (a) described above is 70-75 DEG C; Response time is 1-2 hour.
6-acetoxyl group-the 4-chloro-7-methoxyquinazoline hydrochloride (6) that step (a) described above is used and the chloro-4-fluoroaniline (5) of 3-and Catalysts Cu I, part ethylene glycol and K
3pO
4mol ratio be 1:1.0 ~ 1.3:0.1 ~ 0.2:1.5 ~ 2.5:1.5 ~ 2.5; Preferably, the 6-acetoxyl group-4-chloro-7-methoxyquinazoline hydrochloride (6) that step (a) described above is used and the chloro-4-fluoroaniline (5) of 3-and Catalysts Cu I, part ethylene glycol and K
3pO
4mol ratio be 1:1.2:0.15:2.0:2.0.
The reaction temperature of step (c) described above is 40-50 DEG C, and preferably, the reaction temperature of step (c) described above is 45 DEG C.
The reaction temperature of step (d) described above is 80-100 DEG C, and preferably, the reaction temperature of step (d) described above is 90 DEG C.
The N-(3-methanesulfonyloxypropyl) morpholine (2) that step (d) described above is used can be prepared with reference to EP2226323.
4-(the chloro-4-fluoroanilino of 3-)-6-hydroxyl-7-methoxyquinazoline hydrochloride (3), N-(3-methanesulfonyloxypropyl) morpholine (2) of step (d) described above, K
3pO4 and K
2hPO
4mol ratio be: 1:1.1 ~ 1.4:2.0 ~ 3.0:0.5 ~ 0.7; Preferably 4-(the chloro-4-fluoroanilino of 3-)-6-hydroxyl-7-methoxyquinazoline hydrochloride (3), N-(3-methanesulfonyloxypropyl) morpholine (2), the K of step (d) described above
3pO4 and K
2hPO
4mol ratio be 1:1.2:2.5:0.6.
The K that step (d) described above is used
3pO4 and K
2hPO
4be anhydrous K
3pO4 and K2HPO
4, wherein a part of K
3pO4 plays alkali, another part K
3pO4 and K
2hPO
4share the effect playing buffer agent.
Preferably, step (d) described above also adds 4A molecular sieve, described molecular sieve is through conventional activation processing, and the amount added is the 20-30% of 4-(the chloro-4-fluoroanilino of 3-)-6-hydroxyl-7-methoxyquinazoline hydrochloride (3) quality.
Preparation method of the present invention, compared with prior art, has following beneficial effect:
1, Catalysts Cu I and part ethylene glycol and K in the step (a)
3pO
4use, substantially increase the yield of reaction, use concentrated hydrochloric acid salify simultaneously, product can be made to separate out, the product of higher degree can be obtained by simple washing.
2, in step (d), use N-(3-methanesulfonyloxypropyl) morpholine at K
3pO
4and K
2hPO
4there is lower reaction, product yield is high, and impurity is few, especially after adding 4A molecular sieve, and the better quality of product.
3, shorter, simple to operate, the economic environmental protection of synthesis step, total recovery significantly improve, and are applicable to industrialized great production.
Detailed description of the invention
The detailed description of the invention of form by the following examples, is described in further detail foregoing of the present invention, but this should be interpreted as that the scope of the above-mentioned theme of the present invention is only limitted to following example.All technology realized based on foregoing of the present invention all belong to scope of the present invention.
Embodiment 1
The synthesis of 6-acetoxyl group-4-(the chloro-4-fluoroanilino of 3-)-7-methoxyquinazoline hydrochloride hydrochlorate (4)
25.3g (0.1mol is added in 1L reaction vessel, 1.0eq) the chloro-7-methoxyquinazoline hydrochloride of 6-acetoxyl group-4-, 17.5g (0.12mol, 1.2eq) the chloro-4-fluoroaniline of 3-, 2.86g (0.015mol, 0.15eq) CuI, 1.32g (0.2mol, 2.0eq) ethylene glycol and 42.5g (0.2mol, 2.0eq) K
3pO
4, add 100ml isopropyl alcohol, under stirring condition, be warming up to 75 DEG C, heat 1.5 hours, react complete, be cooled to room temperature, regulate reactant liquor pH=1.0 with concentrated hydrochloric acid, have a large amount of solid to separate out, rapid sucking filtration, filter cake uses isopropyl alcohol, ethanol rinse successively, compound 34.5g is obtained, yield 86.7%, purity 97.1% (HPLC after drying, normalization method), mp > 230 DEG C.
The synthesis of 4-(the chloro-4-fluoroanilino of 3-)-6-hydroxyl-7-methoxy-quinazoline (3)
Get 20g (0.05mol, 1.0eq) 6-acetoxyl group-4-(the chloro-4-fluoroanilino of 3-)-7-methoxyquinazoline hydrochloride hydrochlorate is placed in reaction vessel, add 100ml methanol, the sodium hydrate aqueous solution 45ml of 4mol/L is slowly dripped under stirring, 6h is reacted at 45 DEG C, be chilled to room temperature after completion of the reaction, pH=5.5 is adjusted with 1.0mol/L hydrochloric acid, a large amount of solid is had to separate out, sucking filtration, filter cake is with dry after methanol drip washing, obtain white flakes shape solid 15.2g, yield 95.2%, purity 97.3% (HPLC, normalization method), mp > 240 DEG C.
The preparation of N-(the chloro-4-fluorophenyl of 3-)-7-methoxyl group-6-[3-(morpholine-4-base) propoxyl group]-quinazoline-4-amine (1)
By 4-(the chloro-4-fluoroanilino of 3-)-6-hydroxyl-7-methoxyquinazoline hydrochloride 9.6g (0.03mol, 1.0eq) be placed in reaction vessel, add the DMF of 100ml, 15.9g (0.075mol, 2.5eq) anhydrous K is added successively under stirring
3pO
4, 3.14g (0.018mol, 0.6eq) anhydrous K
2hPO
4, the 4A molecular sieve of the activated mistake of 2g, drip 8.04g (0.036mol, 1.2eq) the N of N-(3-methanesulfonyloxypropyl) morpholine, dinethylformamide solution, in 90 DEG C of reaction 4h, TLC detection reaction is complete, decompression steams solvent, residue adds 100ml water and 300ml toluene, heating makes residue dissolve, after cooling, separatory collects toluene layer, water layer methylbenzene extraction twice, each 100ml, combining methylbenzene layer, saturated common salt water washing 1 time, anhydrous sodium sulfate drying, filter, filtrate adds active carbon in 70-80 DEG C of decolouring 30min, filtered while hot, Slow cooling, obtain light yellow solid 11.4g, yield 84.6%, purity 99.02% (HPLC normalization method, the content 0.2% of impurity A, major impurity summation 0.7%), mp190.5-191.3,
1h-NMR (DMSO): 1.93-1.99 (m, 2H), 2.34-2.54 (m, 6H), 3.54-3.61 (m, 4H), 3.92 (s, 3H), 4.14-4.21 (m, 2H), 7.18 (s, 1H), 7.37-7.45 (m, 1H), 7.45-7.82 (m, 2H), (8.08-8.13 m, 1H), 8.48 (s, 1H), 9.51 (s, 1H), MS-ESI (m/z): 448.1.
Embodiment 2
The synthesis of 6-acetoxyl group-4-(the chloro-4-fluoroanilino of 3-)-7-methoxyquinazoline hydrochloride hydrochlorate (4)
25.3g (0.1mol is added in 1L reaction vessel, 1.0eq) the chloro-7-methoxyquinazoline hydrochloride of 6-acetoxyl group-4-, 16.0g (0.11mol, 1.1eq) the chloro-4-fluoroaniline of 3-, 3.81g (0.020mol, 0.20eq) CuI, 1.55g (0.25mol, 2.5eq) ethylene glycol and 42.5g (0.2mol, 2.0eq) K
3pO
4, add 100ml isopropyl alcohol, under stirring condition, be warming up to 74 DEG C, heat 1.5 hours, react complete, be cooled to room temperature, reactant liquor pH=1.2 is regulated with concentrated hydrochloric acid, have a large amount of solid to separate out, rapid sucking filtration, filter cake uses isopropyl alcohol, ethanol rinse successively, compound 34.7g is obtained after drying, yield 87.1%, purity 96.4% (HPLC, normalization method).
The synthesis of 4-(the chloro-4-fluoroanilino of 3-)-6-hydroxyl-7-methoxy-quinazoline (3)
Get 20g (0.05mol, 1.0eq) 6-acetoxyl group-4-(the chloro-4-fluoroanilino of 3-)-7-methoxyquinazoline hydrochloride hydrochlorate is placed in reaction vessel, add 100ml methanol, the sodium hydrate aqueous solution 40ml of 4mol/L is slowly dripped under stirring, 8h is reacted at 40 DEG C, be chilled to room temperature after completion of the reaction, pH=5-6 is adjusted with 2.0mol/L hydrochloric acid, have a large amount of solid to separate out, sucking filtration, filter cake is with dry after methanol drip washing, obtain white flakes shape solid 15.4g, yield 96.3%, purity 96.8% (HPLC, normalization method).
The preparation of N-(the chloro-4-fluorophenyl of 3-)-7-methoxyl group-6-[3-(morpholine-4-base) propoxyl group]-quinazoline-4-amine (1)
By 4-(the chloro-4-fluoroanilino of 3-)-6-hydroxyl-7-methoxyquinazoline hydrochloride 9.6g (0.03mol, 1.0eq) be placed in reaction vessel, add the DMF of 100ml, 19.1g (0.09mol, 3.0eq) anhydrous K is added successively under stirring
3pO
4, 3.68g (0.21mol, 0.7eq) anhydrous K
2hPO
4, the 4A molecular sieve of the activated mistake of 2.5g, drip 8.71g (0.039mol, 1.3eq) the N of N-(3-methanesulfonyloxypropyl) morpholine, dinethylformamide solution, in 95 DEG C of reaction 4h, TLC detection reaction is complete, decompression steams solvent, residue adds 100ml water and 300ml toluene, heating makes residue dissolve, after cooling, separatory collects toluene layer, water layer methylbenzene extraction twice, each 100ml, combining methylbenzene layer, saturated common salt water washing 1 time, anhydrous sodium sulfate drying, filter, filtrate adds active carbon in 70-80 DEG C of decolouring 30min, filtered while hot, Slow cooling, obtain light yellow solid 11.7g, yield 87.3%, purity 98.89% (HPLC normalization method, the content 0.18% of impurity A, major impurity summation 0.74%).
Embodiment 3
Synthesis 1:1.0 ~ 1.3:0.1 ~ 0.2:1.5 ~ 2.5:1.5 ~ 2.5 of 6-acetoxyl group-4-(the chloro-4-fluoroanilino of 3-)-7-methoxyquinazoline hydrochloride hydrochlorate (4)
25.3g (0.1mol is added in 1L reaction vessel, 1.0eq) the chloro-7-methoxyquinazoline hydrochloride of 6-acetoxyl group-4-, 16.0g (0.11mol, 1.1eq) the chloro-4-fluoroaniline of 3-, 3.05g (0.016mol, 0.16eq) CuI, 1.36g (0.22mol, 2.2eq) ethylene glycol and 46.7g (0.22mol, 2.2eq) K
3pO
4, add 100ml isopropyl alcohol, under stirring condition, be warming up to 70 DEG C, heat 2.0 hours, react complete, be cooled to room temperature, reactant liquor pH=1.5 is regulated with concentrated hydrochloric acid, have a large amount of solid to separate out, rapid sucking filtration, filter cake uses isopropyl alcohol, ethanol rinse successively, compound 34.8g is obtained after drying, yield 87.4%, purity 96.3% (HPLC, normalization method).
The synthesis of 4-(the chloro-4-fluoroanilino of 3-)-6-hydroxyl-7-methoxy-quinazoline (3)
Get 20g (0.05mol, 1.0eq) 6-acetoxyl group-4-(the chloro-4-fluoroanilino of 3-)-7-methoxyquinazoline hydrochloride hydrochlorate is placed in reaction vessel, add 100ml methanol, the sodium hydrate aqueous solution 40ml of 4mol/L is slowly dripped under stirring, 8h is reacted at 45 DEG C, be chilled to room temperature after completion of the reaction, pH=5-6 is adjusted with 2.0mol/L hydrochloric acid, have a large amount of solid to separate out, sucking filtration, filter cake is with dry after methanol drip washing, obtain white flakes shape solid 15.2g, yield 95.1%, purity 97.1% (HPLC, normalization method).
The preparation of N-(the chloro-4-fluorophenyl of 3-)-7-methoxyl group-6-[3-(morpholine-4-base) propoxyl group]-quinazoline-4-amine (1)
By 4-(the chloro-4-fluoroanilino of 3-)-6-hydroxyl-7-methoxyquinazoline hydrochloride 9.6g (0.03mol, 1.0eq) be placed in reaction vessel, add the DMF of 100ml, 17.2g (0.081mol, 2.7eq) anhydrous K is added successively under stirring
3pO
4, 3.40g (0.0195mol, 0.65eq) anhydrous K
2hPO
4, the 4A molecular sieve of the activated mistake of 2.4g, drip 8.71g (0.039mol, 1.3eq) the N of N-(3-methanesulfonyloxypropyl) morpholine, dinethylformamide solution, in 90 DEG C of reaction 4h, TLC detection reaction is complete, decompression steams solvent, residue adds 100ml water and 300ml toluene, heating makes residue dissolve, after cooling, separatory collects toluene layer, water layer methylbenzene extraction twice, each 100ml, combining methylbenzene layer, saturated common salt water washing 1 time, anhydrous sodium sulfate drying, filter, filtrate adds active carbon in 70-80 DEG C of decolouring 30min, filtered while hot, Slow cooling, obtain light yellow solid 11.5g, yield 85.8%, purity 99.12% (HPLC normalization method, the content 0.19% of impurity A, major impurity summation 0.75%).
Comparative example 1
The synthesis of 6-acetoxyl group-4-(the chloro-4-fluoroanilino of 3-)-7-methoxyquinazoline hydrochloride hydrochlorate (4) is carried out with reference to embodiment 1;
The preparation of the synthesis of 4-(the chloro-4-fluoroanilino of 3-)-6-hydroxyl-7-methoxy-quinazoline (3) is carried out with reference to embodiment 1;
The preparation of N-(the chloro-4-fluorophenyl of 3-)-7-methoxyl group-6-[3-(morpholine-4-base) propoxyl group]-quinazoline-4-amine (1) is carried out with reference to embodiment 1, difference does not add activated 4A molecular sieve when being to feed intake, result obtains light yellow solid 10.5g, yield 78.3%, purity 85.7% (HPLC normalization method, the content 0.56% of impurity A, major impurity summation 3.17%).
Comparative example 2
The synthesis of 6-acetoxyl group-4-(the chloro-4-fluoroanilino of 3-)-7-methoxyquinazoline hydrochloride hydrochlorate (4) is carried out with reference to embodiment 1;
The preparation of the synthesis of 4-(the chloro-4-fluoroanilino of 3-)-6-hydroxyl-7-methoxy-quinazoline (3) is carried out with reference to embodiment 1;
The preparation of N-(the chloro-4-fluorophenyl of 3-)-7-methoxyl group-6-[3-(morpholine-4-base) propoxyl group]-quinazoline-4-amine (1) is carried out with reference to embodiment 1, difference is that replacing N-(3-methanesulfonyloxypropyl) morpholine with the thing N-that feeds intake (3-chloropropyl) morpholine participates in reaction, result obtains light yellow solid 8.25g, yield 61.5%, purity 81.5% (HPLC normalization method, the content 1.14% of impurity A, major impurity summation 11.25%).
Comparative example 3
With reference to method described in CN1182421A, ingredient proportion reference example converts, and result obtains light green sticky solid 6.02g, yield 44.9%, purity 78.7% (HPLC normalization method, the content 1.43% of impurity A, major impurity summation 13.89%).
Claims (10)
1. a tablet for gefitinib, is characterized in that, is prepared from by following composition: gefitinib, starch, dextrin and magnesium stearate.
2. the preparation method of gefitinib as claimed in claim 1, it is characterized in that, it comprises the following steps:
(a) with 6-acetoxyl group-4-chloro-7-methoxyquinazoline hydrochloride (6) for initiation material and the chloro-4-fluoroaniline (5) of 3-are at Catalysts Cu I, part ethylene glycol and K
3pO
4under existence, take isopropyl alcohol as solvent reaction;
B () after completion of the reaction, regulate reactant liquor to pH=1-2 with concentrated hydrochloric acid, sucking filtration obtains 6-acetoxyl group-4-(the chloro-4-fluoroanilino of 3-)-7-methoxyquinazoline hydrochloride hydrochlorate (4);
C () 6-acetoxyl group-4-(3-chloro-4-fluoroanilino)-7-methoxyquinazoline hydrochloride hydrochlorate (4) 4mol/L sodium hydroxide hydrolysis obtains 4-(the chloro-4-fluoroanilino of 3-)-6-hydroxyl-7-methoxy-quinazoline (3);
D () 4-(the chloro-4-fluoroanilino of 3-)-6-hydroxyl-7-methoxyquinazoline hydrochloride (3) and N-(3-methanesulfonyloxypropyl) morpholine (2) are at K
3pO
4and K
2hPO
4be obtained by reacting gefitinib (1) under existence, reaction scheme is as follows:
3. the preparation method of gefitinib as claimed in claim 2, is characterized in that the reaction temperature of step (a) is 70-75 DEG C; Response time is 1-2 hour.
4. the preparation method of gefitinib as claimed in claim 2, is characterized in that the 6-acetoxyl group-4-chloro-7-methoxyquinazoline hydrochloride (6) that step (a) is used and the chloro-4-fluoroaniline (5) of 3-and Catalysts Cu I, part ethylene glycol and K
3pO
4mol ratio be 1:1.0 ~ 1.3:0.1 ~ 0.2:1.5 ~ 2.5:1.5 ~ 2.5.
5. the preparation method of gefitinib as claimed in claim 4, is characterized in that the 6-acetoxyl group-4-chloro-7-methoxyquinazoline hydrochloride (6) that step (a) is used and the chloro-4-fluoroaniline (5) of 3-and Catalysts Cu I, part ethylene glycol and K
3pO
4mol ratio be preferably 1:1.2:0.15:2.0:2.0.
6. the preparation method of gefitinib as claimed in claim 2, is characterized in that the reaction temperature of step (c) is 40-50 DEG C.
7. the preparation method of gefitinib as claimed in claim 2, is characterized in that the reaction temperature of step (d) is 80-100 DEG C, is preferably 90 DEG C.
8. the preparation method of gefitinib as claimed in claim 2, is characterized in that 4-(the chloro-4-fluoroanilino of 3-)-6-hydroxyl-7-methoxyquinazoline hydrochloride (3), N-(3-methanesulfonyloxypropyl) morpholine (2), the K of step (d)
3pO
4and K
2hPO
4mol ratio be 1:1.1 ~ 1.4:2.0 ~ 3.0:0.5 ~ 0.7.
9. the preparation method of gefitinib as claimed in claim 8, is characterized in that 4-(the chloro-4-fluoroanilino of 3-)-6-hydroxyl-7-methoxyquinazoline hydrochloride (3), N-(3-methanesulfonyloxypropyl) morpholine (2), the K of step (d)
3pO
4and K
2hPO
4mol ratio be preferably 1:1.2:2.5:0.6.
10. the preparation method of gefitinib as claimed in claim 2, it is characterized in that step (d) also adds 4A molecular sieve, the amount added is the 20-30% of 4-(the chloro-4-fluoroanilino of 3-)-6-hydroxyl-7-methoxyquinazoline hydrochloride (3) quality.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1182421A (en) * | 1995-04-27 | 1998-05-20 | 曾尼卡有限公司 | Quinazoline derivatives |
| US20090185999A1 (en) * | 2008-01-22 | 2009-07-23 | Concert Pharmaceuticals Inc. | Derivatives of gefitinib |
| CN104352464A (en) * | 2014-11-17 | 2015-02-18 | 成都新恒创药业有限公司 | Gefitinib pharmaceutical composition free from surface active agent and preparation method thereof |
-
2015
- 2015-10-12 CN CN201510654609.5A patent/CN105250228B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1182421A (en) * | 1995-04-27 | 1998-05-20 | 曾尼卡有限公司 | Quinazoline derivatives |
| US20090185999A1 (en) * | 2008-01-22 | 2009-07-23 | Concert Pharmaceuticals Inc. | Derivatives of gefitinib |
| CN104352464A (en) * | 2014-11-17 | 2015-02-18 | 成都新恒创药业有限公司 | Gefitinib pharmaceutical composition free from surface active agent and preparation method thereof |
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