CN105250228B - A kind of tablet of Gefitinib and its preparation method of raw material - Google Patents
A kind of tablet of Gefitinib and its preparation method of raw material Download PDFInfo
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Abstract
The invention belongs to drug field, it is related to the preparation method of a kind of Gefitinib tablet and raw material Gefitinib.It is initiation material and the fluoroaniline of 3 chlorine 4 (5) in CuI, ethylene glycol and K that this method, which is mainly included with the methoxyquinazoline hydrochloride (6) of 6 acetoxyl group, 4 chlorine 7,3PO4In the presence of, using isopropanol as solvent reaction, after completion of the reaction, reaction solution is adjusted to pH=1 2 with concentrated hydrochloric acid, suction filtration obtains the methoxyquinazoline hydrochloride hydrochloride (4) of 6 acetoxyl group 4 (fluoroanilino of 3 chlorine 4) 7；(4) hydrolysis obtains the methoxyquinazoline hydrochloride (3) of 4 (fluoroanilino of 3 chlorine 4) 6 hydroxyl 7；(3) with N (3 methanesulfonyloxypropyl) morpholines (2) in K3PO4And K2HPO4In the presence of react and obtain.The routine synthetic steps are shorter, simple to operate, economic and environment-friendly, total yield of products is high, and product purity more preferably, is adapted to industrialized production.
Description
Technical field
The invention belongs to field of medicaments, tablet and its raw material N- (the chloro- 4- fluorobenzene of 3- more particularly to a kind of Gefitinib
Base) -7- methoxyl groups -6- [3- (morpholine -4- bases) propoxyl group]-quinazoline -4- amine (Gefitinib) preparation method.
Background technology
Gefitinib (gefitinib, 1), chemical entitled N- (the chloro- 4- fluorophenyls of 3-) -7- methoxyl groups -6- [3- (morpholine -
4- yls) propoxyl group]-quinazoline -4- amine is EGF-R ELISA (EGFR) tyrosine of AstraZeneca companies research and development
The micromolecular inhibitor of kinases, is clinically used for treating non-small cell lung cancer.2002 first Japan listing, in May, 2003 quilt
U.S. FDA is ratified, and is within 2 25th, 2005 that China national food and medicine supervision and management general bureau (CFDA) ratifies in Discussion on Chinese Listed.
Specification formulation is 250mg/ pieces, and the part or metastatic for receiving chemotherapy invalid or unsuitable chemotherapy in the past for treating are non-small thin
Born of the same parents' lung cancer.Gefitinib (gefitinib, 1) structural formula is as follows：
Be related to the patent document of Gefitinib preparation method have CN1182421, WO2004024703, WO2005023738,
WO2005070909, CN102153518 etc., they disclose a variety of different methods for preparing Gefitinib.
CN1182421 is reported with 6,7- dimethoxyquinazolines -4 (3H) -one as raw material, and chosen property demethoxylation is obtained
To (3H) -one of 6- hydroxyl -7- methoxyquinazoline hydrochlorides -4, chloro after hydroxyl is protected with acetic anhydride, then the nucleophilic displacement of fluorine through arylamine
Reaction, deprotection and it is pendant alkoxylated obtain Gefitinib, synthetic route is as follows：
Although the highway route design is rationally, clearly, raw material market is in liberal supply, in industrialized production for each step reaction mechanism
In still have problem.For example：(1) by initiation material of the chloro- 7- methoxyquinazoline hydrochlorides of 6- acetoxyl groups -4- with the chloro- 4- fluorine of 3-
During aniline nucleophilic displacement of fluorine, yield only has 56%, generates substantial amounts of impurity, is unfavorable for Atom economy；(2) hydrolyzed with concentrated ammonia liquor
Hydrolysis is not thorough during 6- acetoxyl groups -4- (the chloro- 4- fluoroanilinos of 3-) -7- methoxyquinazoline hydrochlorides；(3) 4- (the chloro- 4- fluoroanilines of 3-
Base) reaction of -6- hydroxyl -7- methoxy-quinazolines and morpholinyl propyl chloride obtains Gefitinib its yield and only has 50%, and with
The reaction time extends accordingly, the amplification of reaction scale, and the impurity of reaction generation is continuously increased, especially 6- (3- morpholines third
Epoxide)-N- (the chloro- 4- fluorophenyls of 3-) -7- methoxyl groups-N- (3- morpholines propyl group) quinazoline -4- amine (compound A), due to chemical combination
Thing A is similar to product property, refines and removes difficulty greatly, and this obviously can increase production cost and there may be some other problem example
Such as issues of purification, is unfavorable for industrialized production.
In view of the highway route design is present, reaction scheme is long, preparation method exist with the increase reaction time of reaction scale
Purifying difficulty more than corresponding extension, the impurity produced is big, committed step reaction yield is low, and Atom economy is poor, is not suitable for industrial
The defects such as metaplasia production are, it is necessary to find more preferable synthetic method.
The content of the invention
An object of the present invention is to provide a kind of tablet of the Gefitinib of steady quality, it is characterised in that by below into
Divide and be prepared from：Gefitinib, starch, dextrin and magnesium stearate.The tablet quality is reliable and stable, and formula components are few, prepares work
Skill is simple and easy to apply.
Although having prepared the various reports of Gefitinib, so Gefitinib preparation technology yield is low in the prior art,
Purity is not high.To prepare Tablets, the deficiency existed for prior art described above, it is another object of the present invention to carry
For it is a kind of in high yield, the preparation method of high-purity gefitinib.High-purity gefitinib of the present invention refers to reaction product
Purity more than 95%.
The technical solution adopted by the present invention is as follows：
A kind of preparation method of Gefitinib, it is characterised in that comprise the following steps：
(a) it is that initiation material exists with the chloro- 4- fluoroanilines (5) of 3- with the chloro- 7- methoxyquinazoline hydrochlorides (6) of 6- acetoxyl groups -4-
Catalyst CuI, part ethylene glycol and K3PO4In the presence of, using isopropanol as solvent reaction；
(b) after completion of the reaction, reaction solution is adjusted to pH=1-2 with concentrated hydrochloric acid, suction filtration obtains 6- acetoxyl groups -4-, and (3- is chloro-
4- fluoroanilinos) -7- methoxyquinazoline hydrochlorides hydrochloride (4)；
(c) 6- acetoxyl groups -4- (the chloro- 4- fluoroanilinos of 3-) -7- methoxyquinazoline hydrochlorides hydrochloride (4) uses 4mol/L hydrogen-oxygens
Change sodium hydrolysis and obtain 4- (the chloro- 4- fluoroanilinos of 3-) -6- hydroxyl -7- methoxy-quinazolines (3)；
(d) 4- (the chloro- 4- fluoroanilinos of 3-) -6- hydroxyl -7- methoxyquinazoline hydrochlorides (3) and N- (3- methanesulfonyloxypropyls)
Morpholine (2) is in K3PO4And K2HPO4In the presence of reaction obtain Gefitinib (1), reaction scheme is as follows：
The reaction temperature of step (a) described above is 70-75 DEG C；Reaction time is 1-2 hours.
The chloro- 7- methoxyquinazoline hydrochlorides (6) of 6- acetoxyl groups -4- and the chloro- 4- fluoroanilines of 3- used in step (a) described above
And catalyst CuI, part ethylene glycol and K (5)3PO4Mol ratio be 1：1.0~1.3：0.1~0.2：1.5~2.5：1.5~
2.5；Preferably, the chloro- 7- methoxyquinazoline hydrochlorides (6) of 6- acetoxyl groups -4- and the chloro- 4- fluorine of 3- used in step (a) described above
Aniline (5) and catalyst CuI, part ethylene glycol and K3PO4Mol ratio be 1：1.2：0.15：2.0：2.0.
The reaction temperature of step (c) described above is 40-50 DEG C, it is preferable that the reaction temperature of step (c) described above is
45℃。
The reaction temperature of step (d) described above is 80-100 DEG C, it is preferable that the reaction temperature of step (d) described above
For 90 DEG C.
N- (3- methanesulfonyloxypropyls) morpholines (2) used in step (d) described above are referred to EP 2226323 and made
It is standby.
4- (the chloro- 4- fluoroanilinos of 3-) -6- hydroxyl -7- methoxyquinazoline hydrochlorides (3), the N- (3- of step (d) described above
Methanesulfonyloxypropyl) morpholine (2), K3PO4 and K2HPO4Mol ratio be：1：1.1~1.4：2.0~3.0：0.5~0.7；It is excellent
4- (the chloro- 4- fluoroanilinos of 3-) -6- hydroxyl -7- methoxyquinazoline hydrochlorides (3), N- (the 3- first sulphurs of selection of land step (d) described above
Acryloxypropylethoxysilane) morpholine (2), K3PO4 and K2HPO4Mol ratio be 1：1.2：2.5：0.6.
K used in step (d) described above3PO4 and K2HPO4It is anhydrous K3PO4 and K2HPO4, a portion K3PO4
Play alkali, another part K3PO4 and K2HPO4Share and play a part of buffer.
Preferably, step (d) described above is also added into 4A molecular sieves, described molecular sieve through conventional activation process, plus
The amount entered is the 20-30% of 4- (the chloro- 4- fluoroanilinos of 3-) -6- hydroxyl -7- methoxyquinazoline hydrochlorides (3) quality.
The preparation method of the present invention, compared with prior art, with following beneficial effect：
1st, catalyst CuI and part ethylene glycol and K in step (a)3PO4Use, substantially increase the yield of reaction,
Product can be separated out into salt with concentrated hydrochloric acid simultaneously, the product of higher degree can be obtained by simply washing.
2nd, N- (3- methanesulfonyloxypropyls) morpholine is used in step (d) in K3PO4And K2HPO4In the presence of react, production
Product high income, impurity is few, especially after 4A molecular sieves are added, the better quality of product.
3rd, synthesis step is shorter, simple to operate, economic and environment-friendly, total recovery is significantly improved, and is adapted to industrialized production.
Embodiment
The embodiment of form, does further specifically to the above of the invention by the following examples
It is bright, but this should not be interpreted as to the scope of above-mentioned theme of the invention be only limitted to following example.It is all to be based on the above of the present invention
The technology realized belongs to the scope of the present invention.
Embodiment 1
The synthesis of 6- acetoxyl groups -4- (the chloro- 4- fluoroanilinos of 3-) -7- methoxyquinazoline hydrochlorides hydrochloride (4)
The chloro- 7- methoxyquinazoline hydrochlorides of 25.3g (0.1mol, 1.0eq) 6- acetoxyl groups -4- are added into 1L reaction vessels,
The chloro- 4- fluoroanilines of 17.5g (0.12mol, 1.2eq) 3-, 2.86g (0.015mol, 0.15eq) CuI, 1.32g (0.2mol,
2.0eq) ethylene glycol and 42.5g (0.2mol, 2.0eq) K3PO4, add under 100ml isopropanols, stirring condition and be warming up to 75 DEG C,
Heating 1.5 hours, reaction is finished, and is cooled to room temperature, and reaction solution pH=1.0 is adjusted with concentrated hydrochloric acid, has a large amount of solids to separate out, rapidly
Suction filtration, filter cake uses isopropanol, ethanol rinse successively, and compound 34.5g, yield 86.7%, purity 97.1% are obtained after drying
(HPLC, normalization method), 230 DEG C of mp ＞.
The synthesis of 4- (the chloro- 4- fluoroanilinos of 3-) -6- hydroxyl -7- methoxy-quinazolines (3)
Take 20g (0.05mol, 1.0eq) 6- acetoxyl groups -4- (the chloro- 4- fluoroanilinos of 3-) -7- methoxyquinazoline hydrochloride hydrochloric acid
Salt is placed in reaction vessel, is added 100ml methanol, 4mol/L sodium hydrate aqueous solution 45ml is slowly added dropwise under stirring, in 45
6h is reacted at DEG C, room temperature is cooled to after completion of the reaction, pH=5.5 is adjusted with 1.0mol/L hydrochloric acid, there are a large amount of solids to separate out, suction filtration, filter
Cake is dried after being eluted with methanol, obtains white flakes shape solid 15.2g, yield 95.2%, purity 97.3% (HPLC, normalizing
Method), 240 DEG C of mp ＞.
The system of N- (the chloro- 4- fluorophenyls of 3-) -7- methoxyl groups -6- [3- (morpholine -4- bases) propoxyl group]-quinazoline -4- amine (1)
It is standby
4- (the chloro- 4- fluoroanilinos of 3-) -6- hydroxyl -7- methoxyquinazoline hydrochlorides 9.6g (0.03mol, 1.0eq) are placed in instead
Answer in container, add 100ml DMF, 15.9g (0.075mol, 2.5eq) is sequentially added under stirring anhydrous
K3PO4, 3.14g (0.018mol, 0.6eq) anhydrous K2HPO4, the 4A molecular sieves of the activated mistakes of 2g, dropwise addition 8.04g (0.036mol,
1.2eq) the DMF solution of N- (3- methanesulfonyloxypropyls) morpholine, 4h, TLC detection reactions are reacted in 90 DEG C
Completely, decompression steams solvent, and residue adds 100ml water and 300ml toluene, and heating dissolves residue, and point liquid is received after cooling
Collect toluene layer, water layer is extracted twice with toluene, each 100ml, combining methylbenzene layer, saturated common salt water washing 1 time, anhydrous sodium sulfate
Dry, filtering, filtrate adds activated carbon in 70-80 DEG C of decolouring 30min, filters while hot, Slow cooling obtains light yellow solid
11.4g, yield 84.6%, purity 99.02% (HPLC normalization methods, 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 groups -4- (the chloro- 4- fluoroanilinos of 3-) -7- methoxyquinazoline hydrochlorides hydrochloride (4)
The chloro- 7- methoxyquinazoline hydrochlorides of 25.3g (0.1mol, 1.0eq) 6- acetoxyl groups -4- are added into 1L reaction vessels,
The chloro- 4- fluoroanilines of 16.0g (0.11mol, 1.1eq) 3-, 3.81g (0.020mol, 0.20eq) CuI, 1.55g (0.25mol,
2.5eq) ethylene glycol and 42.5g (0.2mol, 2.0eq) K3PO4, add under 100ml isopropanols, stirring condition and be warming up to 74 DEG C,
Heating 1.5 hours, reaction is finished, and is cooled to room temperature, and reaction solution pH=1.2 is adjusted with concentrated hydrochloric acid, has a large amount of solids to separate out, rapidly
Suction filtration, filter cake uses isopropanol, ethanol rinse successively, and compound 34.7g, yield 87.1%, purity 96.4% are obtained after drying
(HPLC, normalization method).
The synthesis of 4- (the chloro- 4- fluoroanilinos of 3-) -6- hydroxyl -7- methoxy-quinazolines (3)
Take 20g (0.05mol, 1.0eq) 6- acetoxyl groups -4- (the chloro- 4- fluoroanilinos of 3-) -7- methoxyquinazoline hydrochloride hydrochloric acid
Salt is placed in reaction vessel, is added 100ml methanol, 4mol/L sodium hydrate aqueous solution 40ml is slowly added dropwise under stirring, in 40
8h is reacted at DEG C, room temperature is cooled to after completion of the reaction, pH=5-6 is adjusted with 2.0mol/L hydrochloric acid, there are a large amount of solids to separate out, suction filtration, filter
Cake is dried after being eluted with methanol, obtains white flakes shape solid 15.4g, yield 96.3%, purity 96.8% (HPLC, normalizing
Method).
The system of N- (the chloro- 4- fluorophenyls of 3-) -7- methoxyl groups -6- [3- (morpholine -4- bases) propoxyl group]-quinazoline -4- amine (1)
It is standby
4- (the chloro- 4- fluoroanilinos of 3-) -6- hydroxyl -7- methoxyquinazoline hydrochlorides 9.6g (0.03mol, 1.0eq) are placed in instead
Answer in container, add 100ml DMF, 19.1g (0.09mol, 3.0eq) is sequentially added under stirring anhydrous
K3PO4, 3.68g (0.21mol, 0.7eq) anhydrous K2HPO4, the 4A molecular sieves of the activated mistakes of 2.5g, dropwise addition 8.71g
The DMF solution of (0.039mol, 1.3eq) N- (3- methanesulfonyloxypropyls) morpholine, 4h is reacted in 95 DEG C,
TLC detection reactions are complete, and decompression steams solvent, and residue adds 100ml water and 300ml toluene, and heating dissolves residue, cold
But liquid is divided to collect toluene layer afterwards, water layer is extracted twice with toluene, each 100ml, combining methylbenzene layer, saturated common salt water washing 1 time,
Anhydrous sodium sulfate drying, filtering, filtrate adds activated carbon in 70-80 DEG C of decolouring 30min, filters while hot, Slow cooling, obtains shallow
Yellow solid 11.7g, yield 87.3%, (major impurity is total for HPLC normalization methods, the content 0.18% of impurity A for purity 98.89%
With 0.74%).
Embodiment 3
The synthesis 1 of 6- acetoxyl groups -4- (the chloro- 4- fluoroanilinos of 3-) -7- methoxyquinazoline hydrochlorides hydrochloride (4)：1.0~
1.3：0.1~0.2：1.5~2.5：1.5~2.5
The chloro- 7- methoxyquinazoline hydrochlorides of 25.3g (0.1mol, 1.0eq) 6- acetoxyl groups -4- are added into 1L reaction vessels,
The chloro- 4- fluoroanilines of 16.0g (0.11mol, 1.1eq) 3-, 3.05g (0.016mol, 0.16eq) CuI, 1.36g (0.22mol,
2.2eq) ethylene glycol and 46.7g (0.22mol, 2.2eq) K3PO4, add under 100ml isopropanols, stirring condition and be warming up to 70
DEG C, heat 2.0 hours, reaction is finished, and is cooled to room temperature, reaction solution pH=1.5 adjusted with concentrated hydrochloric acid, there are a large amount of solids to separate out,
Rapid suction filtration, filter cake uses isopropanol, ethanol rinse successively, and compound 34.8g, yield 87.4%, purity are obtained after drying
96.3% (HPLC, normalization method).
The synthesis of 4- (the chloro- 4- fluoroanilinos of 3-) -6- hydroxyl -7- methoxy-quinazolines (3)
Take 20g (0.05mol, 1.0eq) 6- acetoxyl groups -4- (the chloro- 4- fluoroanilinos of 3-) -7- methoxyquinazoline hydrochloride hydrochloric acid
Salt is placed in reaction vessel, is added 100ml methanol, 4mol/L sodium hydrate aqueous solution 40ml is slowly added dropwise under stirring, in 45
8h is reacted at DEG C, room temperature is cooled to after completion of the reaction, pH=5-6 is adjusted with 2.0mol/L hydrochloric acid, there are a large amount of solids to separate out, suction filtration, filter
Cake is dried after being eluted with methanol, obtains white flakes shape solid 15.2g, yield 95.1%, purity 97.1% (HPLC, normalizing
Method).
The system of N- (the chloro- 4- fluorophenyls of 3-) -7- methoxyl groups -6- [3- (morpholine -4- bases) propoxyl group]-quinazoline -4- amine (1)
It is standby
4- (the chloro- 4- fluoroanilinos of 3-) -6- hydroxyl -7- methoxyquinazoline hydrochlorides 9.6g (0.03mol, 1.0eq) are placed in instead
Answer in container, add 100ml DMF, 17.2g (0.081mol, 2.7eq) is sequentially added under stirring anhydrous
K3PO4, 3.40g (0.0195mol, 0.65eq) anhydrous K2HPO4, the 4A molecular sieves of the activated mistakes of 2.4g, dropwise addition 8.71g
The DMF solution of (0.039mol, 1.3eq) N- (3- methanesulfonyloxypropyls) morpholine, 4h is reacted in 90 DEG C,
TLC detection reactions are complete, and decompression steams solvent, and residue adds 100ml water and 300ml toluene, and heating dissolves residue, cold
But liquid is divided to collect toluene layer afterwards, water layer is extracted twice with toluene, each 100ml, combining methylbenzene layer, saturated common salt water washing 1 time,
Anhydrous sodium sulfate drying, filtering, filtrate adds activated carbon in 70-80 DEG C of decolouring 30min, filters while hot, Slow cooling, obtains shallow
Yellow solid 11.5g, yield 85.8%, (major impurity is total for HPLC normalization methods, the content 0.19% of impurity A for purity 99.12%
With 0.75%).
Comparative example 1
The synthesis of 6- acetoxyl groups -4- (the chloro- 4- fluoroanilinos of 3-) -7- methoxyquinazoline hydrochlorides hydrochloride (4) is with reference to implementation
Example 1 is carried out；
The preparation of the synthesis of 4- (the chloro- 4- fluoroanilinos of 3-) -6- hydroxyl -7- methoxy-quinazolines (3) is with reference to embodiment 1
Carry out；
The system of N- (the chloro- 4- fluorophenyls of 3-) -7- methoxyl groups -6- [3- (morpholine -4- bases) propoxyl group]-quinazoline -4- amine (1)
Standby to be carried out with reference to embodiment 1, difference does not add activated 4A molecular sieves when being to feed intake, and as a result obtains light yellow solid
10.5g, yield 78.3%, purity 85.7% (HPLC normalization methods, the content 0.56% of impurity A, major impurity summation 3.17%).
Comparative example 2
The synthesis of 6- acetoxyl groups -4- (the chloro- 4- fluoroanilinos of 3-) -7- methoxyquinazoline hydrochlorides hydrochloride (4) is with reference to implementation
Example 1 is carried out；
The preparation of the synthesis of 4- (the chloro- 4- fluoroanilinos of 3-) -6- hydroxyl -7- methoxy-quinazolines (3) is with reference to embodiment 1
Carry out；
The system of N- (the chloro- 4- fluorophenyls of 3-) -7- methoxyl groups -6- [3- (morpholine -4- bases) propoxyl group]-quinazoline -4- amine (1)
Standby to be carried out with reference to embodiment 1, difference is to replace N- (3- methanesulfonyloxypropyls) with the thing N- that feeds intake (3- chloropropyls) morpholine
Quinoline participates in reaction, as a result obtains light yellow solid 8.25g, yield 61.5%, and (HPLC normalization methods, impurity A contains purity 81.5%
Amount 1.14%, major impurity summation 11.25%).
Comparative example 3
With reference to CN1182421A methods describeds, ingredient proportion reference implementation example is converted, and as a result obtains light green sticky
Solid 6.02g, yield 44.9%, purity 78.7% (HPLC normalization methods, the content 1.43% of impurity A, major impurity summation
13.89%).
Claims (6)
1. a kind of preparation method of Gefitinib, it is characterised in that it comprises the following steps：
(a) it is that initiation material is being catalyzed with the chloro- 4- fluoroanilines (5) of 3- with the chloro- 7- methoxyquinazoline hydrochlorides (6) of 6- acetoxyl groups -4-
Agent CuI, part ethylene glycol and K3PO4In the presence of, using isopropanol as solvent reaction；
(b) after completion of the reaction, reaction solution is adjusted to pH=1-2 with concentrated hydrochloric acid, suction filtration obtains 6- acetoxyl groups -4- (the chloro- 4- fluorine of 3-
Anilino-) -7- methoxyquinazoline hydrochlorides hydrochloride (4)；
(c) 6- acetoxyl groups -4- (the chloro- 4- fluoroanilinos of 3-) -7- methoxyquinazoline hydrochlorides hydrochloride (4) uses 4mol/L sodium hydroxides
Hydrolysis obtains 4- (the chloro- 4- fluoroanilinos of 3-) -6- hydroxyl -7- methoxy-quinazolines (3)；
(d) 4- (the chloro- 4- fluoroanilinos of 3-) -6- hydroxyl -7- methoxyquinazoline hydrochlorides (3) and N- (3- methanesulfonyloxypropyls) morpholine
(2) in K3PO4And K2HPO4In the presence of react and obtain, reaction scheme is as follows：
The reaction temperature of step (a) is 70-75 DEG C；Reaction time is 1-2 hours；6- acetoxyl groups -4- used in step (a)
Chloro- 7- methoxyquinazoline hydrochlorides (6) and the chloro- 4- fluoroanilines (5) of 3- and catalyst CuI, part ethylene glycol and K3PO4Mol ratio be
1：1.0~1.3：0.1~0.2：1.5~2.5：1.5~2.5；
Step (d) is also added into 4A molecular sieves, and the amount of addition is 4- (the chloro- 4- fluoroanilinos of 3-) -6- hydroxyl -7- methoxyl group quinoline azoles
The 20-30% of quinoline (3) quality；4- (the chloro- 4- fluoroanilinos of 3-) -6- hydroxyl -7- methoxyquinazoline hydrochlorides (3), the N- of step (d)
(3- methanesulfonyloxypropyls) morpholine (2), K3PO4And K2HPO4Mol ratio be 1：1.1~1.4：2.0~3.0：0.5~0.7.
2. the preparation method of Gefitinib as claimed in claim 1, it is characterised in that 6- acetoxyl groups used in step (a)-
The chloro- 7- methoxyquinazoline hydrochlorides (6) of 4- and the chloro- 4- fluoroanilines (5) of 3- and catalyst CuI, part ethylene glycol and K3PO4Mol ratio
For 1：1.2：0.15：2.0：2.0.
3. the preparation method of Gefitinib as claimed in claim 1, it is characterised in that the reaction temperature of step (c) is 40-50
℃。
4. the preparation method of Gefitinib as claimed in claim 1, it is characterised in that the reaction temperature of step (d) is 80-100
℃。
5. the preparation method of Gefitinib as claimed in claim 4, it is characterised in that the reaction temperature of step (d) is 90 DEG C.
6. the preparation method of Gefitinib as claimed in claim 1, it is characterised in that 4- (the chloro- 4- fluorobenzene of 3- of step (d)
Amido) -6- hydroxyl -7- methoxyquinazoline hydrochlorides (3), N- (3- methanesulfonyloxypropyls) morpholine (2), K3PO4And K2HPO4Mole
Than for 1：1.2：2.5：0.6.
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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
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| Publication number | Priority date | Publication date | Assignee | Title |
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| 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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