CN103304491A - Preparation method of gefitinib - Google Patents
Preparation method of gefitinib Download PDFInfo
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Abstract
The invention relates to a preparation method of gefitinib. The preparation method comprises the following steps of: reacting under the action of an appropriate solvent and alkali by taking 3-hydroxy-4-methoxybenzonitrile and 4-(3-chloropropyl) morpholine as raw materials to prepare 4-(3-chlorine-4-fluorophenyl amido)-7-methoxyl-6-[3-(4-morpholinyl)propoxy] quinazoline; nitrifying the 4-(3-chlorine-4-fluorophenyl amido)-7-methoxyl-6-[3-(4-morpholinyl)propoxy] quinazoline to obtain 2-nitryl-4-methoxyl-5-[3-(4-morpholinyl)propoxy] methyl benzoate, and then reducing the 2-nitryl-4-methoxyl-5-[3-(4-morpholinyl)propoxy] methyl benzoate to obtain 2-amido-4-methoxyl-5-[3-(4-morpholinyl)propoxy] methyl benzoate; reacting 3-chlorine-4-fluoroaniline with N,N-dimethylformamide dimethylacetal to obtain (3-chlorine-4-fluorophenyl)-N,N-dimethyl dimethyleneimine; and carrying out loop closing on the 2-amido-4-methoxyl-5-[3-(4-morpholinyl)propoxy] methyl benzoate and the (3-chlorine-4-fluorophenyl)-N,N-dimethyl dimethyleneimine to obtain the gefitinib. The preparation method disclosed by the invention has the advantages of short process route, safety and easiness for operation, easiness and convenience for post processing, high reduction transformation ratio and yield, less environment pollution, and safety, reliability and stability in product quality.
Description
Technical field
The present invention relates to the preparation method of a kind of synthetic method of cancer therapy drug, particularly a kind of Gefitinib, belong to the technical field of original new drug preparation.
Background technology
Gefitinib is that by Astra Zeneca company exploitation one is for the kinase whose micromolecular inhibitor that can be oral of EGFR TYR.The nonsmall-cell lung cancer that can not perform the operation or recur in Japan's listing treatment first in 2002, in May, 2003 is in the U.S. and Australia is granted is used for advanced Non-small cell lung as three line single therapy medicines, and it is first small molecules TYR enzyme inhibitors for specific target spot that is used for the solid carcinoma treatment.Nikkei State Food and Drug Administration approval February 25 in 2005 is used for the treatment of and previously accepted chemotherapeutical local late period or Metastatic Nsclc formally at Discussion on Chinese Listed.
The technology of Gefitinib mainly contains at present: Bioorangic ﹠amp; Medicinal Chemstry Letters, 2006,16:4102; WO2004024703, synthetic route is as follows:
This route is through reactions such as peroxidation, hydrocarbylation, nitrated, reduction, cyclization, chlorinations, and step is long, and is seriously polluted.
In addition, reported a kind of synthetic method of new Gefitinib in Chinese patent CN200710132258, its synthetic route is as follows:
This route is through reactions such as hydrocarbylation, nitrated, reduction, cyclization, chlorinations, and general line is long, and away from costliness, chlorination is with pollution in the process.
Summary of the invention
The objective of the invention is to overcome deficiency of the prior art, provide a kind of technique simple, reaction time is short, the preparation method of the Gefitinib that environmental friendliness is with low cost.
Technical problem to be solved by this invention is to realize by following technical scheme.The present invention is a kind of preparation method of Gefitinib, is characterized in, the method comprises the steps:
(1) take 3-hydroxyl-4-anisole first cyanogen, 4-(3-chloropropyl) morpholine is as raw material, under appropriate solvent and alkali effect, react, preparation compound 1, i.e. 4-(3-chloro-4-fluorophenyl is amino)-7-methoxyl group-6-[3-(4-morpholinyl) propoxy-] quinazoline;
(2) compound 1 is through the nitrated compound 2 that obtains, i.e. 2-nitro-4-methoxyl group-5-[3-(4-morpholinyl) propoxy-] methyl benzoate;
(3) compound 2 reduction obtain compound 3, i.e. 2-amino-4-methoxyl-5-[3-(4-morpholinyl) propoxy-] methyl benzoate;
(4) reaction of 3-chloro-4-fluoroaniline and DMF dimethylacetal is obtained compound 4, i.e. (3-chloro-4-fluorophenyl)-N, N – dimethylformamide dimethyl imines;
(5) compound 3 and compound 4 cyclization under solvent are obtained Gefitinib.
Among the preparation method of Gefitinib of the present invention, preferred technical scheme or technical characterictic are as follows:
1. in the step (1), reaction solvent is selected from one or more mixing of dimethyl sulfoxide (DMSO), dimethyl formamide, N,N-DIMETHYLACETAMIDE, toluene and dimethylbenzene; Described alkali is mineral alkali or organic bases, and wherein: mineral alkali is selected from one or more mixing of yellow soda ash, sodium bicarbonate, salt of wormwood, saleratus, and organic bases is one or more mixing of Trimethylamine 99, triethylamine, tripropyl amine, tri-n-butylamine.
2. in the step (2), the massfraction of nitric acid is 50%-85%; Reaction times is 1-24 hour, and temperature of reaction is 0-80 ℃.
3. in the step (3), the solvent of reaction is one or more mixing of water, ethanol, methyl alcohol, Virahol, dimethyl formamide and methyl-sulphoxide; Reductive agent is one or more mixing of reduced iron powder, hydrazine hydrate, sodium borohydride and vat powder; Temperature of reaction is 5-90 ℃.
4. in the step (4), reaction solvent is one or more mixing of benzene,toluene,xylene, methyl alcohol, ethanol, propyl alcohol, Virahol, propyl carbinol, methyl-sulphoxide and dimethyl formamide; Temperature of reaction is 30-150 ℃.
5. in the step (5), reaction solvent is one or more mixing of benzene,toluene,xylene, methyl-sulphoxide and dimethyl formamide; Catalyzer is one or more mixing of acetic acid, hydrochloric acid, tetrabutylammonium iodide, Tetrabutyl amonium bromide and tetrabutylammonium chloride; Temperature of reaction is 30-150 ℃.
6. in the step (1): 3-hydroxyl-4-methoxyl methyl benzoate and 4-(3-chloropropyl) molar ratio of morpholine is 1:0.8～1:3; In the step (2): compound 2 is 1:3～1:12 with the molar ratio of nitric acid; In the step (4): the molar ratio of 3-chloro-4-fluoroaniline and DMF dimethylacetal is 1:0.8～1:3; In the step (5): compound 3 is 1:0.8～1:3 with the molar ratio of compound 4.
It below is most preferred technical scheme of the present invention.A kind of preparation method of Gefitinib is characterized in, its concrete steps are as follows:
(1) synthesizing of 4-methoxyl group 3-(morpholinyl-4-propoxy-) benzonitrile: with 3-hydroxyl-4-anisole first cyanogen, 4-(3-chloropropyl) morpholine, salt of wormwood and DMF are made into the reaction solution that mass ratio is 9:10.6:28:13.8, in 50-85 ℃ of reaction, TLC controls reaction, the stirring undershoot is analysed to frozen water after finishing, stir some hours crystallizatioies, filter, washing obtains compound 4-methoxyl group 3-(morpholinyl-4-propoxy-) benzonitrile;
(2) 4-methoxyl group-5-(morpholinyl-4-propoxy-)-2-nitrobenzonitrile is synthetic: 4-methoxyl group 3-(morpholinyl-4-propoxy-) benzonitrile and concentrated nitric acid are made into the reaction solution that mass ratio is 5:20, after reaction finishes, add in an amount of water, solid is separated out in stirring, filter, washing gets 4-methoxyl group-5-(morpholinyl-4-propoxy-)-2-nitrobenzonitrile;
(3) 4-methoxyl group-5-(morpholinyl-4-propoxy-)-2-aminobenzonitrile is synthetic: 4-methoxyl group-5-(morpholinyl-4-propoxy-)-2-nitrobenzonitrile, water, V-Brite B are made into the reaction solution that mass ratio is 8.7:40:8, in 30-70 ℃ of reaction 2h, drip an amount of concentrated hydrochloric acid, finish reaction solution and be cooled to room temperature, the sodium hydroxide solution that adds 20-50% to pH be weakly alkaline, separate out a large amount of solids, filter, get 4-methoxyl group-5-(morpholinyl-4-propoxy-)-2-aminobenzonitrile;
(4) (3-chloro-4-fluorophenyl)-N, synthesizing of N – dimethylformamide dimethyl imines: in there-necked flask, with 3-chloro-4-fluoroaniline, sulfur oxychloride, N, dinethylformamide dimethylacetal, tetrabutylammonium chloride are made into the reaction solution that mass ratio is 4:50:4:0.3, back flow reaction, TLC monitors reaction, concentrated (3-chloro-4-fluorophenyl)-N, the N – dimethylformamide dimethyl imines of obtaining after reaction is finished;
(5) Gefitinib is synthetic: with 4-methoxyl group-5-(morpholinyl-4-propoxy-)-2-aminobenzonitrile, acetic acid, (3-chloro-4-fluorophenyl)-N, N – dimethylformamide dimethyl imines, tetrabutylammonium chloride are made into the reaction solution that mass ratio is 4:30:4.6:0.3, back flow reaction, TLC control reaction finishes, and steams solvent, adds an amount of water, regulate pH to 8-10 with ammoniacal liquor, separate out solid, filtration drying gets Gefitinib.
The concrete synthetic route of the inventive method is as follows:
Compared with prior art, the advantage of technical solution of the present invention is: its operational path is short, and does not need through chlorinating step, avoids using the halide reagent of high-risk, high pollution, such as thionyl chloride, phosphorus oxychloride etc.Do not use hydrogen, operational safety is simple, and reducing medium is an amount of common solvent, and solvent is recyclable.Normal pressure can reduce smoothly, does not need high-pressure reactor, in the last handling process of product, can save with the organic solvent purification operations step of extractive reaction liquid repeatedly, only needs a washing and drying to get final product.Aftertreatment is easy, and reduction transformation efficiency and yield are high, and after testing, the chemical structure of purpose compound is consistent with the prior synthesizing method resulting structures.And production technique environmental pollution of the present invention is little, and Product quality and safety is reliable and stable.
Embodiment
Below ginseng further describes concrete technical scheme of the present invention, so that those skilled in the art understands the present invention further, and does not consist of its Copyright law.
Embodiment 1, a kind of preparation method of Gefitinib, and the method comprises the steps:
(1) take 3-hydroxyl-4-anisole first cyanogen, 4-(3-chloropropyl) morpholine is as raw material, under appropriate solvent and alkali effect, react, preparation compound 1, i.e. 4-(3-chloro-4-fluorophenyl is amino)-7-methoxyl group-6-[3-(4-morpholinyl) propoxy-] quinazoline;
(2) compound 1 is through the nitrated compound 2 that obtains, i.e. 2-nitro-4-methoxyl group-5-[3-(4-morpholinyl) propoxy-] methyl benzoate;
(3) compound 2 reduction obtain compound 3, i.e. 2-amino-4-methoxyl-5-[3-(4-morpholinyl) propoxy-] methyl benzoate;
(4) reaction of 3-chloro-4-fluoroaniline and DMF dimethylacetal is obtained compound 4, i.e. (3-chloro-4-fluorophenyl)-N, N – dimethylformamide dimethyl imines;
(5) compound 3 and compound 4 cyclization under solvent are obtained Gefitinib.
Embodiment 2, the preparation method of embodiment 1 described Gefitinib, and in step (1): reaction solvent is selected from one or more mixing of dimethyl sulfoxide (DMSO), dimethyl formamide, N,N-DIMETHYLACETAMIDE, toluene and dimethylbenzene; Described alkali is mineral alkali or organic bases, and wherein: mineral alkali is selected from one or more mixing of yellow soda ash, sodium bicarbonate, salt of wormwood, saleratus, and organic bases is one or more mixing of Trimethylamine 99, triethylamine, tripropyl amine, tri-n-butylamine.
Embodiment 3, the preparation method of embodiment 1 or 2 described Gefitinib, and in step (2): the massfraction of nitric acid is 50%-85%; Reaction times is 1-24 hour, and temperature of reaction is 0-80 ℃.
Embodiment 4, the preparation method of embodiment 1 or 2 or 3 described Gefitinib, and in step (3), the solvent of reaction is one or more mixing of water, ethanol, methyl alcohol, Virahol, dimethyl formamide and methyl-sulphoxide; Reductive agent is one or more mixing of reduced iron powder, hydrazine hydrate, sodium borohydride and vat powder; Temperature of reaction is 5-90 ℃.
Embodiment 5, the preparation method of any one described Gefitinib of embodiment 1-4, in step (4): reaction solvent is one or more mixing of benzene,toluene,xylene, methyl alcohol, ethanol, propyl alcohol, Virahol, propyl carbinol, methyl-sulphoxide and dimethyl formamide; Temperature of reaction is 30-150 ℃.
Embodiment 6, the preparation method of any one described Gefitinib of embodiment 1-5, and in step (5), reaction solvent is one or more mixing of benzene,toluene,xylene, methyl-sulphoxide and dimethyl formamide; Catalyzer is one or more mixing of acetic acid, hydrochloric acid, tetrabutylammonium iodide, Tetrabutyl amonium bromide and tetrabutylammonium chloride; Temperature of reaction is 30-150 ℃.
Embodiment 7, and the preparation method of any one described Gefitinib of embodiment 1-6 is in the step (1): 3-hydroxyl-4-methoxyl methyl benzoate and 4-(3-chloropropyl) molar ratio of morpholine is 1:0.8～1:3; In the step (2): compound 2 is 1:3～1:12 with the molar ratio of nitric acid; In the step (4): the molar ratio of 3-chloro-4-fluoroaniline and DMF dimethylacetal is 1:0.8～1:3; In the step (5): compound 3 is 1:0.8～1:3 with the molar ratio of compound 4.
Embodiment 8, and the preparation method of any one described Gefitinib of embodiment 1-6 is in the step (1): 3-hydroxyl-4-methoxyl methyl benzoate and 4-(3-chloropropyl) molar ratio of morpholine is 1:2; In the step (2): compound 2 is 1:7 with the molar ratio of nitric acid; In the step (4): the molar ratio of 3-chloro-4-fluoroaniline and DMF dimethylacetal is 1:2; In the step (5): compound 3 is 1:2 with the molar ratio of compound 4.
Embodiment 9, preparation method's experiment of Gefitinib.Raw material if no special instructions, all by mass.
(1) 4-methoxyl group 3-(morpholinyl-4-propoxy-) benzonitrile is synthetic.With 3-hydroxyl-4-anisole first cyanogen, 4-(3-chloropropyl) morpholine, salt of wormwood and DMF be made into the reaction solution that mass ratio is 9:10.6:28:13.8, in 50-85 ℃ of reaction, TLC controls reaction, the stirring undershoot is analysed to frozen water after finishing, stir some hours crystallizatioies, filter, washing, obtain compound 4-methoxyl group 3-(morpholinyl-4-propoxy-) benzonitrile, approximately get 120-145g in 50-70 ℃ of forced air drying.
(2) 4-methoxyl group-5-(morpholinyl-4-propoxy-)-2-nitrobenzonitrile is synthetic.4-methoxyl group 3-(morpholinyl-4-propoxy-) benzonitrile and concentrated nitric acid are made into the reaction solution that mass ratio is about 5:20, after reaction finishes, add in the 700-1000ml water, solid is separated out in stirring, filter, washing gets 4-methoxyl group-5-(morpholinyl-4-propoxy-)-2-nitrobenzonitrile, gets 35-60g in 50-80 ℃ of forced air drying.
(3) 4-methoxyl group-5-(morpholinyl-4-propoxy-)-2-aminobenzonitrile is synthetic.4-methoxyl group-5-(morpholinyl-4-propoxy-)-2-nitrobenzonitrile, water, V-Brite B are made into the reaction solution that mass ratio is 8.7:40:8, in 30-70 ℃ of reaction 2h, drip the 100-200g concentrated hydrochloric acid, finish reaction solution and be cooled to room temperature, the sodium hydroxide solution that adds 20-50% to PH be weakly alkaline, separate out a large amount of solids, filter, get 4-methoxyl group-5-(morpholinyl-4-propoxy-)-2-aminobenzonitrile, in 30-60 ℃ of forced air drying, get 45-75g.
(4) 3-chloro-4-fluorophenyl)-and N, N – dimethylformamide dimethyl imines synthetic.In there-necked flask, with 3-chloro-4-fluoroaniline, sulfur oxychloride, N, dinethylformamide dimethylacetal, tetrabutylammonium chloride are made into the reaction solution that mass ratio is 4:50:4:0.3, back flow reaction, TLC monitors reaction, concentrate after reaction is finished and obtain (3-chloro-4-fluorophenyl)-N, N – dimethylformamide dimethyl imines is 30-60g approximately.
(5) Gefitinib is synthetic.In there-necked flask, with 4-methoxyl group-5-(morpholinyl-4-propoxy-)-2-aminobenzonitrile, acetic acid, (3-chloro-4-fluorophenyl)-N, N – dimethylformamide dimethyl imines, tetrabutylammonium chloride are made into the reaction solution that mass ratio is 4:30:4.6:0.3, back flow reaction, and TLC control reaction finishes, steam solvent, add 200-400ml water, regulate PH to 8-10 with ammoniacal liquor, separate out solid, filtration drying gets approximately 30-65g of Gefitinib.
In this experiment, the product of each step all adopts universal method of the prior art to detect affirmation.
Claims (8)
1. the preparation method of a Gefitinib is characterized in that, the method comprises the steps:
(1) take 3-hydroxyl-4-anisole first cyanogen, 4-(3-chloropropyl) morpholine is as raw material, under appropriate solvent and alkali effect, react, preparation compound 1, i.e. 4-(3-chloro-4-fluorophenyl is amino)-7-methoxyl group-6-[3-(4-morpholinyl) propoxy-] quinazoline;
(2) compound 1 is through the nitrated compound 2 that obtains, i.e. 2-nitro-4-methoxyl group-5-[3-(4-morpholinyl) propoxy-] methyl benzoate;
(3) compound 2 reduction obtain compound 3, i.e. 2-amino-4-methoxyl-5-[3-(4-morpholinyl) propoxy-] methyl benzoate;
(4) reaction of 3-chloro-4-fluoroaniline and DMF dimethylacetal is obtained compound 4, i.e. (3-chloro-4-fluorophenyl)-N, N – dimethylformamide dimethyl imines;
(5) compound 3 and compound 4 cyclization under solvent are obtained Gefitinib.
2. preparation method according to claim 1 is characterized in that, in the step (1), reaction solvent is selected from one or more mixing of dimethyl sulfoxide (DMSO), dimethyl formamide, N,N-DIMETHYLACETAMIDE, toluene and dimethylbenzene; Described alkali is mineral alkali or organic bases, and wherein: mineral alkali is selected from one or more mixing of yellow soda ash, sodium bicarbonate, salt of wormwood, saleratus, and organic bases is one or more mixing of Trimethylamine 99, triethylamine, tripropyl amine, tri-n-butylamine.
3. preparation method according to claim 1 is characterized in that, in the step (2), the massfraction of nitric acid is 50%-85%; Reaction times is 1-24 hour, and temperature of reaction is 0-80 ℃.
4. preparation method according to claim 1 is characterized in that, in the step (3), the solvent of reaction is one or more mixing of water, ethanol, methyl alcohol, Virahol, dimethyl formamide and methyl-sulphoxide; Reductive agent is one or more mixing of reduced iron powder, hydrazine hydrate, sodium borohydride and vat powder; Temperature of reaction is 5-90 ℃.
5. preparation method according to claim 1 is characterized in that, in the step (4), reaction solvent is one or more mixing of benzene,toluene,xylene, methyl alcohol, ethanol, propyl alcohol, Virahol, propyl carbinol, methyl-sulphoxide and dimethyl formamide; Temperature of reaction is 30-150 ℃.
6. preparation method according to claim 1 is characterized in that, in the step (5), reaction solvent is one or more mixing of benzene,toluene,xylene, methyl-sulphoxide and dimethyl formamide; Catalyzer is one or more mixing of acetic acid, hydrochloric acid, tetrabutylammonium iodide, Tetrabutyl amonium bromide and tetrabutylammonium chloride; Temperature of reaction is 30-150 ℃.
7. preparation method according to claim 1 is characterized in that, in the step (1): 3-hydroxyl-4-methoxyl methyl benzoate and 4-(3-chloropropyl) molar ratio of morpholine is 1:0.8～1:3; In the step (2): compound 2 is 1:3～1:12 with the molar ratio of nitric acid; In the step (4): the molar ratio of 3-chloro-4-fluoroaniline and DMF dimethylacetal is 1:0.8～1:3; In the step (5): compound 3 is 1:0.8～1:3 with the molar ratio of compound 4.
8. preparation method according to claim 1 is characterized in that, its concrete steps are as follows:
(1) synthesizing of 4-methoxyl group 3-(morpholinyl-4-propoxy-) benzonitrile: with 3-hydroxyl-4-anisole first cyanogen, 4-(3-chloropropyl) morpholine, salt of wormwood and DMF are made into the reaction solution that mass ratio is 9:10.6:28:13.8, in 50-85 ℃ of reaction, TLC controls reaction, the stirring undershoot is analysed to frozen water after finishing, stir some hours crystallizatioies, filter, washing obtains compound 4-methoxyl group 3-(morpholinyl-4-propoxy-) benzonitrile;
(2) 4-methoxyl group-5-(morpholinyl-4-propoxy-)-2-nitrobenzonitrile is synthetic: 4-methoxyl group 3-(morpholinyl-4-propoxy-) benzonitrile and concentrated nitric acid are made into the reaction solution that mass ratio is 5:20, after reaction finishes, add in an amount of water, solid is separated out in stirring, filter, washing gets 4-methoxyl group-5-(morpholinyl-4-propoxy-)-2-nitrobenzonitrile;
(3) 4-methoxyl group-5-(morpholinyl-4-propoxy-)-2-aminobenzonitrile is synthetic: 4-methoxyl group-5-(morpholinyl-4-propoxy-)-2-nitrobenzonitrile, water, V-Brite B are made into the reaction solution that mass ratio is 8.7:40:8, in 30-70 ℃ of reaction 2h, drip an amount of concentrated hydrochloric acid, finish reaction solution and be cooled to room temperature, the sodium hydroxide solution that adds 20-50% to pH be weakly alkaline, separate out a large amount of solids, filter, get 4-methoxyl group-5-(morpholinyl-4-propoxy-)-2-aminobenzonitrile;
(4) (3-chloro-4-fluorophenyl)-N, synthesizing of N – dimethylformamide dimethyl imines: in there-necked flask, with 3-chloro-4-fluoroaniline, sulfur oxychloride, N, dinethylformamide dimethylacetal, tetrabutylammonium chloride are made into the reaction solution that mass ratio is 4:50:4:0.3, back flow reaction, TLC monitors reaction, concentrated (3-chloro-4-fluorophenyl)-N, the N – dimethylformamide dimethyl imines of obtaining after reaction is finished;
(5) Gefitinib is synthetic: with 4-methoxyl group-5-(morpholinyl-4-propoxy-)-2-aminobenzonitrile, acetic acid, (3-chloro-4-fluorophenyl)-N, N – dimethylformamide dimethyl imines, tetrabutylammonium chloride are made into the reaction solution that mass ratio is 4:30:4.6:0.3, back flow reaction, TLC control reaction finishes, and steams solvent, adds an amount of water, regulate pH to 8-10 with ammoniacal liquor, separate out solid, filtration drying gets Gefitinib.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105503749A (en) * | 2016-01-04 | 2016-04-20 | 南京亚东启天药业有限公司 | Synthetic method of 4-(3-chlorine-4-fluorophenyl)-7-methoxyl-6-[3-(4-morpholinyl) propoxy] quinazoline |
| CN107586279A (en) * | 2017-10-27 | 2018-01-16 | 江苏正大清江制药有限公司 | A kind of new synthetic method of Gefitinib |
| CN108503597A (en) * | 2018-05-16 | 2018-09-07 | 济南爱思医药科技有限公司 | A kind of high efficiency preparation method of Gefitinib |
| CN110747489A (en) * | 2019-11-07 | 2020-02-04 | 湖南大学 | Electroreduction preparation method of intermediate of anticancer drug gefitinib and analogue thereof |
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