CN101463012A - Preparation of gefitinib - Google Patents
Preparation of gefitinib Download PDFInfo
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- CN101463012A CN101463012A CNA200710172473XA CN200710172473A CN101463012A CN 101463012 A CN101463012 A CN 101463012A CN A200710172473X A CNA200710172473X A CN A200710172473XA CN 200710172473 A CN200710172473 A CN 200710172473A CN 101463012 A CN101463012 A CN 101463012A
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Abstract
The invention discloses a preparation method of gefitinib. In the method, isovanillin is taken as a raw material and synthesized to obtain 7-methoxy-6-(3-morpholine-propoxy)quinazoline-4-one which is directly chloridized to obtain a product, the product is allowed to react with 3-chlorine-4-fluoroaniline to obtain gefitinib hydrochloride which neutralized off hydrochloric acid to obtain the gefitinib. The method has mild reaction condition and is applicable to industrialized production.
Description
Technical field:
The present invention relates to the synthetic field of pharmaceutical compound, relate in particular to the preparation method of a kind of 4-(3-chloro-4-fluorophenyl amino)-7-methoxyl group-6-(3-morphine quinoline propoxy-) quinazoline (Gefitinib).
Background technology:
4-(3-chloro-4-fluorophenyl amino)-7-methoxyl group-6-(3-morphine quinoline propoxy-) quinazoline (Gefitinib, Gefitinib, trade(brand)name: Iressa, Iressa) be the selective depressant of Urogastron (EGFR) Tyrosylprotein kinase, the clinical treatment that is mainly used in nonsmall-cell lung cancer at present.
The Gefitinib molecular structural formula
The synthetic route of Gefitinib mainly be Astrazenca AB K.H. Ji Busen report (WO9633980, CN96193526), its synthetic route is as follows:
This route is with 6,7-dimethoxy-3, and 4-dihydroquinazoline-4-ketone is raw material; take off 6 methyl with methylsulfonic acid and L-methionine(Met) selectivity, acetylize protection, then chloro; with the amination of 3-chloro-4-fluoroaniline, deprotection, last and halo-3-morphine quinoline base propane reaction obtains Gefitinib.This method will be used a large amount of methylsulfonic acids and L-methionine(Met) demethylation, and these two kinds of reagent can't reclaim, and environmental pollution is big, the yield of reaction also lower (＜50%).
The Jin Bo of China Medicine University etc. (China Medicine University's journal, 2005,36,92-94) adopt this patented method to prepare Gefitinib substantially, also exist environmental pollution big, the problem that reaction yield is low.
The J.P. gill Mount Tai of Astrazenca AB and D. not flute improve the former synthetic method of company, have designed one and have been fit to industrialized synthetic route (WO2004024703):
This route is raw material with the Isovanillin, earlier aldehyde radical is converted into cyano group, and is nitrated then, the reduction nitro, and hydrolysis cyano group is acid amides, cyclization, chloro, last and 3-chloro-4-fluoroaniline reaction obtains Gefitinib.Though this method has improvement, can carry out suitability for industrialized production, the difficult control of the hydrolysis of its cyano group unavoidably has hydrolysis to arrive the by product of acid.
Hydroxyl-the 4-methoxyl methyl benzoate is a raw material to employing such as the Yuan Li of Shenyang Pharmaceutical University (Chinese pharmaceutical chemistry magazine, 2005,15,39) 3-, and the method for route and J.P. gill Mount Tai etc. is similar substantially, also has the many defectives of byproduct of reaction.
Summary of the invention
Technical problem to be solved by this invention is to provide a kind of preparation method of gefitinib, to solve defective of the prior art.
Preparation method of gefitinib provided by the present invention, its concrete steps are:
1. be that the reaction of raw material and oxammonium hydrochloride is converted into cyano group with aldehyde radical and obtains compound 1 with the Isovanillin;
2. compound 1 and 1-chloro-3-morphine quinoline propane react under inorganic or organic bases effect and obtain compound 2;
3. compound 2 nitrated compound 3 that obtains in nitration mixture;
4. compound 3 oxidations obtain compound 4;
5. compound 4 reduction obtain compound 5;
6. compound 5 cyclisation obtain compound 6;
7. reaction obtains Gefitinib to compound 6 with 3-chloro-4-fluoroaniline behind chloro.
Wherein the concrete structure formula of compound 1-6 is seen the sign in " synthetic route chart of Gefitinib ".
Wherein step 1. in, the solvent of reaction is benzene,toluene,xylene, dimethyl formamide or methyl-sulphoxide; Dewatering agent is anhydrous sodium sulphate, anhydrous magnesium sulfate, aceticanhydride or thionyl chloride;
Step 2. in, the solvent of reaction is benzene,toluene,xylene, dimethyl formamide or methyl-sulphoxide; Mineral alkali is yellow soda ash, salt of wormwood, sodium bicarbonate or saleratus; Organic bases is triethylamine, diisopropyl ethyl amine, Trimethylamine 99, tripropyl amine or tri-n-butylamine; Catalyzer is a tetrabutylammonium iodide, Tetrabutyl amonium bromide or tetrabutylammonium chloride;
Step 3. in, nitration mixture is acetic acid and nitric acid, sulfuric acid and nitric acid, acetic acid and nitrosonitric acid, acetic acid and sulfuric acid and nitrosonitric acid or sulfuric acid and nitrosonitric acid; Temperature of reaction is the 0-70 degree;
Step 4. in, the solvent of reaction is dimethyl formamide, methyl-sulphoxide, methyl alcohol, ethanol or Virahol; Oxidising agent is hydrogen peroxide, tertbutanol peroxide, Sodium peroxoborate, potassium per(oxy)borate or peroxidation phenylformic acid, preferred hydrogen peroxide, Sodium peroxoborate;
Step 5. in, the solvent of reaction is the alcohol or the ethyl acetate of 1-4 carbon, particular methanol and ethanol; Catalyzer is palladium carbon, hydrochloric acid or the acetic acid of 2%-20% (weight percent) content; Also original reagent is hydrogen, ammonium formiate, formyl ammonium, iron powder, zinc powder or vat powder;
Step 6. in, cyclization reagent is formic acid or methane amide;
Step 7. in, chlorinating agent is thionyl chloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride or trichlorine phosphine oxide; Solvent is toluene, methylene dichloride, methyl-sulphoxide, normal hexane or ethylene dichloride.
Concrete synthetic route of the present invention is as follows:
The synthetic route chart of Gefitinib
Those skilled in the art in conjunction with specific embodiments, can realize the present invention without creative work according to technique scheme.
The invention has the advantages that:
One, the present invention has avoided necessary demethylation in the prior art, and the method for last protection and deprotection has shortened synthetic route;
Two, with nitroreduction again hydrolysis cyano group change into oxidation cyano group and then the reduction nitro, thereby avoided the excessive risk of hydrolysis in the cyan-hydrolysis process;
Three, initial oxidation cyano group is to acid amides, and product is a solid, and poorly water-soluble can be easy to centrifugally, avoids using a large amount of solvent extractions.
Four, all reaction conditionss are all very gentle, are suitable for suitability for industrialized production.
Embodiment:
Following embodiment just is used to illustrate the present invention, and unrestricted the present invention.
Embodiment 1
1. compound 1 is synthetic
Add 5L in the 10L four-hole bottle and heavily steam toluene, stir adding raw material Isovanillin 1kg down, the 500g oxammonium hydrochloride, 160g tosic acid and 5kg anhydrous magnesium sulfate, reflux 6 hours is chilled to room temperature, filter, filter cake is carried to TLC detection product-free with the ethyl acetate heat of heat, merges, washing, saturated salt washing, drying, be concentrated into product and separate out in a large number, add the 2.5L sherwood oil, suction filtration, a small amount of petroleum ether, dry getting about product 750g.
2. compound 2 is synthetic
Compound 1 (1kg), 3-morphine quinoline-n-propyl chloride 2kg, salt of wormwood 3kg, tetrabutylammonium iodide 500g and 5 liters of DMSO add in 10 liters of four-hole bottles, reflux, after the TLC detection reaction is complete, cooling, pour in 10 liters of frozen water, use dichloromethane extraction, salt water washing, drying, concentrate and obtain product compound 2 (1.5kg), standby.
3. compound 3 is synthetic
Compound 2 (1kg) is dissolved in 5 liters of acetic acid, be added drop-wise to the nitric acid (3 liters) that is chilled to 0 degree, in, controlled temperature is no more than 10 degree, finish, be stirred to reaction and finish, pour in 50 liters of frozen water under stirring, separate out a large amount of solids, stir centrifugal after 30 minutes, washing, oven dry, recrystallizing methanol gets compound 3 (1kg).
4. compound 4 is synthetic
Compound 3 (1kg) is added among the DMSO (2 liters), adds 2kg salt of wormwood, drip 1 liter in hydrogen peroxide fast, add, pour in 20 liters of frozen water, separate out a large amount of solids, centrifugal, drying, dry compound 4 (1kg).
5. compound 5 is synthetic
Compound 4 (1kg) is added in 8 liters of methyl alcohol, add the 1kg ammonium formiate, 200g Pd/C, reflux after reacting completely, is chilled to room temperature, suction filtration, filtrate concentrating done, and residuum compound 5 is directly used in next step reaction.
6. compound 6 is synthetic
Compound 5 (1kg) is joined in the mixed solution of 4 liters of methane amides and 4 liters of formic acid, heating reflux reaction to raw material disappears, and is cooled to room temperature, and place in the refrigerator and spend the night, suction filtration, the filter cake washing with acetone, oven dry obtains compound 6 about 800g.
7. Gefitinib is synthetic
Compound 6 (1kg) is joined in 20 liters of thionyl chlorides; finish and add 50 milliliters of DMF; reflux was reacted 30 minutes after the solid dissolving again, and careful decompression steams excessive thionyl chloride; be cooled to room temperature; add the methylene dichloride dissolving, carefully be added in the saturated sodium bicarbonate solution, have a large amount of gases to produce; transfer pH to neutral; washing, drying concentrates; product that obtains and m-aminophenyl acetylene hydrochloride 500g add in 10 liters of four-hole bottles; add 5 liters of DMF, the displacement nitrogen protection is heated to 100 degree reactions; react postcooling to 10 degree that spends the night; suction filtration, filter cake washs with ethyl acetate, dry the about 1kg of product Gefitinib hydrochloride; use recrystallizing methanol, content 99.2%.The Gefitinib hydrochloride is dissolved in the hot water, transfers pH to 8-9, separate out a large amount of solids with ammoniacal liquor, centrifugal, the dry about 800g of Gefitinib, the content 99.2% of getting.Spectroscopic data and document coincide.
Embodiment 2
1. compound 1 is synthetic
Add 5L in the 10L four-hole bottle and heavily steam toluene, stir adding raw material Isovanillin 1kg down, the 500g oxammonium hydrochloride, 160g tosic acid and 4kg anhydrous sodium sulphate, reflux 16 hours is chilled to room temperature, filter, filter cake is carried to TLC detection product-free with the ethyl acetate heat of heat, merges, washing, saturated salt washing, drying, be concentrated into product and separate out in a large number, add the 2.5L sherwood oil, suction filtration, a small amount of petroleum ether, dry getting about product 800g.
2. compound 2 is synthetic
Compound 1 (1kg), 3-morphine quinoline-n-propyl chloride 2kg, salt of wormwood 3kg, Tetrabutyl amonium bromide 100g and 5 liters of DMF add in 10 liters of four-hole bottles, reflux, after the TLC detection reaction is complete, cooling, pour in 10 liters of frozen water, use dichloromethane extraction, salt water washing, drying, concentrate and obtain product compound 2 (1.45kg), standby.
3. compound 3 is synthetic
Compound 2 (1kg) is dissolved in 5 liters of acetic acid, be added drop-wise in the nitric acid (3 liters) and sulfuric acid (1 liter) that is chilled to 0 degree, controlled temperature is no more than 10 degree, finishes, and is stirred to reaction and finishes, pour in 50 liters of frozen water under stirring, separate out a large amount of solids, stir centrifugal after 30 minutes, the washing, oven dry, recrystallizing methanol gets compound 3 (1kg).
4. compound 4 is synthetic
Compound 3 (1kg) is added among the DMSO (2 liters), adds 1kg yellow soda ash, drip 1 liter in hydrogen peroxide fast, add, pour in 20 liters of frozen water, separate out a large amount of solids, centrifugal, drying, dry compound 4 (1kg).
5. compound 5 is synthetic
Compound 4 (1kg) is added in 8 liters of ethanol, add the 1kg ammonium formiate, 200g Pd/C, reflux after reacting completely, is chilled to room temperature, suction filtration, filtrate concentrating done, and residuum compound 5 is directly used in next step reaction.
6. compound 6 is synthetic
Compound 5 (1kg) is joined in the mixed solution of 4 liters of methane amides and 4 liters of formic acid, heating reflux reaction to raw material disappears, and is cooled to room temperature, and place in the refrigerator and spend the night, suction filtration, the filter cake washing with acetone, oven dry obtains compound 6 about 800g.
7. Gefitinib is synthetic
Compound 6 (1kg) is joined in 15 liters of thionyl chlorides; finish and add 100 milliliters of DMF; reflux was reacted 30 minutes after the solid dissolving again, and careful decompression steams excessive thionyl chloride; be cooled to room temperature; add the methylene dichloride dissolving, carefully be added in the saturated sodium bicarbonate solution, have a large amount of gases to produce; transfer pH to neutral; washing, drying concentrates; product that obtains and m-aminophenyl acetylene hydrochloride 500g add in 10 liters of four-hole bottles; add 5 liters of DMSO, the displacement nitrogen protection is heated to 100 degree reactions; react postcooling to 10 degree that spends the night; suction filtration, filter cake washs with ethyl acetate, dry the about 1kg of product Gefitinib hydrochloride; use recrystallizing methanol, content 99.2%.The Gefitinib hydrochloride is dissolved in the hot water, transfers pH to 8-9, separate out a large amount of solids with ammoniacal liquor, centrifugal, the dry about 780g of Gefitinib, the content 99.1% of getting.Spectroscopic data and document coincide.
Embodiment 3
1. compound 1 is synthetic
Add 5L in the 10L four-hole bottle and heavily steam benzene, stir adding raw material Isovanillin 1kg down, the 500g oxammonium hydrochloride, 160g tosic acid and 5kg anhydrous magnesium sulfate, reflux 10 hours is chilled to room temperature, filter, filter cake is carried to TLC detection product-free with the ethyl acetate heat of heat, merges, washing, saturated salt washing, drying, be concentrated into product and separate out in a large number, add the 2.5L sherwood oil, suction filtration, a small amount of petroleum ether, dry getting about product 780g.
2. compound 2 is synthetic
Compound 1 (1kg), 3-morphine quinoline-n-propyl chloride 3kg, salt of wormwood 2kg, Tetrabutyl amonium bromide 250g and 5 liters of DMSO add in 10 liters of four-hole bottles, reflux, after the TLC detection reaction is complete, cooling, pour in 10 liters of frozen water, use dichloromethane extraction, salt water washing, drying, concentrate and obtain product compound 2 (1.55kg), standby.
3. compound 3 is synthetic
Compound 2 (1kg) is dissolved in 5 liters of acetic acid, be added drop-wise in the nitric acid (3 liters) and sulfuric acid (1 liter) that is chilled to 0 degree, controlled temperature is no more than 30 degree, finishes, and is stirred to reaction and finishes, pour in 50 liters of frozen water under stirring, separate out a large amount of solids, stir centrifugal after 30 minutes, the washing, oven dry, recrystallizing methanol gets compound 3 (1kg).
4. compound 4 is synthetic
Compound 3 (1kg) is added among the DMSO (2 liters), adds 200g salt of wormwood, drip 1.5 liters in hydrogen peroxide fast, add, pour in 20 liters of frozen water, separate out a large amount of solids, centrifugal, drying, dry compound 4 (1kg).
5. compound 5 is synthetic
Compound 4 (1kg) is added in 8 liters of ethanol, add the 1kg ammonium formiate, 100g Pd/C, reflux after reacting completely, is chilled to room temperature, suction filtration, filtrate concentrating done, and residuum compound 5 is directly used in next step reaction.
6. compound 6 is synthetic
Compound 5 (1kg) is joined in the mixed solution of 5 liters of methane amides and 2 liters of formic acid, heating reflux reaction to raw material disappears, and is cooled to room temperature, and place in the refrigerator and spend the night, suction filtration, the filter cake washing with acetone, oven dry obtains compound 6 about 780g.
7. Gefitinib is synthetic
Compound 6 (1kg) is joined in 25 liters of thionyl chlorides; finish and add 100 milliliters of DMF; reflux was reacted 30 minutes after the solid dissolving again, and careful decompression steams excessive thionyl chloride; be cooled to room temperature; add the methylene dichloride dissolving, carefully be added in the saturated sodium bicarbonate solution, have a large amount of gases to produce; transfer pH to neutral; washing, drying concentrates; product that obtains and m-aminophenyl acetylene hydrochloride 450g add in 10 liters of four-hole bottles; add 5 liters of DMSO, the displacement nitrogen protection is heated to 120 degree reactions; react postcooling to 10 degree that spends the night; suction filtration, filter cake washs with ethyl acetate, dry the about 1.1kg of product Gefitinib hydrochloride; use recrystallizing methanol, content 99.2%.The Gefitinib hydrochloride is dissolved in the hot water, transfers pH to 8-9, separate out a large amount of solids with ammoniacal liquor, centrifugal, the dry about 850g of Gefitinib, the content 99.0% of getting.Spectroscopic data and document coincide.
Claims (10)
1, a kind of preparation method of gefitinib is characterized in that this method comprises the steps:
1. be that the reaction of raw material and oxammonium hydrochloride is converted into cyano group with aldehyde radical and obtains compound 1 with the Isovanillin;
2. compound 1 and 1-chloro-3-morphine quinoline propane react under inorganic or organic bases effect and obtain compound 2;
3. compound 2 nitrated compound 3 that obtains in nitration mixture;
4. compound 3 oxidations obtain compound 4;
5. compound 4 reduction obtain compound 5;
6. compound 5 cyclisation obtain compound 6;
7. reaction obtains Gefitinib to compound 6 with 3-chloro-4-fluoroaniline behind chloro.
2, preparation method according to claim 1 is characterized in that step 1., and the solvent of reaction is benzene,toluene,xylene, dimethyl formamide or methyl-sulphoxide; Dewatering agent is anhydrous sodium sulphate, anhydrous magnesium sulfate, aceticanhydride or thionyl chloride.
3, preparation method according to claim 1 is characterized in that step 2., and the solvent of reaction is benzene,toluene,xylene, dimethyl formamide or methyl-sulphoxide; Mineral alkali is yellow soda ash, salt of wormwood, sodium bicarbonate or saleratus; Organic bases is triethylamine, diisopropyl ethyl amine, Trimethylamine 99, tripropyl amine or tri-n-butylamine; Catalyzer is tetrabutylammonium iodide, Tetrabutyl amonium bromide or tetrabutylammonium chloride.
4, preparation method according to claim 1 is characterized in that step 3., and nitration mixture is acetic acid and nitric acid, sulfuric acid and nitric acid, acetic acid and nitrosonitric acid, acetic acid and sulfuric acid and nitrosonitric acid or sulfuric acid and nitrosonitric acid; Temperature of reaction is the 0-70 degree.
5, preparation method according to claim 1 is characterized in that step 4., and the solvent of reaction is dimethyl formamide, methyl-sulphoxide, methyl alcohol, ethanol or Virahol; Oxidising agent is hydrogen peroxide, tertbutanol peroxide, Sodium peroxoborate, potassium per(oxy)borate or peroxidation phenylformic acid.
6, preparation method according to claim 5 is characterized in that described oxidising agent is hydrogen peroxide or Sodium peroxoborate.
7, preparation method according to claim 1 is characterized in that step 5., and the solvent of reaction is the alcohol or the ethyl acetate of 1-4 carbon; Catalyzer is palladium carbon, hydrochloric acid or the acetic acid of 2%-20% content; Also original reagent is hydrogen, ammonium formiate, formyl ammonium, iron powder, zinc powder or vat powder.
8, preparation method according to claim 7 is characterized in that the solvent that reacts is methyl alcohol or ethanol.
9, preparation method according to claim 1 is characterized in that step 6., and cyclization reagent is formic acid or methane amide;
10, preparation method according to claim 1 is characterized in that step 7., and chlorinating agent is thionyl chloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride or trichlorine phosphine oxide; Solvent is toluene, methylene dichloride, methyl-sulphoxide, normal hexane or ethylene dichloride.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200710172473XA CN101463012B (en) | 2007-12-18 | 2007-12-18 | Preparation of gefitinib |
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| CN200710172473XA CN101463012B (en) | 2007-12-18 | 2007-12-18 | Preparation of gefitinib |
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| CN101463012A true CN101463012A (en) | 2009-06-24 |
| CN101463012B CN101463012B (en) | 2011-06-08 |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102153519A (en) * | 2011-02-18 | 2011-08-17 | 上海长林化学科技有限公司 | Preparation method of quinazoline derivative |
| CN102659716A (en) * | 2012-05-02 | 2012-09-12 | 北京国联诚辉医药技术有限公司 | Method for preparing 4-methoxyl-2-amido-3-[3-(4-morpholino) oxypropyl]cyanophenyl and process for preparing gefitinib |
| CN102898384A (en) * | 2012-08-14 | 2013-01-30 | 邓俐丽 | Intermediate for preparing gefitinib and preparation method of |
| CN103923023A (en) * | 2014-04-11 | 2014-07-16 | 福建医科大学 | New method for performing microwave synthesis on gefitinib and derivative thereof |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB0221245D0 (en) * | 2002-09-13 | 2002-10-23 | Astrazeneca Ab | Chemical process |
| WO2005070909A1 (en) * | 2004-01-22 | 2005-08-04 | Natco Pharma Limited | An improved process for the preparation of gefitinib |
-
2007
- 2007-12-18 CN CN200710172473XA patent/CN101463012B/en active Active
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102153519A (en) * | 2011-02-18 | 2011-08-17 | 上海长林化学科技有限公司 | Preparation method of quinazoline derivative |
| CN102153519B (en) * | 2011-02-18 | 2012-10-24 | 上海长林化学科技有限公司 | Preparation method of quinazoline derivative |
| CN102659716A (en) * | 2012-05-02 | 2012-09-12 | 北京国联诚辉医药技术有限公司 | Method for preparing 4-methoxyl-2-amido-3-[3-(4-morpholino) oxypropyl]cyanophenyl and process for preparing gefitinib |
| CN102659716B (en) * | 2012-05-02 | 2014-09-10 | 北京国联诚辉医药技术有限公司 | Method for preparing 4-methoxyl-2-amido-3-[3-(4-morpholino) oxypropyl]cyanophenyl and process for preparing gefitinib |
| CN102898384A (en) * | 2012-08-14 | 2013-01-30 | 邓俐丽 | Intermediate for preparing gefitinib and preparation method of |
| CN103923023A (en) * | 2014-04-11 | 2014-07-16 | 福建医科大学 | New method for performing microwave synthesis on gefitinib and derivative thereof |
| CN103923023B (en) * | 2014-04-11 | 2016-03-30 | 福建医科大学 | The novel method of a kind of Gefitinib and derivative Microwave synthesize thereof |
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| CN101463012B (en) | 2011-06-08 |
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