CN103570633A - Preparation method of gefitinib - Google Patents
Preparation method of gefitinib Download PDFInfo
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- CN103570633A CN103570633A CN201210265997.4A CN201210265997A CN103570633A CN 103570633 A CN103570633 A CN 103570633A CN 201210265997 A CN201210265997 A CN 201210265997A CN 103570633 A CN103570633 A CN 103570633A
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- gefitinib
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/94—Nitrogen atoms
Abstract
The invention discloses a preparation method of gefitinib. The preparation method takes 4-methoxyl-5-(3-morpholine propoxyl)-2-nitrobenzonitrile as a raw material, then subjecting the raw material to treatments of reduction and salt forming reactions so as to obtain an intermediate 2-amino-4-methoxyl-5-(3-morpholine propoxyl) benzonitrile hydrochloride, then directly subjecting the intermediate to react with N,N-dimethyl formamide dimethyl acetal so as to obtain N'-(2-cyano-5-methoxyl-4-(3-morpholinyl propoxyl)benzyl)-N,N-dimethyl formamidine, and finally subjecting the formamidine intermediate to carry out rearrangement reactions with 3-chloro-4-fluoroaniline so as to obtain the gefitinib. The preparation method has the advantages of mild reaction conditions, convenient intermediate purification method, and suitability for industrial production.
Description
Technical field
The invention belongs to field of medicine preparing technology, be specifically related to the preparation method of anti-non-small cell lung cancer drug Urogastron (EGFR) inhibitor Gefitinib.
Technical background
Gefitinib (Gefitinib) is a kind of Urogastron EGFR Tyrosylprotein kinase type small molecular inhibitor cancer therapy drug of Astra Zeneca company research and development.2002 first in Japan listing, is used for the treatment of and can not performs the operation or the nonsmall-cell lung cancer of transfer and relapse.The 2003 Nian U.S. and Australia are granted, as three line single therapy advanced Non-small cell lung medicines.Gefitinib is that first is for the small molecular protein tyrosine kinase inhibitor class targeted anticancer medicine for the treatment of of solid tumors.Nikkei State Food and Drug Administration (SFDA) approval February 25 in 2005 is (trade(brand)name: Iressa), be used for the treatment of and previously accepted chemotherapeutical local late period or Metastatic Nsclc formally in Discussion on Chinese Listed.
The structural formula of Gefitinib
In Gefitinib synthetic method, key step relates to key intermediate quinazoline-4(3H)-one synthetic.The traditional synthetic method of this intermediate is mainly by 3,4-dimethoxy benzaldehyde or 3,4-resorcylic acid is raw material, through series reaction, complete, wherein relate generally to and use eroding chemical as sulfur oxychloride/phosphoryl chloride, expensive reagent is if platinum oxide and inflammable gas are as the use of hydrogen.For avoiding these unfavorable factors, be there is the method for the synthetic Gefitinib of Dimroth rearrangement reaction in G.C.Redd etc. [Org.Process Res.Dev., 2007,11 (5), pp813-816] report by carbonamidine intermediate and aniline.Its synthetic route is as follows:
Though the method can be carried out suitability for industrialized production, but (1) also generates the by product that itrile group is reduced when being reduced into (2) in step I, because product is difficult for separation and purification, cause carbonamidine intermediate (3) purity and the yield that in step II, generate not high, thereby affect purity and the productive rate of Gefitinib.
Summary of the invention
Based on this, the invention provides a kind of preparation method of Gefitinib.
The technical scheme that realizes above-mentioned purpose is as follows:
A preparation method for Gefitinib, comprises the steps:
(1) take 4-methoxyl group-5-(3-morpholine propoxy-)-2-nitrobenzonitrile is raw material, adds reductive agent and obtains compound 2 through reaction; The structural formula of described compound 2 is:
(2) by the compound 2 of step (1) gained, be dissolved in organic solvent, it is 1-4 that concentrated hydrochloric acid regulates pH, under room temperature, reacts, and salify obtains compound 3; The structural formula of described compound 3 is:
(3) by the compound of step (2) gained 3, be 1:3-5 in molar ratio with DMF dimethylacetal (DMF-DMA), be dissolved in organic solvent, and to regulate pH be 10-14, must compound 5 after reaction; The structural formula of described compound 5 is:
(4) Dimroth rearrangement reaction is occurred to for the compound of step (3) gained 5 and the chloro-4-fluoroaniline of 3-, recrystallization obtains Gefitinib.
In some embodiment, reductive agent described in step (1) is vat powder, iron powder, zinc powder or palladium carbon and hydrogen therein; Reaction solvent is water, dioxane and water, methylene dichloride and water, second alcohol and water or DMF and water; Temperature of reaction is 60 ℃-80 ℃.
In some embodiment, described in step (1), reductive agent is vat powder therein, and reaction solvent is water or dioxane/water, and temperature of reaction is 70 ℃.
Therein in some embodiment, organic solvent described in step (2) is a kind of in ethanol, methyl alcohol, Virahol, propyl alcohol or propyl carbinol.
In some embodiment, described in step (2), organic solvent is dehydrated alcohol therein.
In some embodiment, organic solvent described in step (3) is the wherein a kind of of toluene, dimethylbenzene, benzene, tetrahydrofuran (THF), acetonitrile or dioxane therein.
In some embodiment, described in step (3), organic solvent is toluene therein.
In some embodiment, described in step (4), recrystallization solvent is ethanol, methyl alcohol, Virahol, propyl alcohol or propyl carbinol therein.
The preparation method's of a kind of Gefitinib of the present invention advantage and beneficial effect are as follows:
(1) the present invention has avoided using eroding chemical in the prior synthesizing method of Gefitinib, as reagent such as sulfur oxychloride/phosphoryl chlorides;
(2) compound 2 is the by product that thick solid and nitrile group-containing are reduced, it is 2-amino-4-methoxyl-5-(3-morpholine propoxy-that the present invention is become hydrochloride to obtain compound 3) cyanobenzene hydrochloride reaches the object of purifying, avoid using a large amount of solvent recrystallization to purify, purification process is easy;
(3) to be directly used in synthetic compound 5 be N '-(2-cyano group-5-methoxyl group-4-(morpholinyl propoxy-) phenyl)-N to compound 3, and N-dimethyl carbonamidine, avoids using acetic acid etching reagent as catalyzer;
(4) all reaction conditionss of the present invention are gentle, are suitable for suitability for industrialized production.
Embodiment
The invention provides a kind of preparation method of Gefitinib: 4-methoxyl group-5-(3-morpholine propoxy-)-2-nitrobenzonitrile of take is raw material, through reduction, salify gained intermediate 3 directly and N, the reaction of dinethylformamide dimethylacetal obtains 5,5 and obtains Gefitinib with the chloro-4-fluoroaniline of 3-generation rearrangement reaction.Synthetic route is as follows:
Embodiment 1
(1) compound 2 is synthetic
4-methoxyl group-5-of 30g (3-morpholine propoxy-)-2-nitrobenzonitrile is fed in 400mL tap water, stir, be heated to 50 ℃, more slowly add 45g vat powder, insulation reaction 2h, now solution is not clarified, be warming up to again 70 ℃, drip 151mL concentrated hydrochloric acid, dropwise, solution clarification, TLC(tlc) see that raw material reaction is complete.Reacting liquor while hot is filtered to (filtering a small amount of insoluble solids suspended substance), filtrate is cooled to room temperature, the NaOH solution with 50% is adjusted pH=10, then uses dichloromethane extraction 500mL * 3 time, combined dichloromethane phase, washing, saturated common salt washing, anhydrous Na
2sO
4dry, revolve steaming methylene dichloride, vacuum-drying obtains compound 2 crude product 24g, yield 88%, HPLC purity is 82%.
(2) compound 3 is synthetic
The compound of 24g 2 is dissolved in 150mL dehydrated alcohol, under room temperature, drips concentrated hydrochloric acid, adjust pH=3, in this process, have Precipitation, filter, collect the about 33.5g of solid chemical compound 3, yield 100%.
(3) compound 5 is synthetic
By the N of the compound of 1g 3 and 1.5g, dinethylformamide dimethylacetal is added in 10mL toluene, being heated to 120 degree refluxes, solution clarification, TLC is shown in that raw material disappears, stopped reaction, reaction solution is revolved to steaming, obtain thick substances, the material obtaining is added to about 50mL water, use again dichloromethane extraction 50mL * 3 time, collect methylene dichloride phase, washing 50mL once, saturated common salt washing 150mL, anhydrous sodium sulfate drying, revolve steaming methylene dichloride, vacuum-drying, obtain 1.1g crude product N '-(2-cyano group-5-methoxyl group-4-(morpholinyl propoxy-) phenyl)-N, N-dimethyl carbonamidine, yield 100%, HPLC purity 97.5%.
(4) Gefitinib is synthetic
The chloro-4-fluoroaniline of the 3-of 1g compound 5 and 0.463g is added in 10mL acetic acid to reflux to 130 degree, solution clarification, after 3h, TLC is shown in that raw material disappears, stopped reaction, revolve and steam most of acetic acid, by residuum impouring water, add ammoniacal liquor and adjust pH=9, there is solid to separate out, filter, collect solid, ethyl acetate washing, filters ethyl alcohol recrystallization, collect the about 1.1g of Gefitinib, yield 85.3%, HPLC purity is 95.9% (area normalization method).
1H?NMR(400MHz,d-CDCl
3),δ2.06(m,2H),2.44(t,I＝4.0,5.2Hz,4H),2.50(t,I＝6.8Hz,2H),3.72(t,I＝4.0,5.2Hz,4H),3.94(s,3H),4.10(t,I＝6.8Hz,2H),7.12(t,J＝8.4Hz,1H),7.17(s,1H),7.21(s,1H),7.52(m.1H),7.70(s,1H),7.82(m,1H),8.64(s,1H)。
Embodiment 2
(1) compound 2 is synthetic
1500g compound 1 is fed in the reactor that fills 15L dioxane and the mixing of 15L water, stir, be heated to 50 ℃, more slowly add 2440g vat powder, insulation reaction 2h, now solution is not clarified, be warming up to again 70 ℃, drip 1500mL concentrated hydrochloric acid, dropwise, solution clarification, TLC is shown in that raw material reaction is complete.Reaction solution is cooled to room temperature, adds the saturated solution of about 1200g sodium hydroxide, adjust pH to 10, then use dichloromethane extraction 20L * 3 time, combined dichloromethane phase, washing, saturated common salt washing, anhydrous Na
2sO
4dry, revolve steaming methylene dichloride, the crude product 1251g(that obtains compound 2 is directly used in lower step salt-forming reaction), productive rate 92%.
(2) compound 3 is synthetic
Above-mentioned 1251g compound 2 is dissolved in 5L dehydrated alcohol, under room temperature, drips concentrated hydrochloric acid 3L, adjust pH=3, in this process, have a large amount of Precipitations, filter, collect the about 1394.6g of yellow compound 3.
(3) compound 5 is synthetic
By the N of the compound of 1394.6g 3 and 2964.6g, dinethylformamide dimethylacetal is added in 14L toluene, being heated to 120 degree refluxes, solution clarification, TLC is shown in that raw material disappears, stopped reaction, reaction solution is revolved to steaming, obtain thick substances, the material obtaining is added in about 5L water, adjust pH to 10, use again dichloromethane extraction 5L * 3, collect methylene dichloride phase, washing 5L once, saturated common salt washing 15L, anhydrous sodium sulfate drying, revolve steaming methylene dichloride, vacuum-drying, obtain crude product, crude product is added to 15L dehydrated alcohol, be heated to reflux, cooling crystallization, filter, collect the about 1100g of solid chemical compound 5.
(4) Gefitinib is synthetic
The chloro-4-fluoroaniline of the 3-of the compound of 1100g 5 and 508.4g is added in 11L acetic acid, being heated to 130 degree refluxes, solution clarification, after 3h, TLC is shown in that raw material disappears, stopped reaction, revolve and steam most of acetic acid, residuum impouring is filled in the 10L beaker of 5L frozen water to mechanical stirring, add ammoniacal liquor 2.5L and adjust pH=9, there is solid to separate out, incline and supernatant liquid, add about 3L ethyl acetate washing, filter, collect crude product solid, ethyl alcohol recrystallization, obtains the about 1176g of Gefitinib, productive rate 83%, HPLC purity is 99.9%(area normalization method).
1H?NMR(400MHz,d-CDCl
3),δ2.06(m,2H),2.44(t,I＝4.0,5.2Hz,4H),2.50(t,I＝6.8Hz,2H),3.72(t,I＝4.0,5.2Hz,4H),3.94(s,3H),4.10(t,I＝6.8Hz,2H),7.12(t,J＝8.4Hz,1H),7.17(s,1H),7.21(s,1H),7.52(m.1H),7.70(s,1H),7.82(m,1H),8.64(s,1H)。
The above embodiment has only expressed several embodiment of the present invention, and it describes comparatively concrete and detailed, but can not therefore be interpreted as the restriction to the scope of the claims of the present invention.It should be pointed out that for the person of ordinary skill of the art, without departing from the inventive concept of the premise, can also make some distortion and improvement, these all belong to protection scope of the present invention.Therefore, the protection domain of patent of the present invention should be as the criterion with claims.
Claims (8)
1. a preparation method for Gefitinib, is characterized in that, described preparation method comprises the steps:
(1) take 4-methoxyl group-5-(3-morpholine propoxy-)-2-nitrobenzonitrile is raw material, adds reductive agent and obtains compound 2 through reaction; The structural formula of described compound 2 is:
(2) by the compound 2 of step (1) gained, be dissolved in organic solvent, it is 1-4 that concentrated hydrochloric acid regulates pH, under room temperature, reacts, and salify obtains compound 3; The structural formula of described compound 3 is:
(3) by the compound of step (2) gained 3, be 1:3-5 in molar ratio with DMF dimethylacetal, be dissolved in organic solvent, and to regulate pH be 10-14, must compound 5 after reaction; The structural formula of described compound 5 is:
(4) Dimroth rearrangement reaction is occurred to for the compound of step (3) gained 5 and the chloro-4-fluoroaniline of 3-, recrystallization obtains Gefitinib.
2. the preparation method of Gefitinib according to claim 1, is characterized in that, reductive agent described in step (1) is vat powder, iron powder, zinc powder or palladium carbon/hydrogen; Reaction solvent is water, dioxane/water, methylene dichloride/water, ethanol/water or DMF/water; Temperature of reaction is 60 ℃-80 ℃.
3. the preparation method of Gefitinib according to claim 2, is characterized in that, described in step (1), reductive agent is vat powder, and reaction solvent is water or dioxane/water, and temperature of reaction is 70 ℃.
4. the preparation method of Gefitinib according to claim 1, is characterized in that, organic solvent described in step (2) is a kind of in dehydrated alcohol, methyl alcohol, Virahol, propyl alcohol or propyl carbinol.
5. the preparation method of Gefitinib according to claim 4, is characterized in that, described in step (2), organic solvent is dehydrated alcohol.
6. the preparation method of Gefitinib according to claim 1, is characterized in that, organic solvent described in step (3) is the wherein a kind of of toluene, dimethylbenzene, benzene, tetrahydrofuran (THF), acetonitrile or dioxane.
7. the preparation method of Gefitinib according to claim 6, is characterized in that, described in step (3), organic solvent is toluene.
8. the preparation method of Gefitinib according to claim 1, is characterized in that, described in step (4), recrystallization solvent is ethanol, methyl alcohol, Virahol, propyl alcohol or propyl carbinol.
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Cited By (7)
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| CN104016930A (en) * | 2014-06-03 | 2014-09-03 | 广东药学院 | Preparing method of gefitinib |
| CN105218463A (en) * | 2014-05-30 | 2016-01-06 | 沈阳药科大学 | The synthetic method of Gefitinib |
| CN108395410A (en) * | 2018-05-09 | 2018-08-14 | 日照市普达医药科技有限公司 | A kind of anilinoquinazoline compound and its application in antitumor drug |
| CN108727284A (en) * | 2017-04-14 | 2018-11-02 | 鲁南制药集团股份有限公司 | A kind of preparation method of Gefitinib |
| CN109384747A (en) * | 2018-10-26 | 2019-02-26 | 苏州立新制药有限公司 | Gefitinib related substances and its preparation and detection method |
| CN110747489A (en) * | 2019-11-07 | 2020-02-04 | 湖南大学 | Electroreduction preparation method of intermediate of anticancer drug gefitinib and analogue thereof |
| CN113004212A (en) * | 2019-12-20 | 2021-06-22 | 上海天慈国际药业有限公司 | Preparation method of dacomitinib |
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Cited By (11)
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| CN105218463A (en) * | 2014-05-30 | 2016-01-06 | 沈阳药科大学 | The synthetic method of Gefitinib |
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| CN104016930B (en) * | 2014-06-03 | 2015-11-11 | 广东药学院 | A kind of process for purification of Gefitinib |
| CN108727284A (en) * | 2017-04-14 | 2018-11-02 | 鲁南制药集团股份有限公司 | A kind of preparation method of Gefitinib |
| CN108727284B (en) * | 2017-04-14 | 2020-10-27 | 鲁南制药集团股份有限公司 | Preparation method of gefitinib |
| CN108395410A (en) * | 2018-05-09 | 2018-08-14 | 日照市普达医药科技有限公司 | A kind of anilinoquinazoline compound and its application in antitumor drug |
| CN109384747A (en) * | 2018-10-26 | 2019-02-26 | 苏州立新制药有限公司 | Gefitinib related substances and its preparation and detection method |
| CN110747489A (en) * | 2019-11-07 | 2020-02-04 | 湖南大学 | Electroreduction preparation method of intermediate of anticancer drug gefitinib and analogue thereof |
| CN110747489B (en) * | 2019-11-07 | 2021-05-07 | 湖南大学 | Electroreduction preparation method of intermediate of anticancer drug gefitinib and analogue thereof |
| CN113004212A (en) * | 2019-12-20 | 2021-06-22 | 上海天慈国际药业有限公司 | Preparation method of dacomitinib |
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