CN101638398A - Amidine compound capable of preparing gefitinib and preparation method thereof - Google Patents
Amidine compound capable of preparing gefitinib and preparation method thereof Download PDFInfo
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- CN101638398A CN101638398A CN200910017964A CN200910017964A CN101638398A CN 101638398 A CN101638398 A CN 101638398A CN 200910017964 A CN200910017964 A CN 200910017964A CN 200910017964 A CN200910017964 A CN 200910017964A CN 101638398 A CN101638398 A CN 101638398A
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Abstract
The invention belongs to the field of medicine preparation research and in particular relates to an amidine compound capable of preparing gefitinib. The invention relates to the amidine compound withthe structure as shown in formula (I) and a preparation method thereof. The quinazoline ring of the gefitinib prepared by the amidine compound has high yield which is generally over 80%, purificationis relatively simple and operability is strong.
Description
(1) technical field
The invention belongs to the medication preparation research field, particularly a kind of 4-(3-chloro-4-fluorophenyl amido)-7-methoxyl group-6-[3-(4-morpholinyl) propoxy-for preparing] quinazoline (Gefitinib, amidine compound Gefitinib) and preparation method thereof.
(2) background technology
Gefitinib (Gefitinib) is a kind of new type antineoplastic medicine by the exploitation of Astra Zeneca company, is a kind of EGFR Tyrosylprotein kinase micromolecular inhibitor that can be oral.Found Iressa (ZD1839) molecule in 1994, follow-up Iressa (ZD1839) molecule of discovering can suppress the growth and the survival of nonsmall-cell lung cancer (NSCLC) and other tumours such as colorectal cancer, incidence cancer, prostate cancer, breast cancer cell, its possible mechanism comprises: Mg-ATP binding site on (1) competition EGFR-TK catalysis region, block its signal transmission; (2) activation of inhibition mitogen activated protein kinase promotes apoptosis; (3) suppress tumor-blood-vessel growth.The approval of Nikkei Japanese health ministry was used for the treatment of nonsmall-cell lung cancer in late period (NSCLC) to Iressa July 5 in 2002, on May 5th, 2003, propose during lung cancer Professional Committee of Chinese Anti-Cancer Association guided the treatment of inoperable NSCLC in 2003: Iressa recommended to be used for the treatment of the nonsmall-cell lung cancer platiniferous class scheme of local late period or distant metastasis and the patient of Docetaxel chemotherapy failure by the three-way medicine of FDA approval as NSCLC.Nikkei State Food and Drug Administration (SFDA) approval February 25 in 2005 is formally at China's listing (commodity popular name: Gefitinib), be used for previously accepting chemotherapeutical local late period or transitivity nonsmall-cell lung cancer.Its chemical structure is as follows:
Existing preparation method of gefitinib has following five kinds:
Method one (the synthetic patent of application in 1993, EP566226, WO9633980, WO9742187) operational path of Miao Shuing:
This route is with 6; 7-dimethyl quinazoline-4 (3H)-ketone is raw material; obtain 6-hydroxyl-7-methoxyl group quinazoline-4 (3H)-ketone through the selectivity demethoxylation; hydroxyl is obtained the 4-chloro-quinazoline with aceticanhydride protection back chloro; through the nucleophilic substitution of arylamine, deprotection and side chain alkoxylate obtain target compound again.This synthetic route raw material costliness, the regioselectivity demethyl need consume more L-methionine(Met) and expendable methanesulfonic, and chlorination need be used halide reagent such as thionyl chloride, the phosphorus oxychloride etc. of high risk, high pollution.And in the building-up process, hydroxyl needs protection and goes protection, thereby makes that the entire reaction route is longer, is not suitable for industrialized production.
Method two (CN1733738) synthetic route is as follows:
This route is with 3, the 4-mesitylenic acid be raw material through nitrated, seven steps reaction such as the nucleophilic substitution of demethylation, reduction, pass ring, chloro, arylamine and the alkoxylate of pendant hydroxyl group obtains Gefitinib.This synthetic route reactions steps is long, and chloro is still used halide reagent thionyl chloride, phosphorus oxychloride of high risk, high pollution etc., and the side reaction in this step of chloro is more, and yield is low.
Method three (CN101148439A) synthetic route is as follows:
This route is a raw material with 3-hydroxyl-4 methoxyl methyl benzoate, at first by the side chain alkoxylate, introduces 3-morpholine propoxy-, and then through six synthetic Gefitinib of reaction such as nucleophilic substitution nitrated, that reduce, close ring, chloro, arylamine.But, not eco-friendly synthetic route because this building-up process still will be used the halide reagent of high risk such as more thionyl chloride, phosphorus oxychloride and high pollution.
Method four (Bioorganic ﹠amp; Medicinal Chemistry Letters, 2006,16 (15): 4102; WO2004024703) synthetic route is as follows:
This route is a raw material with 3 hydroxyls-4-methoxybenzaldehyde, through reduction condensation, oxidation, side chain alkoxylate, nitrated, reduction, close ring, obtain the 4-chloro-quinazoline through chloro, with 3-chloro-4-fluoroaniline affine replacement takes place again, altogether through eight synthetic Gefitinib of reaction.Though this route has passed through pilot scale, but still do not break away from the halide reagent of high-risk, high pollution, as the chlorine sulfoxide, the use of phosphorus oxychloride etc., and reactions steps is long, and total recovery is on the low side.
Method five (CN200810122242.2) synthetic route is as follows:
This route is a raw material with 3-hydroxyl-4-methoxybenzaldehyde; the intermediate that obtains reacting through reduction condensation, side chain alkoxylate; avoid the protection of hydroxyl and go to protect and the use of the halide reagent of high-risk, high pollution, reduced environmental pollution, simplified operation.
The most of 3-hydroxyl-4-methoxybenzaldehyde that adopts of the raw material of existing preparation Gefitinib can not substitute and there are other materials, has limited industrial production to a certain extent, and has improved the price of raw material.
(3) summary of the invention
The present invention is in order to remedy the deficiencies in the prior art, and amidine compound of a kind of simple to operate, brand-new prepared Gefitinib of being convenient to purify and preparation method thereof is provided.
The present invention is achieved through the following technical solutions:
A kind of amidine compound for preparing Gefitinib is characterized in that: the general structure of described amidine compound (I) is
R wherein
1For
(N-morpholine propoxy-), OH (hydroxyl),
(acetoxyl).
Amidine compound of the present invention by structure suc as formula the adjacent amino-benzene cyanogen derivative shown in (II) and structure suc as formula the 3-chloro-4-fluoroaniline shown in (III) at anhydrous AlCl
3Katalysis down reaction obtain.
Wherein, R
1For
The chemical equation of synthetic this amidine analog derivative is:
Be starting raw material and then obtain two kinds of methods that can prepare Gefitinib with the amidine compound for preparing, as follows.
Method one:
Method two:
Prepare the quinazoline ring yield height of Gefitinib by this amidine compound, generally can be at the yield more than 80%, purifying is simple relatively, and is workable.
(4) embodiment
The preparation of amidine compound
Embodiment 1:
With 3-chloro-4-fluoroaniline 0.5 mole (72.8g) and etc. move in the glass reaction container when the adjacent amino-benzene cyanogen derivative of molar weight; mix; the nitrogen atmosphere protection; be heated to 50 degree and begin fusing; be heated to the basic completely dissolve of 80～100 degree solids, the anhydrous AlCl of repeatedly a small amount of input under the agitation condition
3, after adding finishes, reaction mixture is heated to 180 degree kept 30 minutes, heating stops then, and reactant is reduced to room temperature, is added dropwise to cold 10% hydrochloric acid soln 200ml under ice-water bath cooling condition, reactant dissolves fully, with the sodium hydroxide solution of 2 mol concentration with this solution furnishing PH=6, with 100ml chloroform extraction 3 times, aqueous phase separation, sodium hydroxide solution alkalization with 2 mol concentration, there is the off-white color solid to separate out, filters, solid benzene and sherwood oil recrystallization.Yield 69～71%.
Embodiment 2:
With 3-chloro-4-fluoroaniline 0.5 mole (72.8g) and etc. move in the glass reaction container when the adjacent amino-benzene cyanogen derivative of molar weight, mix, the nitrogen atmosphere protection is heated to the basic completely dissolve of solid, drops into anhydrous AlCl repeatedly on a small quantity under the agitation condition
3, after adding finishes, reaction mixture is heated to 150 degree kept 50 minutes, stop heating then, reactant is reduced to room temperature, is added dropwise to cold 10% hydrochloric acid soln 200ml under ice-water bath cooling condition, reactant dissolves fully, with the sodium hydroxide solution of 2 mol concentration with this solution furnishing PH=6, with 100ml chloroform extraction 3 times, aqueous phase separation, sodium hydroxide solution alkalization with 2 mol concentration, there is the off-white color solid to separate out, filters recrystallization behind the solid drying.Yield is below 50%.
Embodiment 3: the preparation of Gefitinib
Get embodiment 1 operation products therefrom 0.15mol material, move in the 500ml there-necked flask, add 3 times of normal anhydrous formic acids, the dehydrated alcohol of 300ml, reflux 2.5 hours, cooling adds the 5g gac slightly, decolours heat filtering 20 minutes.Crystallization is waited in cooling, perhaps reaction soln is removed under reduced pressure, adds 650ml toluene, is heated to boiling 10 minutes, Rapid Thermal filter, filtrate naturally cooling crystallization.Yield 80～82%.
Claims (3)
1. amidine compound that can prepare Gefitinib, it is characterized in that: the general structure of described amidine compound (I) is
R wherein
1For
2. the preparation method who prepares the amidine compound of Gefitinib according to claim 1 is characterized in that: described amidine compound is reacted under the effect of catalyzer suc as formula the 3-chloro-4-fluoroaniline shown in (III) suc as formula the adjacent amino-benzene cyanogen derivative of the aromatic nucleus shown in (II) and structure by structure and obtains.
Wherein, R
1For
3. the preparation method who prepares the amidine compound of Gefitinib according to claim 2 is characterized in that: described catalyzer is anhydrous AlCl
3
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| CN200910017964A CN101638398A (en) | 2009-08-26 | 2009-08-26 | Amidine compound capable of preparing gefitinib and preparation method thereof |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102432553A (en) * | 2011-10-28 | 2012-05-02 | 云南维和控股有限公司 | Preparation method and intermediate of quinazoline derivative |
| US20160200688A1 (en) * | 2014-06-10 | 2016-07-14 | Scinopharm (Changeshu) Oharmaceuticals, Ltd. | Process of Preparing a Quinazoline Derivative |
| CN110577520A (en) * | 2018-06-11 | 2019-12-17 | 新发药业有限公司 | Preparation method of 6-nitro-4-substituted amino quinazoline derivative |
-
2009
- 2009-08-26 CN CN200910017964A patent/CN101638398A/en active Pending
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102432553A (en) * | 2011-10-28 | 2012-05-02 | 云南维和控股有限公司 | Preparation method and intermediate of quinazoline derivative |
| CN102432553B (en) * | 2011-10-28 | 2014-12-10 | 云南维和控股有限公司 | Preparation method and intermediate of quinazoline derivative |
| US20160200688A1 (en) * | 2014-06-10 | 2016-07-14 | Scinopharm (Changeshu) Oharmaceuticals, Ltd. | Process of Preparing a Quinazoline Derivative |
| KR20170013800A (en) * | 2014-06-10 | 2017-02-07 | 시노팜 (창수) 파마슈티컬즈, 리미티드 | Process of Preparing a Quinazoline Derivative |
| US9617227B2 (en) * | 2014-06-10 | 2017-04-11 | Scinopharm (Changshu) Pharmaceuticals, Ltd. | Process of preparing a quinazoline derivative |
| EP3154951A4 (en) * | 2014-06-10 | 2017-12-06 | Scinopharm (Changshu) Pharmaceuticals Ltd. | Process for preparing quinazoline derivative |
| KR102349981B1 (en) | 2014-06-10 | 2022-01-12 | 시노팜 (창수) 파마슈티컬즈, 리미티드 | Process of Preparing a Quinazoline Derivative |
| CN110577520A (en) * | 2018-06-11 | 2019-12-17 | 新发药业有限公司 | Preparation method of 6-nitro-4-substituted amino quinazoline derivative |
| CN110577520B (en) * | 2018-06-11 | 2020-12-01 | 新发药业有限公司 | Preparation method of 6-nitro-4-substituted amino quinazoline derivative |
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Application publication date: 20100203 |