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A technology of gefitinib and compounds, which is applied in the field of innovative drug preparation, can solve the problems of chlorination pollution, long total route, etc., and achieve the effects of low environmental pollution, simple post-processing, safe, reliable and stable product quality
Inactive Publication Date: 2013-09-18
LIANYUNGANG SHENGHE BIOTECH
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[0008] This route undergoes reactions such as hydrocarbylation, nitration, reduction, ring closure, and chlorination. The total route is long and far from expensive, and the chlorination process is polluted.
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Embodiment 1
[0033] Embodiment 1, a kind of preparation method of gefitinib, this method comprises the steps:
[0034] (1) Using 3-hydroxy-4-methoxybenzocyanide and 4-(3-chloropropyl)morpholine as raw materials, react under the action of an appropriate solvent and base to prepare compound 1, namely 4-(3- Chloro-4-fluorophenylamino)-7-methoxy-6-[3-(4-morpholinyl)propoxy]quinazoline;
[0035] (2) Compound 1 was nitrated to obtain compound 2, methyl 2-nitro-4-methoxy-5-[3-(4-morpholinyl)propoxy]benzoate;
[0036] (3) Compound 2 was reduced to obtain compound 3, namely methyl 2-amino-4-methoxy-5-[3-(4-morpholinyl)propoxy]benzoate;
[0037] (4) React 3-chloro-4-fluoroaniline with N,N-dimethylformamide dimethyl acetal to obtain compound 4, namely (3-chloro-4-fluorophenyl)-N,N-dimethyl dimethylimine;
[0038] (5) Ring closure of compound 3 and compound 4 in a solvent to obtain gefitinib.
Embodiment 2
[0039] Example 2, the preparation method of gefitinib described in Example 1, in step (1): the reaction solvent is selected from dimethyl sulfoxide, dimethylformamide, dimethylacetamide, toluene and dimethicone One or more mixtures of toluene; the base is an inorganic base or an organic base, wherein: the inorganic base is selected from sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate; The base is one or a mixture of trimethylamine, triethylamine, tripropylamine and tri-n-butylamine.
Embodiment 3
[0040] Embodiment 3, the preparation method of gefitinib described in embodiment 1 or 2, in step (2): the mass fraction of nitric acid is 50%-85%; The reaction time is 1-24 hours, and the reaction temperature is 0 -80°C.
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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 [0001] The invention relates to a method for synthesizing anticancer drugs, in particular to a method for preparing gefitinib, and belongs to the technical field of innovative drug preparation. Background technique [0002] Gefitinib is an orally available small molecule inhibitor of EGFR tyrosine kinase developed by Astra Zeneca. In 2002, it was first launched in Japan for the treatment of inoperable or recurrent non-small cell lung cancer. In May 2003, it was approved in the United States and Australia as a third-line monotherapy for advanced non-small cell lung cancer. It is the first treatment for solid cancer Small molecule tyrosinase inhibitors targeting specific targets. Approved by the State Food and Drug Administration on February 25, 2005, it was officially launched in China for the treatment of locally advanced or metastatic non-small cell lung cancer who have previously received chemotherapy. [0003] The current technology of gefitinib mainly i...
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