CN103183678A - Preparation method for nevirapine - Google Patents
Preparation method for nevirapine Download PDFInfo
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- CN103183678A CN103183678A CN2011104476884A CN201110447688A CN103183678A CN 103183678 A CN103183678 A CN 103183678A CN 2011104476884 A CN2011104476884 A CN 2011104476884A CN 201110447688 A CN201110447688 A CN 201110447688A CN 103183678 A CN103183678 A CN 103183678A
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Abstract
The invention discloses a preparation method for nevirapine. The method comprises the following steps: 1) reacting 2-chloro-N-(2-chloro-4-methyl-3-pyridyl)-3-pyridinecarboxamide with cyclopropylamine in an organic solvent in the presence of alkylamine so as to obtain a reaction mixture containing 2-cyclopropylamino-N-(2-chloro-4-methyl-3-pyridyl)-3-pyridinecarboxamide; and 2) mixing the reaction mixture obtained in the step (1) with an ether solvent or with a mixed solvent of the ether solvent and an aromatic hydrocarbon solvent in the presence of a base and allowing 2-cyclopropylamino-N-(2-chloro-4-methyl-3-pyridyl)-3-pyridinecarboxamide to undergo a cyclization reaction so as to obtain a reaction mixture containing nevirapine. The method may further comprise a step of nevirapine purification. The method provided by the invention has mild reaction conditions and is easy to control; process operation of the method is simple and safe; and the product nevirapine has good yield and high purity.
Description
Technical field
The invention belongs to the pharmaceutical chemistry technical field, be specifically related to the preparation method of nevirapine.
Background technology
Nevirapine (nevirapine) is the sweet class reverse transcriptase inhibitors of the non-nuclear of HIV-1 (Non-Nucleoside Reverse Transcriptase Inhibitor, NNRTI), chemistry 11-cyclopropyl-5 by name, 11-dihydro-4-methyl-6H-two pyridos [3,2-b:2 ', 3 '-e] [1,4] diazepine-6-ketone, its structural formula is suc as formula shown in (I).
The preparation method of nevirapine, open in patent US 5,366,972 in early days, shown in flow process 1.
Flow process 1
The shortcoming of this technology maximum be compound shown in the formula (III) (2-chloro-N-(2-chloro-4-methyl-3-pyridyl)-3-pyridine carboxamide) with the substitution reaction of cyclopropylamine in the consumption excessive (nearly 4 times molar weight) of cyclopropylamine, be easy to generate as shown in the formula the by product shown in the compound shown in 3.
In the later stage, patent US 5,569, and 760 pairs of above-mentioned operational paths have been done improvement, added calcium oxide when compound and cyclopropylamine carry out substitution reaction shown in the formula (III), reduced the consumption of cyclopropylamine, reduced production of by-products.
But still there are many shortcomings in this technology, and for example, the reaction of compound and cyclopropylamine shown in (1) formula (III) finishes afterreaction liquid to be needed to filter, concentrate complicated operation; (2) the last two-step reaction of above-mentioned technology uses diethylene glycol dimethyl ether to make solvent, and the consumption of diethylene glycol dimethyl ether is big, and diethylene glycol dimethyl ether boiling point height reclaim difficulty, and price is more expensive, the production cost height; (3) above-mentioned technology final step reaction (ring-closure reaction) uses sodium hydride as alkali, and is well-known, and sodium hydride can spontaneous combustion in damp atmosphere, is heated or contact with moisture, acids and namely emit heat and cause with hydrogen and burn and explode.
Therefore, it is a kind of easy and simple to handle to press for exploitation, the preparation method of the nevirapine that production cost is low.
Summary of the invention
Purpose of the present invention provides a kind of easy and simple to handle, the nevirapine preparation method that production cost is low.
Another purpose of the present invention provides a kind of process for purification of nevirapine.
First aspect present invention provides a kind of method for preparing nevirapine, comprises the steps:
(1) in organic solvent, in the presence of alkylamine, 2-chloro-N-(2-chloro-4-methyl-3-pyridyl)-3-pyridine carboxamide and cyclopropylamine are reacted, thereby obtain containing the reaction mixture of 2-cyclopropyl amino-N-(2-chloro-4-methyl-3-pyridyl)-3-pyridine carboxamide;
(2) in the presence of alkali, the reaction mixture that step (1) is obtained mixes with the mixed solvent of aromatic hydrocarbon solvent with ether solvent or ether solvent, and make 2-cyclopropyl amino-N-(2-chloro-4-methyl-3-pyridyl)-3-pyridine carboxamide carry out ring-closure reaction, thereby obtain containing the reaction mixture of nevirapine.
In another preference, described mixing is the mixed solvent that the reaction mixture that step (1) obtains is added ether solvent or ether solvent and aromatic hydrocarbon solvent.
In another preference, between step (1) and (2), do not comprise the step that reaction mixture that step (1) is obtained filters.
In another preference, the organic solvent in the described step (1) is selected from down group: benzene, toluene, ethylbenzene, dimethylbenzene, methyl-phenoxide, tetrahydrofuran (THF), 2-methyltetrahydrofuran, N, dinethylformamide, N,N-dimethylacetamide, acetonitrile or its combination.
In another preference, the alkylamine in the described step (1) is selected from down group: triethylamine, diisopropylethylamine or its combination.
In another preference, described alkylamine is triethylamine.
In another preference, described ether solvent is selected from down group: diethylene glycol dimethyl ether, diethylene glycol diethyl ether, glycol dimethyl ether, ethylene glycol diethyl ether or its combination; And/or
Described aromatic hydrocarbon solvent is selected from toluene or dimethylbenzene.
In another preference, described ether solvent is diethylene glycol dimethyl ether.
In another preference, the alkali in the described step (2) is selected from down group: sodium amide, potassium tert.-butoxide, sodium tert-butoxide, sodium methylate, potassium methylate or its combination.
In another preference, described alkali is sodium amide or potassium tert.-butoxide.
In another preference, the mol ratio of described 2-chloro-N-(2-chloro-4-methyl-3-pyridyl)-3-pyridine carboxamide, alkylamine, cyclopropylamine and alkali is 1: 2～2.5: 2～2.5: 2～4.
In another preference, also comprise between described step (1) and (2): the reaction mixture of the described 2-of containing cyclopropyl amino-N-(2-chloro-4-methyl-3-pyridyl)-3-pyridine carboxamide is cooled to room temperature.
In another preference, comprise step:
(i) in toluene or dimethylbenzene, in the presence of the alkylamine of 2～2.5 equivalents, in 125～135 ℃, 2-chloro-N-(2-chloro-4-methyl-3-the pyridyl)-3-pyridine carboxamide of 1 equivalent and the cyclopropylamine of 2～2.5 equivalents are reacted 8～15 hours, thereby obtain containing the reaction mixture of 2-cyclopropyl amino-N-(2-chloro-4-methyl-3-pyridyl)-3-pyridine carboxamide;
(ii) in the presence of the sodium amide or potassium tert.-butoxide of 2～4 equivalents, under 100～115 ℃, the reaction mixture that step (1) is obtained adds the mixed solvent of diethylene glycol dimethyl ether or diethylene glycol dimethyl ether and toluene, and make 2-cyclopropyl amino-N-(2-chloro-4-methyl-3-pyridyl)-3-pyridine carboxamide carry out ring-closure reaction 2～5 hours, thereby obtain containing the reaction mixture of nevirapine.
In another preference, also comprise following post-processing step:
Separate out step: the reaction mixture that contains nevirapine is separated out processing, thereby separate out the crude product of nevirapine; With
Purification step: the crude product to described nevirapine carries out recrystallization, thereby obtains through refining nevirapine.
In another preference, described purification step comprises:
(a) in halohydrocarbon, with the processing of pulling an oar of the crude product of nevirapine, thereby obtain crude product through the nevirapine of making beating;
The crude product of the nevirapine through pulling an oar that (b) step (a) is obtained carries out recrystallization with pure water mixed solution, thereby obtains through refining nevirapine.
In another preference, the described step of separating out also comprises: the crude product of the separating out aqueous solution with glacial acetic acid is neutralized, filters, thereby obtain the nevirapine crude product.
In another preference, the HPLC purity of the nevirapine that described warp is refining is greater than 99%; Preferably greater than 99.5%.
In another preference, described halohydrocarbon is selected from down group: methylene dichloride, ethylene dichloride, trichloromethane, tetracol phenixin or its combination; It preferably is methylene dichloride.
In another preference, described alcohol is selected from down group: methyl alcohol, ethanol, Virahol or its combination; Preferably be ethanol.
Second aspect present invention provides a kind of process for purification of nevirapine, comprises step:
(a) in halohydrocarbon, with the processing of pulling an oar of nevirapine crude product, thereby obtain crude product through the nevirapine of making beating;
The crude product of the nevirapine through pulling an oar that (b) step (a) is obtained carries out recrystallization with pure water mixed solution, thereby obtains through refining nevirapine.
In another preference, the HPLC purity of the nevirapine that described warp is refining is greater than 99%; Preferably greater than 99.5%.
In another preference, described halohydrocarbon is selected from down group: methylene dichloride, ethylene dichloride, trichloromethane, tetracol phenixin or its combination; It preferably is methylene dichloride.
In another preference, described alcohol is selected from down group: methyl alcohol, ethanol, Virahol or its combination; Preferably be ethanol.
In another preference, comprise step:
(a) in methylene dichloride, under 30～40 ℃, with the processing (as 0.5～3 hour) of pulling an oar of nevirapine crude product, filter, thereby obtain crude product through the nevirapine of making beating;
(b) under 60～80 ℃, the crude product of nevirapine through making beating that step (a) is obtained is that 50～60% aqueous ethanolic solution carries out recrystallization with weight percent, thereby obtains the nevirapine through making with extra care.
In should be understood that within the scope of the present invention, above-mentioned each technical characterictic of the present invention and can making up mutually between specifically described each technical characterictic in below (eg embodiment), thus constitute new or optimized technical scheme.As space is limited, this tired stating no longer one by one.
Embodiment
The inventor is by long-term and deep research, be surprised to find that the preparation method of the nevirapine that a kind of operation is very easy, described method has adopted alkylamine as alkali, reaction finishes afterreaction liquid and need not to do any processing, just can directly carry out the reaction of subsequent step, whole process has been saved the complex process such as filtration between the step, operates very easyly, and has saved relevant cost.The method of the invention has reduced the usage quantity of high boiling solvent (as diethylene glycol dimethyl ether) simultaneously, has also correspondingly reduced the production cost of nevirapine.On this basis, the contriver has finished the present invention.
The preparation method
2-chloro-N-(2-chloro-4-methyl-3-pyridyl) but-3-pyridine carboxamide reference US 5,366,972 prepares, also can obtain by being familiar with the known mode of organic synthesis technology personnel.
The invention provides a kind of method of preferred preparation nevirapine, comprise step:
(1) in organic solvent, in the presence of alkylamine, in certain temperature (as 100-150 ℃, preferably be 125-135 ℃) under, 2-chloro-N-(2-chloro-4-methyl-3-pyridyl)-3-pyridine carboxamide (formula III compound) and cyclopropylamine are reacted for some time (as 3-25 hour, preferably 8～15 hours), thus obtain containing the reaction mixture of 2-cyclopropyl amino-N-(2-chloro-4-methyl-3-pyridyl)-3-pyridine carboxamide (compound shown in the formula II);
In another preference, described organic solvent can be selected from down group: benzene, toluene, ethylbenzene, dimethylbenzene, methyl-phenoxide, tetrahydrofuran (THF), 2-methyltetrahydrofuran, N, dinethylformamide, N,N-dimethylacetamide, acetonitrile or its combination.
In another preference, described alkylamine can be selected from down group: triethylamine, diisopropylethylamine or its combination, preferred triethylamine.
In another preference, described step (1) comprises that also the reaction mixture with the described 2-of containing cyclopropyl amino-N-(2-chloro-4-methyl-3-pyridyl)-3-pyridine carboxamide is cooled to room temperature.
(2) in the presence of alkali, the reaction mixture that step (1) is obtained mixes with the mixed solvent of aromatic hydrocarbon solvent with ether solvent or ether solvent, in certain temperature (as 80-130 ℃, preferably be 100-115 ℃) under, and 2-cyclopropyl amino-N-(2-chloro-4-methyl-3-pyridyl)-3-pyridine carboxamide is carried out ring-closure reaction for some time (as 30min-8 hour, preferably 2～5 hours), thus obtain containing the reaction mixture of nevirapine (compound shown in the formula I).
In another preference, described mixing is the mixed solvent that the reaction mixture that step (1) obtains is added ether solvent or ether solvent and aromatic hydrocarbon solvent.
In another preference, described ether solvent can be selected from down group: diethylene glycol dimethyl ether, diethylene glycol diethyl ether, glycol dimethyl ether, ethylene glycol diethyl ether or its combination, preferred diethylene glycol dimethyl ether.
Described aromatic hydrocarbon solvent is selected from toluene or dimethylbenzene.
In another preference, described alkali can be sodium amide, potassium tert.-butoxide, sodium tert-butoxide, sodium methylate, potassium methylate etc., preferred sodium amide or potassium tert.-butoxide.
In another preference, in described step (1) and the step (2), the mol ratio of 2-chloro-N-(2-chloro-4-methyl-3-pyridyl)-3-pyridine carboxamide, alkylamine, cyclopropylamine, alkali is 1: 2～2.5: 2～2.5: 2～4.
Preferably prepare the method for nevirapine, comprise step:
(i) in toluene or dimethylbenzene, in the presence of the alkylamine of 2～2.5 equivalents, in 125～135 ℃, 2-chloro-N-(2-chloro-4-methyl-3-the pyridyl)-3-pyridine carboxamide of 1 equivalent and the cyclopropylamine of 2～2.5 equivalents are reacted 8～15 hours, thereby obtain containing the reaction mixture of 2-cyclopropyl amino-N-(2-chloro-4-methyl-3-pyridyl)-3-pyridine carboxamide;
(ii) in the presence of the sodium amide or potassium tert.-butoxide of 2～4 equivalents, under 100～115 ℃, the reaction mixture that step (1) is obtained adds the mixed solvent of diethylene glycol dimethyl ether or diethylene glycol dimethyl ether and toluene, and make 2-cyclopropyl amino-N-(2-chloro-4-methyl-3-pyridyl)-3-pyridine carboxamide carry out ring-closure reaction 2～5 hours, thereby obtain containing the reaction mixture of nevirapine.
The method for preparing nevirapine can also comprise following post-processing step:
Separate out step:
The reaction mixture that contains nevirapine is separated out processing, thereby separate out the crude product of nevirapine;
In another preference, the described step of separating out also comprises: the crude product of the separating out aqueous solution with glacial acetic acid is neutralized, filters, thereby obtain the nevirapine crude product.
Purification step
Crude product to described nevirapine carries out recrystallization, thereby obtains through refining nevirapine.
In another preference, described purification step comprises:
(a) in halohydrocarbon, under certain temperature (as the halohydrocarbon reflux temperature), the nevirapine crude product pulled an oar handle for some time (as 0.5～3 hour, preferably 0.5～2 hour), thereby obtain the crude product through the nevirapine of making beating;
In another preference, described halohydrocarbon is selected from down group: methylene dichloride, ethylene dichloride, trichloromethane, tetracol phenixin or its combination; It preferably is methylene dichloride.
The crude product of the nevirapine through pulling an oar that (b) step (a) is obtained carries out recrystallization with pure water mixed solution, thereby obtains through refining nevirapine.
In another preference, described alcohol is selected from down group: methyl alcohol, ethanol, Virahol or its combination; Preferably be ethanol.
In another preference, described pure water mixed solution is that pure content is the aqueous solution of 35-80wt%, is preferably the aqueous solution that pure content is 45-70wt%.
Preferably make with extra care the method for nevirapine, comprise step:
(a) in methylene dichloride, under 30～40 ℃, the nevirapine crude product was pulled an oar processing after 0.5～2 hour, be cooled to 0-20 ℃, the continuation stirring was filtered after 0.5～2 hour, thereby obtained the crude product through the nevirapine of making beating;
(b) under 60～80 ℃, the crude product of nevirapine through making beating that step (a) is obtained is that 50～60% aqueous ethanolic solution carries out recrystallization with weight percent, thereby obtains the nevirapine through making with extra care.
The HPLC purity of the nevirapine that the warp that the method for the invention obtains is refining is greater than 99%; Preferably greater than 99.5%.
Major advantage of the present invention has:
(1) preparation method's reaction conditions gentleness of the present invention, easy to control, technological operation is simple, safety, and Financial cost is low.
(2) the nevirapine molar yield height (can reach 84% or higher) of the method for the invention preparation, the nevirapine purity height that makes, impurity is few, and single impurity meets the American Pharmacopeia requirement all less than 0.1%.
Below in conjunction with concrete enforcement, further set forth the present invention.Should be understood that these embodiment only to be used for explanation the present invention and be not used in and limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example, usually according to normal condition, or the condition of advising according to manufacturer.Unless otherwise indicated, otherwise per-cent and umber calculate by weight.
Embodiment 1
Add toluene 200ml in autoclave pressure, (100.0g, 0.35mol), (100ml, 0.72mol), (51.0ml 0.74mol), opens and stirs cyclopropylamine triethylamine 2-chloro-N-(2-chloro-4-methyl-3-pyridyl)-3-pyridine carboxamide.Slowly be warming up to 130 ℃, insulation reaction 10 hours.Sampling is closed stirring after detecting surplus stock＜2%, and water of condensation feeds in the still and makes temperature be reduced to room temperature, obtains containing the reaction mixture of 2-cyclopropyl amino-N-(2-chloro-4-methyl-3-pyridyl)-3-pyridine carboxamide.
Open autoclave pressure, above-mentioned mixed solution is poured in the reaction flask, add diethylene glycol dimethyl ether 100ml, stir, be cooled to 15 ℃, and the adding sodium amide (44.0g, 1.13mol), insulated and stirred 10 minutes.Heating slowly is warming up to 110 ℃, insulation reaction 2 hours.After TLC detection raw material reaction is intact, pressure reducing and steaming toluene.Residue cools to 20 ℃, drips water 500ml, separates out faint yellow solid gradually.The aqueous solution of Dropwise 5 0% glacial acetic acid under ice-water bath is neutralized to pH 7-7.5 again, restir half an hour.Suction filtration with 50ml water washing filter cake, dries the crude product that obtains nevirapine naturally.
In above-mentioned crude product, add methylene dichloride 200ml, be warming up to backflow, pull an oar 1 hour, be cooled to 5 ℃, suction filtration after stirring half an hour.The aqueous ethanolic solution 1000ml that adds 55% weight percent in the filter cake, be warming up to backflow, stir half an hour, the solid dissolving, activated carbon decolorizing, suction filtration while hot, about 500 milliliters to volume of filtrate air distillations, freezing 1 hour of frozen water, suction filtration, the nevirapine 80.2g that obtains making with extra care, yield 86%, HPLC detects purity 99.8%.
Embodiment 2
Add toluene 50ml in autoclave pressure, (10.0g, 0.035mol), (12.0ml, 0.086mol), (5.0ml 0.072mol), opens and stirs cyclopropylamine triethylamine 2-chloro-N-(2-chloro-4-methyl-3-pyridyl)-3-pyridine carboxamide.Slowly be warming up to 135 ℃, insulation reaction 13 hours.Sampling is closed stirring after detecting surplus stock＜2%, and water of condensation feeds in the still and makes temperature be reduced to room temperature, obtains containing the reaction mixture of 2-cyclopropyl amino-N-(2-chloro-4-methyl-3-pyridyl)-3-pyridine carboxamide.
Open autoclave pressure, above-mentioned mixed solution is poured in the reaction flask, add diethylene glycol dimethyl ether 15ml, stir, be cooled to 5 ℃, and the adding potassium tert.-butoxide (10.0g, 0.089mol), insulated and stirred 15 minutes.Heating slowly is warming up to 100 ℃, insulation reaction 3 hours.After TLC detection raw material reaction is intact, pressure reducing and steaming toluene.Residue cools to 20 ℃, drips water 60ml, separates out faint yellow solid gradually.The aqueous solution of Dropwise 5 0% glacial acetic acid under ice-water bath is neutralized to pH 7-7.5 again, restir half an hour.Suction filtration with 10ml water washing filter cake, dries the crude product that obtains nevirapine naturally.
In above-mentioned crude product, add methylene dichloride 30ml, be warming up to backflow, pull an oar half an hour, be cooled to 0 ℃, stir suction filtration after 1 hour.The aqueous ethanolic solution 100ml that adds 50% weight percent in the filter cake, be warming up to backflow, stir half an hour, solid dissolving, activated carbon decolorizing, suction filtration while hot, about 50 milliliters to volume of filtrate air distillations, freezing 2 hours of frozen water, the nevirapine 8.3g that suction filtration obtains making with extra care, yield 89%, HPLC detects purity 99.5%.
Embodiment 3
Add dimethylbenzene 40ml in autoclave pressure, (10.0g, 0.035mol), (12.5ml, 0.072mol), (6.0ml 0.087mol), opens and stirs cyclopropylamine diisopropylethylamine 2-chloro-N-(2-chloro-4-methyl-3-pyridyl)-3-pyridine carboxamide.Slowly be warming up to 125 ℃, insulation reaction 8 hours.Sampling is closed stirring after detecting surplus stock＜2%, and water of condensation feeds in the still and makes temperature be reduced to room temperature, obtains containing the reaction mixture of 2-cyclopropyl amino-N-(2-chloro-4-methyl-3-pyridyl)-3-pyridine carboxamide.
Open autoclave pressure, above-mentioned mixed solution is poured in the reaction flask, add diethylene glycol dimethyl ether 20ml, stir, be cooled to 10 ℃, and the adding sodium methylate (7.5g, 0.14mol), insulated and stirred 15 minutes.Heating slowly is warming up to 115 ℃, insulation reaction 5 hours.After TLC detection raw material reaction is intact, pressure reducing and steaming dimethylbenzene.Residue cools to 20 ℃, drips water 60ml, separates out faint yellow solid gradually.Under ice-water bath, drip the aqueous solution of 60% glacial acetic acid again, be neutralized to pH 7-7.5, restir half an hour.Suction filtration with 15ml water washing filter cake, dries the crude product that obtains nevirapine naturally.
In above-mentioned crude product, add methylene dichloride 30ml, be warming up to backflow, pulled an oar 2 hours, be cooled to 10 ℃, stir suction filtration after 2 hours.The aqueous ethanolic solution 80ml that adds 60% weight percent in the filter cake, be warming up to backflow, stir half an hour, solid dissolving, activated carbon decolorizing, suction filtration while hot, about 40 milliliters to volume of filtrate air distillations, freezing 2 hours of frozen water, the nevirapine 7.8g that suction filtration obtains making with extra care, yield 84%, HPLC detects purity 99.5%.
Embodiment 4
Add toluene 60ml in autoclave pressure, (10.0g, 0.035mol), (10.0ml, 0.072mol), (5.0ml 0.072mol), opens and stirs cyclopropylamine triethylamine 2-chloro-N-(2-chloro-4-methyl-3-pyridyl)-3-pyridine carboxamide.Slowly be warming up to 135 ℃, insulation reaction 15 hours.Sampling is closed stirring after detecting surplus stock＜2%, and water of condensation feeds in the still and makes temperature be reduced to room temperature, obtains containing the reaction mixture of 2-cyclopropyl amino-N-(2-chloro-4-methyl-3-pyridyl)-3-pyridine carboxamide.
Open autoclave pressure, above-mentioned mixed solution is poured in the reaction flask, add diethylene glycol dimethyl ether 15ml, stir, be cooled to 5 ℃, and the adding sodium amide (4.0g, 0.10mol), insulated and stirred 15 minutes.Heating slowly is warming up to 110 ℃, insulation reaction 2 hours.After TLC detection raw material reaction is intact, pressure reducing and steaming toluene.Residue cools to 20 ℃, drips water 50ml, separates out faint yellow solid gradually.The aqueous solution of Dropwise 5 0% glacial acetic acid under ice-water bath is neutralized to pH 7-7.5 again, restir half an hour.Suction filtration with 10ml water washing filter cake, dries the crude product that obtains nevirapine naturally.
In above-mentioned crude product, add trichloromethane 30ml, be warming up to 50 ℃, pull an oar half an hour, be cooled to 0 ℃, stir suction filtration after 1 hour.The aqueous ethanolic solution 120ml that in filter cake, adds 45% weight percent, be warming up to backflow, stir half an hour, solid dissolving, activated carbon decolorizing, suction filtration while hot, about 50 milliliters to volume of filtrate air distillations, freezing 2 hours of frozen water, the nevirapine 8.1g that suction filtration obtains making with extra care, yield 87%, HPLC detects purity 99.2%.
Embodiment 5
Add toluene 50ml in autoclave pressure, (10.0g, 0.035mol), (10.0ml, 0.072mol), (6.0ml 0.087mol), opens and stirs cyclopropylamine triethylamine 2-chloro-N-(2-chloro-4-methyl-3-pyridyl)-3-pyridine carboxamide.Slowly be warming up to 125 ℃, insulation reaction 8 hours.Sampling is closed stirring after detecting surplus stock＜2%, and water of condensation feeds in the still and makes temperature be reduced to room temperature, obtains containing the reaction mixture of 2-cyclopropyl amino-N-(2-chloro-4-methyl-3-pyridyl)-3-pyridine carboxamide.
Open autoclave pressure, above-mentioned mixed solution is poured in the reaction flask, add diethylene glycol dimethyl ether 20ml, stir, be cooled to 5 ℃, and the adding sodium tert-butoxide (10.0g, 0.10mol), insulated and stirred 15 minutes.Heating slowly is warming up to 115 ℃, insulation reaction 3 hours.After TLC detection raw material reaction is intact, pressure reducing and steaming toluene.Residue cools to 20 ℃, drips water 60ml, separates out faint yellow solid gradually.The aqueous solution of Dropwise 5 0% glacial acetic acid under ice-water bath is neutralized to pH 7-7.5 again, restir half an hour.Suction filtration with 10ml water washing filter cake, dries the crude product that obtains nevirapine naturally.
In above-mentioned crude product, add methylene dichloride 30ml, be warming up to backflow, pull an oar half an hour, be cooled to 0 ℃, stir suction filtration after 1 hour.The aqueous ethanolic solution 90ml that adds 65% weight percent in the filter cake, be warming up to backflow, stir half an hour, solid dissolving, activated carbon decolorizing, suction filtration while hot, about 50 milliliters to volume of filtrate air distillations, freezing 2 hours of frozen water, the nevirapine 8.0g that suction filtration obtains making with extra care, yield 86%, HPLC detects purity 99.3%.
Embodiment 6
Add toluene 50ml in autoclave pressure, (10.0g, 0.035mol), (10.0ml, 0.072mol), (5.5ml 0.080mol), opens and stirs cyclopropylamine triethylamine 2-chloro-N-(2-chloro-4-methyl-3-pyridyl)-3-pyridine carboxamide.Slowly be warming up to 130 ℃, insulation reaction 11 hours.Sampling is closed stirring after detecting surplus stock＜2%, and water of condensation feeds in the still and makes temperature be reduced to room temperature, obtains containing the reaction mixture of 2-cyclopropyl amino-N-(2-chloro-4-methyl-3-pyridyl)-3-pyridine carboxamide.
Open autoclave pressure, above-mentioned mixed solution is poured in the reaction flask, add diethylene glycol dimethyl ether 20ml, stir, be cooled to 5 ℃, and the adding potassium methylate (8.0g, 0.11mol), insulated and stirred 15 minutes.Heating slowly is warming up to 115 ℃, insulation reaction 4 hours.After TLC detection raw material reaction is intact, pressure reducing and steaming toluene.Residue cools to 20 ℃, drips water 60ml, separates out faint yellow solid gradually.The aqueous solution of Dropwise 5 0% glacial acetic acid under ice-water bath is neutralized to pH 7-7.5 again, restir half an hour.Suction filtration with 10ml water washing filter cake, dries the crude product that obtains nevirapine naturally.
In above-mentioned crude product, add methylene dichloride 30ml, be warming up to backflow, pull an oar half an hour, be cooled to 0 ℃, stir suction filtration after 1 hour.The aqueous ethanolic solution 100ml that adds 55% weight percent in the filter cake, be warming up to backflow, stir half an hour, solid dissolving, activated carbon decolorizing, suction filtration while hot, about 50 milliliters to volume of filtrate air distillations, freezing 2 hours of frozen water, the nevirapine 7.9g that suction filtration obtains making with extra care, yield 85%, HPLC detects purity 99.1%.
Reference examples 1
Add toluene 50ml in autoclave pressure, (10.0g, 0.035mol), (10.0ml, 0.072mol), (5.1ml 0.074mol), opens and stirs cyclopropylamine triethylamine 2-chloro-N-(2-chloro-4-methyl-3-pyridyl)-3-pyridine carboxamide.Slowly be warming up to 130 ℃, insulation reaction 10 hours.Sampling is closed stirring after detecting surplus stock＜2%, and water of condensation feeds in the still and makes temperature be reduced to room temperature, obtains containing the reaction mixture of 2-cyclopropyl amino-N-(2-chloro-4-methyl-3-pyridyl)-3-pyridine carboxamide.
Open autoclave pressure, above-mentioned mixed solution is poured in the reaction flask, add toluene 50ml, stir, be cooled to 5 ℃, and the adding sodium amide (4.4g, 0.11mol), insulated and stirred 15 minutes.Heating slowly is warming up to 115 ℃, insulation reaction 8 hours.Pressure reducing and steaming toluene.Residue cools to 20 ℃, drips water 50ml, separates out pale brown look solid gradually.The aqueous solution of Dropwise 5 0% glacial acetic acid under ice-water bath is neutralized to pH 7-7.5 again, restir half an hour.Suction filtration with 10ml water washing filter cake, dries the crude product that obtains nevirapine naturally.
In above-mentioned crude product, add methylene dichloride 30ml, be warming up to backflow, pulled an oar 1 hour, be cooled to 5 ℃, stir suction filtration after 1 hour.The aqueous ethanolic solution 100ml that adds 75% weight percent in the filter cake, be warming up to backflow, stir half an hour, solid dissolving, activated carbon decolorizing, suction filtration while hot, about 50 milliliters to volume of filtrate air distillations, freezing 2 hours of frozen water, the nevirapine 6.5g that suction filtration obtains making with extra care, yield 70%, HPLC detects purity 93.6%.
Compare as can be known with reference examples, the nevirapine molar yield for preparing with the method for the invention significantly improves (can reach 84% or higher), purity is also obviously improved (HPLC detects purity and all surpassed 99%), and the nevirapine that makes meets the American Pharmacopeia requirement.
All quote in this application as a reference at all documents that the present invention mentions, just quoted as a reference separately as each piece document.Should be understood that in addition those skilled in the art can make various changes or modifications the present invention after having read above-mentioned teachings of the present invention, these equivalent form of values fall within the application's appended claims institute restricted portion equally.
Claims (10)
1. a method for preparing nevirapine is characterized in that, comprises the steps:
(1) in organic solvent, in the presence of alkylamine, 2-chloro-N-(2-chloro-4-methyl-3-pyridyl)-3-pyridine carboxamide and cyclopropylamine are reacted, thereby obtain containing the reaction mixture of 2-cyclopropyl amino-N-(2-chloro-4-methyl-3-pyridyl)-3-pyridine carboxamide;
(2) in the presence of alkali, the reaction mixture that step (1) is obtained mixes with the mixed solvent of aromatic hydrocarbon solvent with ether solvent or ether solvent, and make 2-cyclopropyl amino-N-(2-chloro-4-methyl-3-pyridyl)-3-pyridine carboxamide carry out ring-closure reaction, thereby obtain containing the reaction mixture of nevirapine.
2. the method for claim 1, it is characterized in that, organic solvent in the described step (1) is selected from down group: benzene, toluene, ethylbenzene, dimethylbenzene, methyl-phenoxide, tetrahydrofuran (THF), 2-methyltetrahydrofuran, N, dinethylformamide, N,N-dimethylacetamide, acetonitrile or its combination.
3. the method for claim 1 is characterized in that, the alkylamine in the described step (1) is selected from down group: triethylamine, diisopropylethylamine or its combination.
4. the method for claim 1 is characterized in that, described ether solvent is selected from down group: diethylene glycol dimethyl ether, diethylene glycol diethyl ether, glycol dimethyl ether, ethylene glycol diethyl ether or its combination; And/or
Described aromatic hydrocarbon solvent is selected from toluene or dimethylbenzene.
5. the method for claim 1 is characterized in that, the alkali in the described step (2) is selected from down group:
Sodium amide, potassium tert.-butoxide, sodium tert-butoxide, sodium methylate, potassium methylate or its combination.
6. the method for claim 1 is characterized in that, the mol ratio of described 2-chloro-N-(2-chloro-4-methyl-3-pyridyl)-3-pyridine carboxamide, alkylamine, cyclopropylamine and alkali is 1: 2～2.5: 2～2.5: 2～4.
7. as arbitrary described method in the claim 1～6, it is characterized in that, comprise step:
(i) in toluene or dimethylbenzene, in the presence of the alkylamine of 2～2.5 equivalents, in 125～135 ℃, 2-chloro-N-(2-chloro-4-methyl-3-the pyridyl)-3-pyridine carboxamide of 1 equivalent and the cyclopropylamine of 2～2.5 equivalents are reacted 8～15 hours, thereby obtain containing the reaction mixture of 2-cyclopropyl amino-N-(2-chloro-4-methyl-3-pyridyl)-3-pyridine carboxamide;
(ii) in the presence of the sodium amide or potassium tert.-butoxide of 2～4 equivalents, under 100～115 ℃, the reaction mixture that step (1) is obtained adds the mixed solvent of diethylene glycol dimethyl ether or diethylene glycol dimethyl ether and toluene, and make 2-cyclopropyl amino-N-(2-chloro-4-methyl-3-pyridyl)-3-pyridine carboxamide carry out ring-closure reaction 2～5 hours, thereby obtain containing the reaction mixture of nevirapine.
8. the method for claim 1 is characterized in that, also comprises following post-processing step:
Separate out step: the reaction mixture that contains nevirapine is separated out processing, thereby separate out the crude product of nevirapine; With
Purification step: the crude product to described nevirapine carries out recrystallization, thereby obtains through refining nevirapine.
9. the process for purification of a nevirapine is characterized in that, comprises step:
(a) in halohydrocarbon, with the processing of pulling an oar of nevirapine crude product, thereby obtain crude product through the nevirapine of making beating;
The crude product of the nevirapine through pulling an oar that (b) step (a) is obtained carries out recrystallization with pure water mixed solution, thereby obtains through refining nevirapine.
10. process for purification as claimed in claim 9 is characterized in that, comprises step:
(a) in methylene dichloride, under 30～40 ℃, with the processing (as 0.5～3 hour) of pulling an oar of nevirapine crude product, filter, thereby obtain crude product through the nevirapine of making beating;
(b) under 60～80 ℃, the crude product of nevirapine through making beating that step (a) is obtained is that 50～60% aqueous ethanolic solution carries out recrystallization with weight percent, thereby obtains the nevirapine through making with extra care.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5366972A (en) * | 1989-04-20 | 1994-11-22 | Boehringer Ingelheim Pharmaceuticals, Inc. | 5,11-dihydro-6H-dipyrido(3,2-B:2',3'-E)(1,4)diazepines and their use in the prevention or treatment of HIV infection |
| US5569760A (en) * | 1994-02-03 | 1996-10-29 | Boehringer Ingelheim Kg | Process for preparing nevirapine |
-
2011
- 2011-12-28 CN CN201110447688.4A patent/CN103183678B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5366972A (en) * | 1989-04-20 | 1994-11-22 | Boehringer Ingelheim Pharmaceuticals, Inc. | 5,11-dihydro-6H-dipyrido(3,2-B:2',3'-E)(1,4)diazepines and their use in the prevention or treatment of HIV infection |
| US5569760A (en) * | 1994-02-03 | 1996-10-29 | Boehringer Ingelheim Kg | Process for preparing nevirapine |
Non-Patent Citations (2)
| Title |
|---|
| NICOLE STIEGER 等: "Influence of the Composition of Water/Ethanol Mixtures on the Solubility and Recrystallization of Nevirapine", 《CRYSTAL GROWTH & DESIGN》 * |
| 姜芳 等: "奈韦拉平的合成工艺", 《中国药科大学学报》 * |
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