CN102127077A - Method for preparing nevirapine - Google Patents
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- CN102127077A CN102127077A CN 201010611305 CN201010611305A CN102127077A CN 102127077 A CN102127077 A CN 102127077A CN 201010611305 CN201010611305 CN 201010611305 CN 201010611305 A CN201010611305 A CN 201010611305A CN 102127077 A CN102127077 A CN 102127077A
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Abstract
The invention discloses a method for preparing nevirapine, which comprises the steps of: A. enabling 2-chlorine-3 picolinic acid shown in the structural formula (II) and carbonyl diimidazole to react to produce active amide; B. enabling the active amide produced in the step A to react with 2, 6- dichloro-3-amino-4-methylpyridine shown in the structural formula (I), and producing N-(2, 6-dichloro-4-methyl-3-pyridyl)-2-chlorine niacinamide; C. carrying out nucleophilic substitution reaction on the N-(2, 6-dichloro-4-methyl-3-pyridyl)-2-chlorine niacinamide obtained in the step B and cyclopropylamine, then carrying out cyclization on the obtained products to obtain 2-chloro nevirapine with structure shown in the formula (III); and D. under the presence of catalyst, carrying out hydrogenation reaction on the 2-chloro nevirapine with structure shown in the formula (III) in the step C and non-hydrogen hydrogen source, to obtain the nevirapine with structure shown in the formula (IV). The invention aims at providing a method for preparing the nevirapine, which is low in cost, environment-friendly, higher in safety and suitable for production.
Description
Technical field
The present invention relates to a kind of method for preparing nevirapine.
Background technology
Nevirapine (Nevirapine) is the non-nucleosidic inhibitors of HIV ThermoScript II, and it is used for the treatment of human infection HIV.Chemical name is a 11-cyclopropyl-5, and 11-dihydro-4-methyl-6H-pyridyl [3,2-b:2 ', 3 '-e] [1,4] diazepine-6-ketone is by the research and development of German BoehringerIngelheim company, in September, 1996 drugs approved by FDA listing, commodity are called Viramune, now in multinational listing.
This product can near the combination catalytic site of enzyme, and directly effect and reversed transcriptive enzyme suppress its activity, suppresses HIV and duplicates the clinical being transmitted from a mother to her unborn child that is used to suppress acquired immune deficiency syndrome (AIDS).Nowadays, in the prescription to AIDS patient's drug cocktail therapy (treatment), all contain nevirapine, annual market demands are huge.
The nevirapine synthetic route of report mainly contains two at present: route one is a starting raw material elder generation Synthetic 2 with 3-oxo-butanic acid ethyl ester and malonamide nitrile, 6-two chloro-3-cyano group-4-picolines, resynthesis 2-chloro-3-amino-4-picoline, synthetic at last nevirapine.Route two also is to be starting raw material elder generation Synthetic 2 with 3-oxo-butanic acid ethyl ester and malonamide nitrile, 6-two chloro-3-cyano group-4-picolines, Synthetic 2 then, 6-two chloro-3-amino-4-picolines, synthetic at last nevirapine.From 2, the yield of 6-two chloro-3-cyano group-reactions that the 4-picoline begins calculates to these two lines, and the total recovery of route two is much higher than the total recovery of route one, and domesticly bought 2 easily, 6-two chloro-3-cyano group-4-picolines, comprehensive all factors, route two costs are lower.
No matter route one still is a route two, becomes the reaction of acid amides all to select chloride method.As U.S. Pat 5366972, US5569760 and J.Heterocyclic Chem.32,259 (1995) etc. describe, and as chlorizating agent, generate 2-chloronicotinoyl chloride with the reaction of 2-chlorine apellagrin with thionyl chloride.Secondly, 2-chloronicotinoyl chloride and 2-chloro-3-amino-4-picoline or 2,6-two chloro-3-amino-4-picoline reaction obtains corresponding amide.All there is significant disadvantages in these methods, and are longer as the reaction times, generally want more than 10 hours; And the tail gas that produces particularly sulfurous gas is serious to atmospheric pollution, need factory building that air washer is housed, thereby increase production cost.
In the route two, Grozinger etc. are at J.Heterocyclic Chem.32, and 259 (1995) have described 2-chloro nevirapine obtains nevirapine through the hydrogenation dechlorination.There is significant disadvantages in this method, as in autoclave, feeds hydrogen, reacts under 50 ℃, the condition of 50atm, has certain danger aborning, and yield has only 73%, and the hydrogenation dechlorination efficiency is lower.
Summary of the invention
The objective of the invention is in order to overcome weak point of the prior art, provide a kind of with low cost, environmental friendliness, security higher, be fit to a kind of method for preparing nevirapine of producing.
In order to achieve the above object, the present invention adopts following scheme:
A kind of method for preparing nevirapine of the present invention, see following formula for details:
Specifically may further comprise the steps:
A, structure is generated active amide suc as formula the reaction of 2-chloro-3 pyridine carboxylic acids shown in (II) and phosphinylidyne diimidazole;
B, with the active amide that generates in the steps A and structure suc as formula 2 shown in (I), 6-two chloro-3-amino-4-picoline reaction generates N-(2,6-two chloro-4-methyl-3-pyridyl)-2-chloro-nicotinamide;
The N-of C, step B gained (2,6-two chloro-4-methyl-3-pyridyl)-2-chloro-nicotinamide and cyclopropylamine carry out nucleophilic substitution reaction, and the product that obtains carries out cyclization again and obtains the 2-chloro nevirapine of structure shown in (III);
The 2-chloro nevirapine of structure shown in (III) with non-hydrogen hydrogen source generation hydrogenation, obtains the nevirapine of structure shown in (IV) among D, the step C under catalyst action;
Aforesaid a kind of method for preparing nevirapine is characterized in that the mol ratio of reactant in the steps A is: 2-chloro-3 pyridine carboxylic acids: phosphinylidyne diimidazole=1.0: 1.0～1.6; Temperature of reaction is-20 ℃～-30 ℃.
Aforesaid a kind of method for preparing nevirapine, it is characterized in that 2-chloro-3 pyridine carboxylic acids and being reflected in the reaction solvent of phosphinylidyne diimidazole described in the steps A take place, described reaction solvent is from anhydrous methylene dichloride, chloroform, ethylene dichloride, benzene, toluene, ethylbenzene, dimethylbenzene, N, a kind of or both above mixtures in dinethylformamide, N,N-dimethylacetamide or the N-Methyl pyrrolidone.
Aforesaid a kind of method for preparing nevirapine is characterized in that the mol ratio of reactant among the step B is: 2, and 6-two chloro-3-amino-4-picolines: 2-chloro-3 pyridine carboxylic acids=1.0: 1.0～1.4, temperature of reaction are-15 ℃～-25 ℃.
Aforesaid a kind of method for preparing nevirapine, it is characterized in that the active amide described in the step B with shown in 2,6-two chloro-3-amino-4-picolines are reflected in the reaction solvent and take place, described reaction solvent is anhydrous methylene dichloride, chloroform, ethylene dichloride, benzene, toluene, ethylbenzene, dimethylbenzene, N, the mixture of one or more in dinethylformamide, N,N-dimethylacetamide or the N-Methyl pyrrolidone.
Aforesaid a kind of method for preparing nevirapine is characterized in that the catalyzer described in the step D is 5%Pd/C or 10%Pd/C, and catalyst levels with respect to 2-chloro nevirapine is: 5%～20%mol.
Aforesaid a kind of method for preparing nevirapine is characterized in that a kind of in alkaline earth salt, ammonium formiate or the hydrazine of an alkali metal salt that the non-hydrogen hydrogen source described in the step D is formic acid, formic acid, formic acid.
Aforesaid a kind of method for preparing nevirapine, it is characterized in that being reflected in the reaction solvent described in the step D take place, described reaction solvent is anhydrous: the mixture of one or more in toluene, dimethylbenzene, glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, methyl alcohol, ethanol, Virahol, the trimethyl carbinol or the sec-butyl alcohol.
Aforesaid a kind of method for preparing nevirapine, the temperature of reaction that it is characterized in that step D are 20 ℃～40 ℃.
Aforesaid a kind of method for preparing nevirapine, the reaction pressure that it is characterized in that step D are a normal atmosphere.
It is of the present invention that (process that the II) prepares compound (IV) is roughly as follows: (1) adds compound (II), solvent etc. there-necked flask, and nitrogen protection was stirred 15 minutes down from compound; Be cooled to-30 ℃, gradation adds the phosphinylidyne diimidazole, during temperature control at-20 ℃～-30 ℃, finish, keep-20 ℃～-30 ℃ reactions 45 minutes; (2) drip the toluene solution of compound (I) then, finish ,-15 ℃～-25 ℃ reactions 2 hours; Reaction finishes, and filters, and the filter cake water, freezes toluene wash, drains, and vacuum-drying gets compound (VIII); (3) in autoclave, add compound (VIII), solvent, airtight autoclave deflates, and with nitrogen replacement three times; From inlet pipe suction compound (V), airtight autoclave is warming up to 120 ℃ of reactions 36 hours; Stop heating, placement is spent the night; Pour out reaction solution and solvent evaporated, resistates adds water and stirs, gained solid filtering, filter cake water, ether washing, solid drying; (4) in there-necked flask, add solvent, 60% sodium hydride, be heated to 100 ℃ under the nitrogen protection; (3) step drying solid is dissolved in the solvent, slowly splashes in the solution of 60% sodium hydride, with 130 ℃～135 ℃ reactions 1.5 hours, the back cooling that reacts completely added an amount of ethanol, and gained solution directly enters next step; (5) in last step solution, add catalyzer, non-hydrogen hydrogen source, normal temperature and pressure reaction 2 hours removes by filter catalyzer, pressure reducing and steaming ethanol; Resistates is transferred pH to 7.0 with Glacial acetic acid, adds entry, stirs and separates out solid; Filter, filter cake is dissolved in the hot pyridine, adds elutriation and goes out solid, filter, and with trimethyl carbinol washing, the dry nevirapine crude product that gets; (6) the crude product recrystallization gets nevirapine.
In sum, beneficial effect of the present invention:
The shortcoming of (1) avoided environmental pollution in the usefulness chloride method synthesizing amide in other report, adding purge unit, long reaction time just can be finished reaction in the short period of time, and aftertreatment is simple;
(2) avoided 2-chloro nevirapine to prepare the used condition of high voltage of nevirapine, replaced hydrogen hydrogenation with non-hydrogen hydrogen source, normal temperature and pressure just can carry out the hydrogenation dechlorination reaction, improves the hydrogenation yield, reduces equipment requirements, reduces to have risk, thereby reduces cost.
Embodiment
Below in conjunction with embodiment the present invention is described further:
Embodiment 1
The preparation of (1.N-2,6-two chloro-4-methyl-3-pyridyl)-2-chloro-nicotinamide:
In the 1000mL there-necked flask, add 120.0g 2-chloro-3-pyridine carboxylic acid, toluene 650mL, 4-picoline 0.5mL, stirring at room is 15 minutes under the nitrogen protection; Be cooled to-25 ℃, gradation adds phosphinylidyne diimidazole 123.6g, during temperature control at-20 ℃～-25 ℃, finish, keep-20 ℃～-25 ℃ reactions 45 minutes; With 116.0g 2,6-two chloro-3-amino-4-picolines are dissolved in the 750mL dry toluene, splash into then in the active amide solution in step, during keep-15 ℃～-20 ℃, finish-15 ℃～-20 ℃ the reaction 2 hours; After TLC checks that reaction finishes, add 500mL water and stir, separate out solid, filter.Solid is used 100mL water respectively, the flushing of 100mL toluene.Obtain solid 170.0g after the vacuum-drying, 178～180 ℃ of fusing points, yield are 81.9%.
2.2, the preparation of 6-two chloro-3-(2 '-cyclopropylamino-3 '-pyridyl)-formamido group-4-picoline:
In the autoclave pressure of 2L, add 90.0g N-(2,6-two chloro-4-methyl-3-pyridyl)-2-chloro-nicotinamide, 500ml dimethylbenzene, the sealing load still, air in the still is extracted in decompression out.Suck 200ml cyclopropylamine and 400ml dimethylbenzene from inlet pipe in autoclave pressure, the sealing load still is heated with stirring to 120～130 ℃, reacts 36 hours.Stop heating, placement is spent the night.Reaction solution everywhere, pressure reducing and steaming dimethylbenzene, resistates adds 1000ml water, stirs.The gained solid filtering, difference water, ether flushing.Solid drying obtains 75.0g, and 173～175 ℃ of fusing points, yield are 78.3%.
3.2-the preparation of chloro nevirapine:
In the 1000mL there-necked flask, add the 100ml diethylene glycol dimethyl ether, 33.0g60%NaH stirs, and is heated to 120 ℃.Under nitrogen protection, slowly drip 80.0g 2,6-two chloro-3-(2 '-cyclopropylamino-3 '-pyridyl)-formamido group-4-picoline is dissolved in the solution of 400ml diethylene glycol dimethyl ether, and reaction solution reacted 1.5 hours in 130～135 ℃ of stirrings.Complete substantially when the TLC detection reaction, reaction solution is cooled to room temperature.Drip dehydrated alcohol and destroy the NaH that does not react completely, gained solution directly carries out next step reaction.
4. the preparation of nevirapine:
To go up adding 8.0g 10%Pd/C in the step reaction solution, the anhydrous shin of 9.6g, normal temperature and pressure reacted 2 hours down.Remove by filter catalyzer, pressure reducing and steaming ethanol.Resistates is neutralized to 7.0 with Glacial acetic acid, adds 3000ml water, and stirring is spent the night.Filter out solid, solid is dissolved in the hot pyridine, adds entry and makes it produce solid precipitation, filters.Solid washes with the trimethyl carbinol, and vacuum-drying obtains product 35.0g, and 242～246 ℃ of fusing points, yield are 55.4%.
5. the recrystallization of crude product:
The crude product 10.0g of nevirapine is dissolved in the 20ml chloroform, after the heating for dissolving, adds the 60ml ethyl acetate and is heated to backflow.Naturally cooling is separated out solid in the solution then.Cross filter solid, with a spot of ethyl acetate rinse solid, 40 ℃ of vacuum-dryings then obtain exquisite nevirapine 9.76g, and fusing point is 246～248 ℃, and yield is 97.6%, HPLC content 99.4%.
Embodiment 2
The preparation of (1.N-2,6-two chloro-4-methyl-3-pyridyl)-2-chloro-nicotinamide:
In the 1000mL there-necked flask, add 115.0g 2-chloro-3-pyridine carboxylic acid, toluene 650mL, 4-picoline 0.5mL, stirring at room is 15 minutes under the nitrogen protection; Be cooled to-25 ℃, gradation adds phosphinylidyne diimidazole 118.4g, during temperature control at-20 ℃～-25 ℃, finish, keep-20 ℃～-25 ℃ reactions 45 minutes; With 116.0g 2,6-two chloro-3-amino-4-picolines are dissolved in the 750mL dry toluene, splash into then in the active amide solution in step, during keep-15 ℃～-20 ℃, finish-15 ℃～-20 ℃ the reaction 2 hours; After TLC checks that reaction finishes, add 500mL water and stir, separate out solid, filter.Solid is used 100mL water respectively, the flushing of 100mL toluene.Obtain solid 169.2g after the vacuum-drying, 178～180 ℃ of fusing points, yield are 81.5%.
2.2, the preparation of 6-two chloro-3-(2 '-cyclopropylamino-3 '-pyridyl)-formamido group-4-picoline:
In the autoclave pressure of 2L, add 90.0g N-(2,6-two chloro-4-methyl-3-pyridyl)-2-chloro-nicotinamide, 500ml dimethylbenzene, the sealing load still, air in the still is extracted in decompression out.Suck 200ml cyclopropylamine and 400ml dimethylbenzene from inlet pipe in autoclave pressure, the sealing load still is heated with stirring to 120～130 ℃, reacts 36 hours.Stop heating, placement is spent the night.Reaction solution everywhere, pressure reducing and steaming dimethylbenzene, resistates adds 1000ml water, stirs.The gained solid filtering, difference water, ether flushing.Solid drying obtains 74.9g, and 173～175 ℃ of fusing points, yield are 78.2%.
3.2-the preparation of chloro nevirapine:
In the 1000mL there-necked flask, add the 100ml diethylene glycol dimethyl ether, 33.0g60%NaH stirs, and is heated to 120 ℃.Under nitrogen protection, slowly drip 80.0g 2,6-two chloro-3-(2 '-cyclopropylamino-3 '-pyridyl)-formamido group-4-picoline is dissolved in the solution of 400ml diethylene glycol dimethyl ether, and reaction solution reacted 1.5 hours in 130～135 ℃ of stirrings.Complete substantially when the TLC detection reaction, reaction solution is cooled to room temperature.Drip dehydrated alcohol and destroy the NaH that does not react completely, gained solution directly carries out next step reaction.
4. the preparation of nevirapine:
To go up adding 8.0g 10%Pd/C in the step reaction solution, 20.4g anhydrous formic acid sodium, normal temperature and pressure reacted 2 hours down.Remove by filter catalyzer, pressure reducing and steaming ethanol.Resistates is neutralized to 7 with Glacial acetic acid, adds 3000ml water, and stirring is spent the night.Filter out solid, solid is dissolved in the hot pyridine, adds entry and makes it produce solid precipitation, filters.Solid washes with the trimethyl carbinol, and vacuum-drying obtains product 34.2g, and 242～246 ℃ of fusing points, yield are 54.1%.
5. the recrystallization of crude product:
The crude product 10.0g of nevirapine is dissolved in the 20ml chloroform, after the heating for dissolving, adds the 60ml ethyl acetate and is heated to backflow.Naturally cooling is separated out solid in the solution then.Cross filter solid, with a spot of ethyl acetate rinse solid, 40 ℃ of vacuum-dryings then obtain exquisite nevirapine 9.75g, and fusing point is 246～248 ℃, and yield is 97.5%, HPLC content 99.6%.
Embodiment 3
The preparation of (1.N-2,6-two chloro-4-methyl-3-pyridyl)-2-chloro-nicotinamide:
In the 1000mL there-necked flask, add 125.0g 2-chloro-3-pyridine carboxylic acid, toluene 650mL, 4-picoline 0.5mL, stirring at room is 15 minutes under the nitrogen protection; Be cooled to-25 ℃, gradation adds phosphinylidyne diimidazole 128.7g, during temperature control at-20 ℃～-25 ℃, finish, keep-20 ℃～-25 ℃ reactions 45 minutes; With 116.0g 2,6-two chloro-3-amino-4-picolines are dissolved in the 750mL dry toluene, splash into then in the active amide solution in step, during keep-15 ℃～-20 ℃, finish-15 ℃～-20 ℃ the reaction 2 hours; After TLC checks that reaction finishes, add 500mL water and stir, separate out solid, filter.Solid is used 100mL water respectively, the flushing of 100mL toluene.Obtain solid 169.0g after the vacuum-drying, 178～180 ℃ of fusing points, yield are 81.4%.
2.2, the preparation of 6-two chloro-3-(2 '-cyclopropylamino-3 '-pyridyl)-formamido group-4-picoline:
In the autoclave pressure of 2L, add 90.0g N-(2,6-two chloro-4-methyl-3-pyridyl)-2-chloro-nicotinamide, 500ml dimethylbenzene, the sealing load still, air in the still is extracted in decompression out.Suck 200ml cyclopropylamine and 400ml dimethylbenzene from inlet pipe in autoclave pressure, the sealing load still is heated with stirring to 120～130 ℃, reacts 36 hours.Stop heating, placement is spent the night.Reaction solution everywhere, pressure reducing and steaming dimethylbenzene, resistates adds 1000ml water, stirs.The gained solid filtering, difference water, ether flushing.Solid drying obtains 74.8g, and 173～175 ℃ of fusing points, yield are 78.1%.
3.2-the preparation of chloro nevirapine:
In the 1000mL there-necked flask, add the 100ml diethylene glycol dimethyl ether, 33g60%NaH stirs, and is heated to 120 ℃.Under nitrogen protection, slowly drip 80.0g 2,6-two chloro-3-(2 '-cyclopropylamino-3 '-pyridyl)-formamido group-4-picoline is dissolved in the solution of 400ml diethylene glycol dimethyl ether, and reaction solution reacted 1.5 hours in 130～135 ℃ of stirrings.Complete substantially when the TLC detection reaction, reaction solution is cooled to room temperature.Drip dehydrated alcohol and destroy the NaH that does not react completely, gained solution directly carries out next step reaction.
4. the preparation of nevirapine:
To go up adding 8.0g 10%Pd/C in the step reaction solution, 18.0g anhydrous formic acid ammonium, normal temperature and pressure reacted 2 hours down.Remove by filter catalyzer, pressure reducing and steaming ethanol.Resistates is neutralized to 7 with Glacial acetic acid, adds 3000ml water, and stirring is spent the night.Filter out solid, solid is dissolved in the hot pyridine, adds entry and makes it produce solid precipitation, filters.Solid washes with the trimethyl carbinol, and vacuum-drying obtains product 34.5g, and 242～246 ℃ of fusing points, yield are 54.6%.
5. the recrystallization of crude product:
The crude product 10.0g of nevirapine is dissolved in the 20ml chloroform, after the heating for dissolving, adds the 60ml ethyl acetate and is heated to backflow.Naturally cooling is separated out solid in the solution then.Cross filter solid, with a spot of ethyl acetate rinse solid, 40 ℃ of vacuum-dryings then obtain exquisite nevirapine 9.78g, and fusing point is 246～248 ℃, and yield is 97.8%.HPLC content 99.4%.
Claims (10)
1. method for preparing nevirapine is characterized in that may further comprise the steps:
A, structure is generated active amide suc as formula the reaction of 2-chloro-3 pyridine carboxylic acids shown in (II) and phosphinylidyne diimidazole;
B, with the active amide that generates in the steps A and structure suc as formula 2 shown in (I), 6-two chloro-3-amino-4-picoline reaction generates N-(2,6-two chloro-4-methyl-3-pyridyl)-2-chloro-nicotinamide;
The N-of C, step B gained (2,6-two chloro-4-methyl-3-pyridyl)-2-chloro-nicotinamide and cyclopropylamine carry out nucleophilic substitution reaction, and the product that obtains carries out cyclization again and obtains the 2-chloro nevirapine of structure shown in (III);
The 2-chloro nevirapine of structure shown in (III) with non-hydrogen hydrogen source generation hydrogenation, obtains the nevirapine of structure shown in (IV) among D, the step C under catalyst action;
2. a kind of method for preparing nevirapine according to claim 1 is characterized in that the mol ratio of reactant in the steps A is: 2-chloro-3 pyridine carboxylic acids: phosphinylidyne diimidazole=1.0: 1.0～1.6; Temperature of reaction is-20 ℃～-30 ℃.
3. a kind of method for preparing nevirapine according to claim 1, it is characterized in that 2-chloro-3 pyridine carboxylic acids and being reflected in the reaction solvent of phosphinylidyne diimidazole described in the steps A take place, described reaction solvent is from anhydrous methylene dichloride, chloroform, ethylene dichloride, benzene, toluene, ethylbenzene, dimethylbenzene, N, a kind of or both above mixtures in dinethylformamide, N,N-dimethylacetamide or the N-Methyl pyrrolidone.
4. a kind of method for preparing nevirapine according to claim 1, the mol ratio that it is characterized in that reactant among the step B is: 2,6-two chloro-3-amino-4-picolines: 2-chloro-3 pyridine carboxylic acids=1.0: 1.0～1.4, temperature of reaction are-15 ℃～-25 ℃.
5. a kind of method for preparing nevirapine according to claim 1, it is characterized in that the active amide described in the step B with shown in 2,6-two chloro-3-amino-4-picolines are reflected in the reaction solvent and take place, described reaction solvent is anhydrous methylene dichloride, chloroform, ethylene dichloride, benzene, toluene, ethylbenzene, dimethylbenzene, N, the mixture of one or more in dinethylformamide, N,N-dimethylacetamide or the N-Methyl pyrrolidone.
6. a kind of method for preparing nevirapine according to claim 1 is characterized in that the catalyzer described in the step D is 5%Pd/C or 10%Pd/C, and catalyst levels with respect to 2-chloro nevirapine is: 5%～20%mol.
7. a kind of method for preparing nevirapine according to claim 1 is characterized in that a kind of in alkaline earth salt, ammonium formiate or the hydrazine of an alkali metal salt that the non-hydrogen hydrogen source described in the step D is formic acid, formic acid, formic acid.
8. a kind of method for preparing nevirapine according to claim 1, it is characterized in that being reflected in the reaction solvent described in the step D take place, described reaction solvent is anhydrous: the mixture of one or more in toluene, dimethylbenzene, glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, methyl alcohol, ethanol, Virahol, the trimethyl carbinol or the sec-butyl alcohol.
9. a kind of method for preparing nevirapine according to claim 1, the temperature of reaction that it is characterized in that step D are 20 ℃～40 ℃.
10. a kind of method for preparing nevirapine according to claim 1, the reaction pressure that it is characterized in that step D are a normal atmosphere.
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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 |
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- 2010-12-29 CN CN201010611305A patent/CN102127077B/en not_active Expired - Fee Related
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 (1)
| Title |
|---|
| 《齐鲁药事》 20090815 李淑敏等 奈韦拉平合成研究进展 485-487 1-10 第28卷, 第8期 * |
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