CN101585836A - Novel method for preparing Nevirapine - Google Patents
Novel method for preparing Nevirapine Download PDFInfo
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Abstract
The invention relates to a novel method for preparing Nevirapine and discloses a novel method for preparing 11-cyclopropyl-5,11-dihydrogen-4-methyl-6H-II naphthyridine (3,2-b:2',3'-e)(1,4) azatropylidene (I) starting from 2-chlorin-N-(2-chlorin-4-methyl-3-pyridyl)-3-pyridine carboxamide (II). The method comprises the steps: a compound (II) reacts with cyclopropylamine under the existence of organic solvent and alkali and the catalysis of cupric salt under normal temperature and pressure to produce a compound (III), and the obtained compound (III) produces 11-cyclopropyl-5,11-dihydrogen-4-methyl-6H-II naphthyridine (3,2-b:2',3'-e)(1,4) azatropylidene (I) after intramolecular cyclization under the action of a certain organic solvent and the alkali. The method has low cost, environmental protection and wild reaction condition, thereby being suitable for commercial process.
Description
Technical field
The present invention relates to treat the preparation method of the medicine nevirapine of acquired immune deficiency syndrome (AIDS).
Background technology
Nevirapine, English name is Nevirapine, chemical name is a 11-cyclopropyl-5, and 11-dihydro-4-methyl-6H-two pyridos [3,2-b:2 ', 3 '-e] [1,4] diazepine is the non-nucleoside reverse transcriptase inhibitor by the research and development of German Boehringer Ingelheim company, in September, 1996 drugs approved by FDA listing, commodity are called Viramune, now multinational listing.This product can near the combination catalytic site of enzyme, directly acts on reversed transcriptive enzyme, suppresses 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).One of 1999 studies confirm that, from parent vertical infection hiv virus (HIV), nevirapine is more effective more than older AIDS-treating medicine zidovudine (Zidovudine) the prevention newborn infant.Initial result shows that the drug effect of nevirapine almost is the twice of zidovudine.Nowadays, in the prescription to AIDS patient's drug cocktail therapy (treatment), nevirapine is indispensable medicament simply, and great demand is arranged every year.Domestic also have several producers producing nevirapine bulk drug and preparation.
The present synthetic method that several different nevirapines are arranged of report.But the last two-step reaction in most of synthetic method all need to experience compound (II) under high temperature, pressurization, alkaline situation with the cyclopropylamine condensation, obtain nevirapine (I) at highly basic, high temperature ShiShimonoseki ring then.The for example description in the U.S. Pat 5366972, compound (II) is carrying out in the closed stainless steel autoclave under 165 ℃ the high temperature with the reaction needed of cyclopropylamine; Compound in the U.S. Pat 5569760 (II) also need carry out in the closed stainless steel autoclave under 135～145 ℃ the high temperature with the reaction of cyclopropylamine.These methods exist and all have very big shortcoming, and as being the volatilization of avoiding cyclopropylamine, compound (II) need carry out in autoclave with the condensation course of cyclopropylamine; Temperature of reaction is up to 140 ℃, the energy consumption height that needs of production process not only, and have certain danger; The employing diethylene glycol dimethyl ether is a solvent, reclaims difficulty; Thereby production cost is higher relatively.
Summary of the invention
The invention provides a kind of new with low cost, environmental friendliness, reaction conditions gentleness, simple to operate, be fit to suitability for industrialized production (2-chloro-4-methyl-3-pyridyl)-(the II) prepares 11-cyclopropyl-5 to the 3-pyridine carboxamide from 2-chloro-N-, 11-dihydro-4-methyl-6H-two pyridos [3,2-b:2 ', 3 '-e] method of [1,4] diazepine (I).The present invention is characterized in that compound (II) reacts generation (III) with cyclopropylamine under the catalysis in the presence of organic solvent and the alkali, at mantoquita under normal temperature, normal pressure, resulting (III) intramolecular cyclization in certain organic solvent, under the effect of alkali generates (I).
Involved in the present invention to reaction can represent with following reaction formula:
Reaction from compound (II) preparation compound (III) of the present invention is to carry out under the catalysis of mantoquita, and selected catalyzer is: the cuprous salt that is selected from cuprous chloride, cuprous bromide, cuprous iodide, Red copper oxide etc.; Perhaps be selected from the cupric salt of copper sulfate, cupric chloride, cupric oxide etc.First-selected catalyzer is cuprous chloride, cuprous bromide, Red copper oxide, cuprous iodide.The amount of used catalyzer is 5%-100%mol with respect to compound (II).
Reaction from compound (II) preparation compound (III) of the present invention is to carry out under the effect of alkali, and selected alkali is: the mineral alkali that is selected from yellow soda ash, salt of wormwood, saleratus, sodium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, calcium oxide etc.; Or be selected from the organic bases of triethylamine, pyridine, quinoline, diisopropyl ethyl amine etc.First-selected alkali is yellow soda ash, salt of wormwood, saleratus, sodium bicarbonate, sodium hydroxide, potassium hydroxide, triethylamine.
Reaction from compound (II) preparation compound (III) of the present invention is to carry out organic solvent, and selected solvent is: the aromatic hydrocarbon that is selected from benzene, toluene, ethylbenzene, dimethylbenzene; Be selected from the halohydrocarbon of methylene dichloride, chloroform, ethylene dichloride; Be selected from the ether of tetrahydrofuran (THF), ether, 2-methyltetrahydrofuran, dioxane, glycol dimethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether; N, dinethylformamide, N,N-dimethylacetamide; Or acetonitrile.First-selected is toluene, dimethylbenzene, methylene dichloride, tetrahydrofuran (THF), dioxane,, N,N-dimethylacetamide, acetonitrile.
Reaction from compound (III) preparation compound (I) of the present invention is to carry out under the alkali effect, and wherein selected alkali is: sodium hydride, potassium tert.-butoxide, sodium tert-butoxide.Reaction from compound (III) preparation compound (I) of the present invention is to carry out the organic solvent, and wherein said organic solvent is: be selected from toluene, dimethylbenzene, glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol diethyl ether, diethylene glycol dimethyl ether.
The temperature of the reaction from compound (II) preparation compound (III) of the present invention is 20-40 ℃, and pressure is a normal atmosphere.
The operating process of the reaction from compound (II) preparation compound (I) of the present invention is roughly as follows:
Add compound (II), cyclopropylamine, catalyzer, alkali and solvent in there-necked flask, at room temperature stirred then 15 hours, filter, gained filtrate is concentrated, reclaim solvent and unnecessary cyclopropylamine, the solid that obtains after concentrating is directly used in next step reaction.Solid with the appropriate solvent dissolving obtains previously adds alkali, heated and stirred 1～2 hour.Pressure reducing and steaming solvent then, the light brown solid, add entry, be stirred to solid and all dissolve, transfer pH=7-8, separate out a large amount of sundown solids this moment, filter, filter cake washes with water, obtains pale yellowly to the sundown solid, is the nevirapine crude product.
Compare with prior preparation method, the invention has the advantages that: the present invention has avoided employed high temperature, highly compressed condition in the reaction process of compound (II) that other documents report and cyclopropylamine, just can realize this linked reaction smoothly at normal temperatures and pressures, the reaction conditions gentleness, used catalyzer low price, consumption are few, can realize simultaneously the recovery set usefulness of solvent and cyclopropylamine smoothly, when cutting down the consumption of energy, reduce production cost, increase the security of technology.The yield of the resulting product of method provided by the present invention is higher than the report of document.
Embodiment
Further specify technical scheme of the present invention with specific embodiment below, but protection scope of the present invention is not limited thereto:
Embodiment one
Digest compound (II), 0.8 gram cuprous chloride, 11 gram yellow soda ash, 400 milliliters of toluene with 22.5 and add successively in 1000 milliliters of three mouthfuls of reaction flasks, add 18 gram cyclopropylamines under the induction stirring, 25 ℃ were stirred 15 hours down.
With reacting liquid filtering, filtrate is used anhydrous magnesium sulfate drying, filters, and with solvent evaporated under reduced pressure in the filtrate, obtains the sundown solid, is compound (III), and the HPLC detection level is 92%, is directly used in next step reaction.Gained compound (III) is stand-by with 100 milliliters of diethylene glycol dimethyl ether dissolvings.
11 gram NaH are added in 500 milliliters of exsiccant there-necked flasks, add 100 milliliters of diethylene glycol dimethyl ethers again, stir and be warming up to 120 ℃, be added dropwise to the diethylene glycol dimethyl ether solution of gained compound (III) then, after dripping, continued insulated and stirred 1 hour.System is cooled to about 80 ℃, and pressure reducing and steaming solvent diethylene glycol dimethyl ether cools the temperature to and adds 200 ml waters after the room temperature, be stirred to solid and all dissolve, add 100 milliliters of hexanaphthenes again, the good stirring down drips glacial acetic acid to pH=7-8, separate out a large amount of sundown solids this moment, suction filtration, and filter cake washes with water, get light yellow solid, oven dry gets 18.0 grams, is the nevirapine crude product, yield 84%, HPLC purity 98%.
Embodiment two
Digest compound (II), 1.0 gram cuprous bromides, 11 gram yellow soda ash, 400 milliliters of toluene with 22.5 and add successively in 1000 milliliters of three mouthfuls of reaction flasks, add 18 gram cyclopropylamines under the induction stirring, 25 ℃ were stirred 15 hours down.
With reacting liquid filtering, filtrate is used anhydrous magnesium sulfate drying, filters, and with solvent evaporated under reduced pressure in the filtrate, obtains the sundown solid, is compound (III), is directly used in next step reaction.Gained compound (III) is stand-by with 100 milliliters of diethylene glycol dimethyl ether dissolvings.
11 gram NaH are added in 500 milliliters of exsiccant there-necked flasks, add 100 milliliters of diethylene glycol dimethyl ethers again, stir and be warming up to 120 ℃, be added dropwise to the diethylene glycol dimethyl ether solution of gained compound (III) then, after dripping, continued insulated and stirred 1 hour.System is cooled to about 80 ℃, and pressure reducing and steaming solvent diethylene glycol dimethyl ether cools the temperature to and adds 200 ml waters after the room temperature, being stirred to solid all dissolves, add 100 milliliters of hexanaphthenes again, the good stirring down drips glacial acetic acid to pH=7-8, separates out a large amount of sundown solids this moment, suction filtration, filter cake washes with water, gets light yellow solid, oven dry, get 18.2 nevirapine crude products gram, yield 85%.
Embodiment three
Digest compound (II), 1.2 gram cuprous iodides, 11 gram yellow soda ash, 400 milliliters of toluene with 22.5 and add successively in 1000 milliliters of three mouthfuls of reaction flasks, add 18 gram cyclopropylamines under the induction stirring, 25 ℃ were stirred 15 hours down.
With reacting liquid filtering, filtrate is used anhydrous magnesium sulfate drying, filters, and with solvent evaporated under reduced pressure in the filtrate, obtains the sundown solid, is compound (III), is directly used in next step reaction.Gained compound (III) is stand-by with 100 milliliters of diethylene glycol dimethyl ether dissolvings.
11 gram NaH are added in 500 milliliters of exsiccant there-necked flasks, add 100 milliliters of diethylene glycol dimethyl ethers again, stir and be warming up to 120 ℃, be added dropwise to the diethylene glycol dimethyl ether solution of gained compound (III) then, after dripping, continued insulated and stirred 1 hour.System is cooled to about 80 ℃, and pressure reducing and steaming solvent diethylene glycol dimethyl ether cools the temperature to and adds 200 ml waters after the room temperature, being stirred to solid all dissolves, add 100 milliliters of hexanaphthenes again, the good stirring down drips glacial acetic acid to pH=7-8, separates out a large amount of sundown solids this moment, suction filtration, filter cake washes with water, gets light yellow solid, oven dry, get 18.3 nevirapine crude products gram, yield 86%.
Experimental example four
Digest compound (II), 1.2 gram copper sulfate, 11 gram yellow soda ash, 400 milliliters of N,N-dimethylacetamide with 22.5 and add successively in 1000 milliliters of three mouthfuls of reaction flasks, add 18 gram cyclopropylamines under the induction stirring, 25 ℃ were stirred 15 hours down.
With reacting liquid filtering, filtrate is used anhydrous magnesium sulfate drying, filters, and with solvent evaporated under reduced pressure in the filtrate, obtains the sundown solid, is compound (III), is directly used in next step reaction.Gained compound (III) is stand-by with 100 milliliters of diethylene glycol dimethyl ether dissolvings.
11 gram NaH are added in 500 milliliters of exsiccant there-necked flasks, add 100 milliliters of diethylene glycol dimethyl ethers again, stir and be warming up to 120 ℃, be added dropwise to the diethylene glycol dimethyl ether solution of gained compound (III) then, after dripping, continued insulated and stirred 1 hour.System is cooled to about 80 ℃, and pressure reducing and steaming solvent diethylene glycol dimethyl ether cools the temperature to and adds 200 ml waters after the room temperature, being stirred to solid all dissolves, add 100 milliliters of hexanaphthenes again, the good stirring down drips glacial acetic acid to pH=7-8, separates out a large amount of sundown solids this moment, suction filtration, filter cake washes with water, gets light yellow solid, oven dry, get 17.8 nevirapine crude products gram, yield 80%.
Embodiment five
Digest compound (II), 0.8 gram cuprous chloride, 11 gram yellow soda ash, 400 milliliters of tetrahydrofuran (THF)s with 22.5 and add successively in 1000 milliliters of three mouthfuls of reaction flasks, add 18 gram cyclopropylamines under the induction stirring, 25 ℃ were stirred 15 hours down.
With reacting liquid filtering, filtrate is used anhydrous magnesium sulfate drying, filters, and with solvent evaporated under reduced pressure in the filtrate, obtains the sundown solid, is compound (III), is directly used in next step reaction.Gained compound (III) is stand-by with 100 milliliters of diethylene glycol dimethyl ether dissolvings.
11 gram NaH are added in 500 milliliters of exsiccant there-necked flasks, add 100 milliliters of diethylene glycol dimethyl ethers again, stir and be warming up to 120 ℃, be added dropwise to the diethylene glycol dimethyl ether solution of gained compound (III) then, after dripping, continued insulated and stirred 1 hour.System is cooled to about 80 ℃, and pressure reducing and steaming solvent diethylene glycol dimethyl ether cools the temperature to and adds 200 ml waters after the room temperature, being stirred to solid all dissolves, add 100 milliliters of hexanaphthenes again, the good stirring down drips glacial acetic acid to pH=7-8, separates out a large amount of sundown solids this moment, suction filtration, filter cake washes with water, gets light yellow solid, oven dry, get nevirapine crude product 18.0 grams, yield 84%.
Embodiment six
Digest compound (II), 0.8 gram cuprous chloride, 12 gram saleratus, 400 milliliters of dimethylbenzene with 22.5 and add successively in 1000 milliliters of three mouthfuls of reaction flasks, add 18 gram cyclopropylamines under the induction stirring, 25 ℃ were stirred 20 hours down.
With reacting liquid filtering, filtrate is used anhydrous magnesium sulfate drying, filters, and filtrate is concentrated into about 100 milliliters, is used for next step reaction.
24 gram potassium tert.-butoxides are added in 500 milliliters of exsiccant there-necked flasks, add 100 milliliters of dimethylbenzene again, stir and be warming up to 120 ℃, be added dropwise to the xylene solution of gained compound (III) then, after dripping, continued insulated and stirred 1 hour.System is cooled to about 80 ℃, and the pressure reducing and steaming solvent xylene cools the temperature to and adds 200 ml waters after the room temperature, being stirred to solid all dissolves, add 100 milliliters of hexanaphthenes again, the good stirring down drips glacial acetic acid to pH=7-8, separates out a large amount of sundown solids this moment, suction filtration, filter cake washes with water, gets light yellow solid, oven dry, get nevirapine crude product 17.0 grams, yield 78%.
Embodiment seven
Digest compound (II), 0.8 gram cuprous chloride, 9 gram sodium hydroxide, 400 milliliters of acetonitriles with 22.5 and add successively in 1000 milliliters of three mouthfuls of reaction flasks, add 18 gram cyclopropylamines under the induction stirring, 25 ℃ were stirred 20 hours down.
With reacting liquid filtering, filtrate is used anhydrous magnesium sulfate drying, filters, and with solvent evaporated under reduced pressure in the filtrate, obtains the sundown solid, is compound (III), is directly used in next step reaction.Gained compound (III) is stand-by with 100 milliliters of xylene soluble.
24 gram potassium tert.-butoxides are added in 500 milliliters of exsiccant there-necked flasks, add 100 milliliters of dimethylbenzene again, stir and be warming up to 120 ℃, be added dropwise to the xylene solution of gained compound (III) then, after dripping, continued insulated and stirred 1 hour.System is cooled to about 80 ℃, and the pressure reducing and steaming solvent xylene cools the temperature to and adds 200 ml waters after the room temperature, being stirred to solid all dissolves, add 100 milliliters of hexanaphthenes again, the good stirring down drips glacial acetic acid to pH=7-8, separates out a large amount of sundown solids this moment, suction filtration, filter cake washes with water, gets light yellow solid, oven dry, get nevirapine crude product 17.4 grams, yield 82%.
Embodiment eight
Digest compound (II), 0.8 gram cuprous chloride, 10 gram triethylamines, 400 milliliters of dioxane with 22.5 and add successively in 1000 milliliters of three mouthfuls of reaction flasks, add 18 gram cyclopropylamines under the induction stirring, 25 ℃ were stirred 20 hours down.
With reacting liquid filtering, filtrate is used anhydrous magnesium sulfate drying, filters, and with solvent evaporated under reduced pressure in the filtrate, obtains the sundown solid, is compound (III), and the HPLC detection level is 92%, is directly used in next step reaction.Gained compound (III) is stand-by with 100 milliliters of xylene soluble.
22 gram sodium tert-butoxides are added in 500 milliliters of exsiccant there-necked flasks, add 100 milliliters of dimethylbenzene again, stir and be warming up to 120 ℃, be added dropwise to the xylene solution of gained compound (III) then, after dripping, continued insulated and stirred 1 hour.System is cooled to about 80 ℃, and the pressure reducing and steaming solvent xylene cools the temperature to and adds 200 ml waters after the room temperature, being stirred to solid all dissolves, add 100 milliliters of hexanaphthenes again, the good stirring down drips glacial acetic acid to pH=7-8, separates out a large amount of sundown solids this moment, suction filtration, filter cake washes with water, gets light yellow solid, oven dry, get nevirapine crude product 16.0 grams, yield 70%.
Embodiment nine
Digest compound (II), 0.8 gram cuprous chloride, 9 gram sodium hydroxide, 400 milliliters of methylene dichloride with 22.5 and add successively in 1000 milliliters of three mouthfuls of reaction flasks, add 18 gram cyclopropylamines under the induction stirring, 25 ℃ were stirred 20 hours down.
With reacting liquid filtering, filtrate is used anhydrous magnesium sulfate drying, filters, and with solvent evaporated under reduced pressure in the filtrate, obtains the sundown solid, is compound (III), is directly used in next step reaction.Gained compound (III) is stand-by with 100 milliliters of xylene soluble.
25 gram potassium tert.-butoxides are added in 500 milliliters of exsiccant there-necked flasks, add 100 milliliters of dimethylbenzene again, stir and be warming up to 120 ℃, be added dropwise to the xylene solution of gained compound (III) then, after dripping, continued insulated and stirred 1 hour.System is cooled to about 80 ℃, and the pressure reducing and steaming solvent xylene cools the temperature to and adds 200 ml waters after the room temperature, being stirred to solid all dissolves, add 100 milliliters of hexanaphthenes again, the good stirring down drips glacial acetic acid to pH=7-8, separates out a large amount of sundown solids this moment, suction filtration, filter cake washes with water, gets light yellow solid, oven dry, get nevirapine crude product 17.3 grams, yield 81%.
Claims (8)
1. one kind by 2-chloro-N-(2-chloro-4-methyl-3-pyridyl)-3-pyridine carboxamide (II) preparation 11-cyclopropyl-5 of setting out, 11-dihydro-4-methyl-6H-two pyridos [3,2-b:2 ', 3 '-e] [1,4] method of diazepine (I), its feature comprises that compound (II) is in the presence of organic solvent and alkali, under the catalysis of mantoquita with cyclopropylamine reacting generating compound (III) at normal temperatures and pressures, resulting compound (III) is in organic solvent, and intramolecular cyclization generates 11-cyclopropyl-5 under the effect of alkali, 11-dihydro-4-methyl-6H-two pyridos [3,2-b:2 ', 3 '-e] [1,4] diazepine (I).
2. the method for claim 1 is wherein carried out under the catalysis that is reflected at mantoquita of compound (II) preparation compound (III), and wherein said catalyzer is: the cuprous salt that is selected from chlorination industry copper, cuprous bromide, cuprous iodide, Red copper oxide etc.; Be selected from the cupric salt of copper sulfate, cupric chloride, cupric oxide etc.
3. method as claimed in claim 2, wherein from the reaction of compound (II) preparation compound (III), the amount of the catalyzer of its usefulness is 5%-100%mol with respect to compound (II).
4. the method for claim 1, wherein carry out under the effect that is reflected at alkali of compound (II) preparation compound (III), wherein said alkali is: the mineral alkali that is selected from yellow soda ash, salt of wormwood, saleratus, sodium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, calcium oxide etc.; Or be selected from the organic bases of triethylamine, pyridine, quinoline, diisopropyl ethyl amine etc.
5. the method for claim 1, wherein from the reaction of compound (II) preparation compound (III), wherein said organic solvent is: the aromatic hydrocarbon that is selected from benzene, toluene, ethylbenzene, dimethylbenzene; Be selected from the halohydrocarbon of methylene dichloride, chloroform, ethylene dichloride; Be selected from the ether of tetrahydrofuran (THF), ether, 2-methyltetrahydrofuran, dioxane, glycol dimethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether; N, dinethylformamide, N,N-dimethylacetamide; Or acetonitrile.
6. the method for claim 1 is wherein carried out from being reflected under the suitable alkali effect of compound (III) preparation compound (I), and wherein said alkali is: sodium hydride, potassium tert.-butoxide, sodium tert-butoxide.
7. the method for claim 1, wherein carry out from being reflected at the organic solvent of compound (III) preparation compound (I), wherein said organic solvent is: be selected from toluene, dimethylbenzene, glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol diethyl ether, diethylene glycol dimethyl ether.
8. the method for claim 1, wherein the temperature from the reaction of compound (II) preparation compound (III) is 20-40 ℃, pressure is a normal atmosphere.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102321015A (en) * | 2011-06-30 | 2012-01-18 | 江苏德峰药业有限公司 | Method for preparing key intermediate 2-(cyclopropylamido)-3-pyridine formic acid of anti-aids medicament Nevirapine |
| WO2012168949A2 (en) * | 2011-06-06 | 2012-12-13 | Laurus Labs Private Limited | A process for preparation of nevirapine |
| CN103804378A (en) * | 2012-11-07 | 2014-05-21 | 上海迪赛诺化学制药有限公司 | Preparation method for 5,11-dihydro-6H-bispyridino-[3,2-b:2',3'-e][1,4]diazepines |
| CN106938981A (en) * | 2016-11-10 | 2017-07-11 | 浙江华海药业股份有限公司 | A kind of preparation method of NVP intermediate sphaerocrystal |
Family Cites Families (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 |
| DE4403311C1 (en) * | 1994-02-03 | 1995-04-20 | Boehringer Ingelheim Kg | Process for the preparation of nevirapine (11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4-d iazepin]-6-one) |
-
2008
- 2008-05-25 CN CN2008101078934A patent/CN101585836B/en active Active
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012168949A2 (en) * | 2011-06-06 | 2012-12-13 | Laurus Labs Private Limited | A process for preparation of nevirapine |
| WO2012168949A3 (en) * | 2011-06-06 | 2013-03-28 | Laurus Labs Private Limited | A process for preparation of nevirapine |
| CN102321015A (en) * | 2011-06-30 | 2012-01-18 | 江苏德峰药业有限公司 | Method for preparing key intermediate 2-(cyclopropylamido)-3-pyridine formic acid of anti-aids medicament Nevirapine |
| CN103804378A (en) * | 2012-11-07 | 2014-05-21 | 上海迪赛诺化学制药有限公司 | Preparation method for 5,11-dihydro-6H-bispyridino-[3,2-b:2',3'-e][1,4]diazepines |
| CN106938981A (en) * | 2016-11-10 | 2017-07-11 | 浙江华海药业股份有限公司 | A kind of preparation method of NVP intermediate sphaerocrystal |
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Address after: 317024 Development Zone of Linhai bridge, Linhai City, Zhejiang Patentee after: ZHEJIANG HUAHAI PHARMACEUTICAL Co.,Ltd. Patentee after: Shanghai Aobo biomedical Co.,Ltd. Address before: 317024 Development Zone of Linhai bridge, Linhai City, Zhejiang Patentee before: ZHEJIANG HUAHAI PHARMACEUTICAL Co.,Ltd. Patentee before: Shanghai Aobo Biomedical Technology Co.,Ltd. |