CN102952068A - Synthesis method for Nevirapine intermediates - Google Patents
Synthesis method for Nevirapine intermediates Download PDFInfo
- Publication number
- CN102952068A CN102952068A CN 201110249349 CN201110249349A CN102952068A CN 102952068 A CN102952068 A CN 102952068A CN 201110249349 CN201110249349 CN 201110249349 CN 201110249349 A CN201110249349 A CN 201110249349A CN 102952068 A CN102952068 A CN 102952068A
- Authority
- CN
- China
- Prior art keywords
- nitro
- methyl pyridine
- chloro
- amino
- synthetic method
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Landscapes
- Pyridine Compounds (AREA)
Abstract
The invention discloses a synthesis method of a nevirapine intermediate 2-amino-3-nitro-4-methylpyridine shown as the chemical formula I. The synthesis method includes steps: under catalysis of inorganic base or organic base and actions of concentrated sulphuric acid and dilute nitric acid, subjecting the 2-amino-3-nitro-4-methylpyridine shown as the chemical formula I to nitration reaction in organic solvent. The inorganic base can be calcium hydroxide, barium hydroxide, sodium hydroxide or zinc hydroxide; and the organic base can be sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide or potassium tert-butylate. The invention further discloses a synthesis method of a nevirapine intermediate 2-chloro-N-(2-chloro-4-methylpyridin-3-yl)nicotinamide. The synthesis method is easy and safe in operation, high in yield, low-cost, low in pollution to environments and suitable for industrial production in scale.
Description
Technical field
The present invention is specifically related to the synthetic method of the intermediate of nevirapine.
Background technology
2-chloro-N-(2-chloro-4-picoline-3-yl) niacinamide is the important intermediate of synthetic medical nevirapine.And nevirapine is the research and development of German Boehringer Ingelheim (BoehringerIngelheim) company, is used for the anti-AIDS drug of the Transmission From Mothers To Their Infants of prevention HIV.Nevirapine is the sweet class reverse transcriptase inhibitors of the non-nuclear of HIV-1 (Non-Nucleoside Reverse Transcriptase Inhibitor, NNRTI).Nevirapine directly is connected with the reversed transcriptive enzyme of HIV-1 and breaks to block the dna polymerase activity that RNA relies on and DNA relies on by the catalysis end that makes this enzyme, thereby effectively reduces the viral load in the body, recovers immune function of human body.Nevirapine is one of present most popular anti-AIDS drug, is mainly used in preventing and treating mother and baby's viral communication.Therefore, the preparation method of Low-cost high-level efficiency 2-chloro-N-(2-chloro-4-picoline-3-yl) niacinamide is significant.
Document (US Pat.NO.5366972; US Pat.NO.5569760; WO, 2007010352) 2-chloro-N-(2-chloro-4-picoline-3-yl) the niacinamide preparation method of report is take 2-AMINO-4-PICOLINE as raw material, passes through nitrated, diazotization, chlorination, palladium charcoal hydrogenating reduction, again chlorination, condensation reaction obtains target molecule.And be the meeting a large amount of reddish-brown gases of generation and produce two kinds of isomer in nitration reaction, thereby cause subsequent reactions processing complexity and use precious metal palladium, environment is caused huge destruction.
The operational path of the document is as follows:
Also has other bibliographical information with 4,4-dimethoxy two butanone are raw material, through replacing, close ring, chlorination, hydrolysis, Hofmann degradation, condensation reaction obtains target molecule, and use two kinds of isomer of the same generation of toluene in the substitution reaction stage, thereby cause subsequent reactions complicated, and use bromine and degrade, equally environment is caused huge destruction.
Its operational path is as follows:
Summary of the invention
Technical problem to be solved by this invention is among the preparation method for the intermediate 2-chloro-N-that overcomes existing nevirapine (2-chloro-4-picoline-3-yl) niacinamide, when nitration reaction, can produce a large amount of reddish-brown gases and produce two kinds of isomer, thereby cause subsequent reactions processing complexity and use precious metal palladium, environment is caused the defective of huge destruction, and a kind of synthetic method of intermediate of nevirapine is provided.Method of the present invention is simple to operate, safety, yield high, cost is low, has reduced greatly the pollution to environment, is fit to large-scale commercial production.
Therefore, the present invention relates to the synthetic method of a kind of intermediate 2-amino suc as formula the nevirapine shown in the I-3-nitro-4-methyl pyridine, it comprises the following step: in the organic solvent, under the catalysis of mineral alkali or organic bases, under the effect of the vitriol oil and rare nitric acid, to carry out nitration reaction suc as formula the 2-AMINO-4-PICOLINE shown in the II, get final product; Wherein, described mineral alkali is calcium hydroxide, hydrated barta, sodium hydroxide or zinc hydroxide; Described organic bases is sodium methylate, potassium methylate, sodium ethylate, potassium ethylate, sodium tert-butoxide or potassium tert.-butoxide;
Wherein, described organic solvent can be this type of nitration reaction of this area solvent commonly used, and the present invention is toluene and/or dimethylbenzene particularly preferably.The consumption of organic solvent can be conventional solubilizing reaction thing institute expense, and that the volume mass of organic solvent and Compound I I is better is 3.0～5.0ml/g.
Wherein, the kind of the described vitriol oil and rare nitric acid and consumption all can be this type of reaction of this area kind and consumption commonly used.Among the present invention, what the mass concentration of the described vitriol oil was better is 95%～98%.What the mol ratio of the described vitriol oil and Compound I I was better is 10: 1～10.5: 1.What the mass concentration of described rare nitric acid was better is 20%～80%.What the mol ratio of described rare nitric acid and Compound I I was better is 1.0: 1～1.2: 1.
The consumption of described mineral alkali or organic bases can be catalytic amount, 0.05～0.1 times of the quality of better is Compound I I, and better is 0.08～0.1 times.
Among the present invention, the temperature of described nitration reaction can be the conventional temperature of this type of nitration reaction, and better is 20～80 ℃.Till the time of described nitration reaction can no longer carry out with detection reaction, better was 0.5～5 hour.
Among the present invention, after above-mentioned nitration reaction finished, only by the simple solid of collecting, the steps such as recrystallization can make pure Compound I.Its content can reach more than 99.5%, and yield can reach 95～98%.
Wherein, in the described recrystallization, used recrystallization solvent can be one or more in ethanol, propyl alcohol, Virahol, butanols, sherwood oil and the acetone etc.
The invention further relates to a kind of synthetic method of intermediate 2-chloro-N-(2-chloro-4-picoline-3-yl) niacinamide of nevirapine, it comprises the following step:
(1) synthetic method according to aforesaid 2-amino-3-nitro-4-methyl pyridine prepares 2-amino-3-nitro-4-methyl pyridine;
(2) the 2-amino of step (1) gained-3-nitro-4-methyl pyridine is carried out diazotization reaction and hydrolysis reaction, gets 2-hydroxyl-3-nitro-4-methyl pyridine;
(3) the 2-hydroxyl of step (2) gained-3-nitro-4-methyl pyridine is carried out the chlorination of hydroxyl, gets 2-chloro-3-nitro-4-methyl pyridine;
(4) the 2-chloro-3-nitro-4-methyl pyridine of step (3) gained is carried out the reduction reaction of nitro, get the 2-chlorin-3-amido-4-methyl pyridine;
(5) the 2-chlorin-3-amido-4-methyl pyridine and the 2-chloronicotinoyl chloride that step (4) are obtained react, and can make 2-chloro-N-(2-chloro-4-picoline-3-yl) niacinamide;
Wherein, the method in step (2)～(5) all can be carried out with reference to the ordinary method of this area.
Among the present invention, the synthetic method of described 2-chloro-N-(2-chloro-4-picoline-3-yl) niacinamide is better comprises the following step:
(1) synthetic method according to aforesaid 2-amino-3-nitro-4-methyl pyridine prepares 2-amino-3-nitro-4-methyl pyridine;
(2) 2-hydroxyl-3-nitro-4-methyl pyridine is synthetic
The 2-amino of step (1) gained-3-nitro-4-methyl pyridine is dissolved in the dilute sulphuric acid, drips the aqueous solution of Sodium Nitrite, obtain faint yellow solid, i.e. 2-hydroxyl-3-nitro-4-methyl pyridine.Yield can reach 95～98%;
(3) 2-chloro-3-nitro-4-methyl pyridine is synthetic
With step (2) gained solid, be dissolved in the phosphorus oxychloride, heating reflux reaction namely gets 2-chloro-3-nitro-4-methyl pyridine.It is 95～98% that yield can reach.
(4) the 2-chlorin-3-amido-4-methyl pyridine is synthetic
Step (3) gained dissolution of solid in solvent, is added reductive agent, add mineral acid, through aftertreatment, collect solid.Yield can reach 95～98%;
Wherein said solvent is a kind of in ethanol, propyl alcohol, Virahol and the butanols etc.; Selected reductive agent is a kind of in the metal-powders such as iron powder, zinc powder and aluminium powder; Selected mineral acid is a kind of in hydrochloric acid, sulfuric acid, nitric acid and the ammonia chloride etc.;
(5) 2-chloro-N-(2-chloro-4-picoline-3-yl) niacinamide is synthetic
In toluene and anhydrous pyridine, and the condensation of 2-chloronicotinoyl chloride namely gets 2-chloro-N-(2-chloro-4-picoline-3-yl) niacinamide with step (4) gained solid.Yield can reach 95～98%.
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, but arbitrary combination namely get the preferred embodiments of the invention.
Except specified otherwise, agents useful for same of the present invention and raw material be commercially available getting all.
Positive progressive effect of the present invention is: the present invention can obtain high yield and highly purified 2-amino-3-nitro-4-methyl pyridine take 2-AMINO-4-PICOLINE as raw material through suitable nitration reaction.Proceed again follow-up diazotization reaction, chlorination reaction, suitable reduction reaction and condensation reaction, can obtain 2-chloro-N-(2-chloro-4-picoline-3-yl) niacinamide.Method of the present invention is simple to operate, safety, yield high, cost is low, has reduced greatly the pollution to environment, is fit to large-scale commercial production.
Embodiment
Mode below by embodiment further specifies the present invention, but does not therefore limit the present invention among the described scope of embodiments.The experimental technique of unreceipted actual conditions in the following example according to ordinary method and condition, or is selected according to catalogue.
Embodiment 1
(1) 2-amino-3-nitro-4-methyl pyridine is synthetic
In a reaction flask, add 200ml toluene and the 1000g95% vitriol oil, start and stir, and under 25 ℃, slowly add 108g2-amino-4-methylpyridine and 10g hydrated barta in batches, be stirred to whole dissolvings.Then slowly drip 20% rare nitric acid 330g, dropwise, 25 ℃ of lower insulations 5 hours.Namely get reaction solution.
In another reaction flask, add 1000ml water, start and stir, be cooled to 10 ℃, above-mentioned reaction solution slowly is added to the water, the control temperature is at 10 ℃, dropwise, transfer PH=8～8.5 with ammoniacal liquor, collect solid, get the mixture of 2-amino-3-nitro-4-methyl pyridine and 2-amino-4-methyl-5-nitro pyridine.Its mol ratio is: 2-amino-3-nitro-4-methyl pyridine: 2-amino-4-methyl-5-nitro pyridine=100: 5.
With dehydrated alcohol recrystallization said mixture, get 2-amino-3-nitro-4-methyl pyridine sterling 145.0g yield: 95%, content: 99.5%.
(2) 2-hydroxyl-3-nitro-4-methyl pyridine is synthetic
In a reaction flask, add 2-amino-3-nitro-4-methyl pyridine 145g, vitriol oil 260g and water 2000ml, dripping water (240ml) solution of Sodium Nitrite (83g) below 10 ℃, drip and finish, insulation 1h collects solid, the dry 2-hydroxyl-3-nitro-4-methyl pyridine 138g that gets, yield: 95%, content (HPLC): 99.5%
(3) 2-chloro-3-nitro-4-methyl pyridine is synthetic
In a reaction flask, add 2-hydroxyl-3-nitro-4-methyl pyridine 138g and phosphorus oxychloride 450g, be heated to backflow, back flow reaction 4 hours.Normal pressure is slowly poured reaction mixture in the frozen water after reclaiming phosphorus oxychloride, collects solid.Be drying to obtain 2-chloro-3-nitro-4-methyl pyridine 147g, yield: 95%, content: 99.6%
(4) the 2-chlorin-3-amido-4-methyl pyridine is synthetic
In a reaction flask, add 2-chloro-3-nitro-4-methyl pyridine 147g, iron powder 190g and ethanol 800ml, 20 ℃ of stirrings, and under this temperature, slowly drip 10% dilute hydrochloric acid, until emerge without bubble, can end.It is confused to filter removal iron, and the normal pressure Recycled ethanol adds entry to doing, and transfers PH=8 with ammoniacal liquor, collects solid, and washing is dried and namely got 2-chlorin-3-amido-4-methyl pyridine 118g.Yield: 97%, content: 99.7%.
(5) 2-chloro-N-(2-chloro-4-picoline-3-yl) niacinamide is synthetic
In a reaction flask, add 2-chlorin-3-amido-4-methyl pyridine 118g, toluene (900ml) and anhydrous pyridine (80g), 20 ℃ of stirrings splash into 2-chloronicotinoyl chloride (160g) and get toluene (600ml) solution, drip off and continue slowly to be added to the water behind the stirring 20min, collect solid, washing, oven dry namely gets 2-chloro-N-(2-chloro-4-picoline-3-yl) niacinamide 222g.Yield: 95%, content: 99.7%.
Embodiment 2
(1) 2-amino-3-nitro-4-methyl pyridine is synthetic
In a reaction flask, add 200ml dimethylbenzene and the 1000g vitriol oil, start and stir, and under 35 ℃, slowly add 108g2-amino-4-methylpyridine and 10g zinc hydroxide in batches, be stirred to whole dissolvings.Then slowly drip 30% rare nitric acid 220g, dropwise, 35 ℃ of lower insulations 5 hours.Namely get reaction solution.
In another reaction flask, add 1000ml water, start and stir, be cooled to 10 ℃, above-mentioned reaction solution slowly is added to the water, the control temperature is at 10 ℃, dropwise, transfer PH=8～8.5 with ammoniacal liquor, collect solid, get the mixture of 2-amino-3-nitro-4-methyl pyridine and 2-amino-4-methyl-5-nitro pyridine.Its mol ratio is: 2-amino-3-nitro-4-methyl pyridine: 2-amino-4-methyl-5-nitro pyridine=100: 4.
With propyl alcohol recrystallization said mixture, get 2-amino-3-nitro-4-methyl pyridine sterling 146.50g yield: 96%, content: 99.5%.
(2) 2-hydroxyl-3-nitro-4-methyl pyridine is synthetic
In a reaction flask, add 2-amino-3-nitro-4-methyl pyridine 145g, vitriol oil 260g and water 2000ml, dripping water (240ml) solution of Sodium Nitrite (83g) below 10 ℃, drip and finish, insulation 1h collects solid, the dry 2-hydroxyl-3-nitro-4-methyl pyridine 138g that gets, yield: 95%, content (HPLC): 99.5%
(3) 2-chloro-3-nitro-4-methyl pyridine is synthetic
In a reaction flask, add 2-hydroxyl-3-nitro-4-methyl pyridine 138g and phosphorus oxychloride 450g, be heated to backflow, back flow reaction 4 hours.Normal pressure is slowly poured reaction mixture in the frozen water after reclaiming phosphorus oxychloride, collects solid.Be drying to obtain 2-chloro-3-nitro-4-methyl pyridine 147g, yield: 95%, content: 99.6%
(4) the 2-chlorin-3-amido-4-methyl pyridine is synthetic
In a reaction flask, add 2-chloro-3-nitro-4-methyl pyridine 147g, zinc powder 215g and ethanol 800ml, 20 ℃ of stirrings, and under this temperature, slowly drip 10% dilute hydrochloric acid, until emerge without bubble, can end.It is confused to filter removal iron, and the normal pressure Recycled ethanol adds entry to doing, and transfers PH=8 with ammoniacal liquor, collects solid, and washing is dried and namely got 2-chlorin-3-amido-4-methyl pyridine 119.20g.Yield: 98%, content: 99.7%.
(5) 2-chloro-N-(2-chloro-4-picoline-3-yl) niacinamide is synthetic
In a reaction flask, add 2-chlorin-3-amido-4-methyl pyridine 118g, toluene (900ml) and anhydrous pyridine (80g), 20 ℃ of stirrings splash into 2-chloronicotinoyl chloride (160g) and get toluene (600ml) solution, drip off and continue slowly to be added to the water behind the stirring 20min, collect solid, washing, oven dry namely gets 2-chloro-N-(2-chloro-4-picoline-3-yl) niacinamide 222g.Yield: 95%, content: 99.7%.
Embodiment 3
(1) 2-amino-3-nitro-4-methyl pyridine is synthetic
In a reaction flask, add 150ml and the toluene 1000g vitriol oil, start and stir, and under 45 ℃, slowly add 108g2-amino-4-methylpyridine and 8g aluminium hydroxide in batches, be stirred to whole dissolvings.Then slowly drip 40% rare nitric acid 165g, dropwise, 45 ℃ of lower insulations 5 hours.Namely get reaction solution.
In another reaction flask, add 1000ml water, start and stir, be cooled to 10 ℃, above-mentioned reaction solution slowly is added to the water, the control temperature is at 10 ℃, dropwise, transfer PH=8～8.5 with ammoniacal liquor, collect solid, get the mixture of 2-amino-3-nitro-4-methyl pyridine and 2-amino-4-methyl-5-nitro pyridine.Its mol ratio is: 2-amino-3-nitro-4-methyl pyridine: 2-amino-4-methyl-5-nitro pyridine=100: 3.
With trimethyl carbinol recrystallization said mixture, get 2-amino-3-nitro-4-methyl pyridine sterling 148.0g yield: 97%, content: 99.5%.
(2) 2-hydroxyl-3-nitro-4-methyl pyridine is synthetic
In a reaction flask, add 2-amino-3-nitro-4-methyl pyridine 145g, vitriol oil 260g and water 2000ml, dripping water (240ml) solution of Sodium Nitrite (83g) below 10 ℃, drip and finish, insulation 1h collects solid, the dry 2-hydroxyl-3-nitro-4-methyl pyridine 138g that gets, yield: 95%, content (HPLC): 99.5%
(3) 2-chloro-3-nitro-4-methyl pyridine is synthetic
In a reaction flask, add 2-hydroxyl-3-nitro-4-methyl pyridine 138g and phosphorus oxychloride 450g, be heated to backflow, back flow reaction 4 hours.Normal pressure is slowly poured reaction mixture in the frozen water after reclaiming phosphorus oxychloride, collects solid.Be drying to obtain 2-chloro-3-nitro-4-methyl pyridine 147g, yield: 95%, content: 99.6%
(4) the 2-chlorin-3-amido-4-methyl pyridine is synthetic
In a reaction flask, add 2-chloro-3-nitro-4-methyl pyridine 147g, aluminium powder 92g and ethanol 800ml, 20 ℃ of stirrings, and under this temperature, slowly drip 10% dilute hydrochloric acid, until emerge without bubble, can end.It is confused to filter removal iron, and the normal pressure Recycled ethanol adds entry to doing, and transfers PH=8 with ammoniacal liquor, collects solid, and washing is dried and namely got 2-chlorin-3-amido-4-methyl pyridine 118g.Yield: 97%, content: 99.7%.
(5) 2-chloro-N-(2-chloro-4-picoline-3-yl) niacinamide is synthetic
In a reaction flask, add 2-chlorin-3-amido-4-methyl pyridine 118g, toluene (900ml) and anhydrous pyridine (80g), 20 ℃ of stirrings splash into 2-chloronicotinoyl chloride (160g) and get toluene (600ml) solution, drip off and continue slowly to be added to the water behind the stirring 20min, collect solid, washing, oven dry namely gets 2-chloro-N-(2-chloro-4-picoline-3-yl) niacinamide 222g.Yield: 95%, content: 99.7%.
Embodiment 4
(1) 2-amino-3-nitro-4-methyl pyridine is synthetic
In a reaction flask, add 200ml dimethylbenzene and the 1000g vitriol oil, start and stir, and under 55 ℃, slowly add 108g2-amino-4-methylpyridine and 9g sodium ethylate in batches, be stirred to whole dissolvings.Then slowly drip 50% rare nitric acid 198g, dropwise, 55 ℃ of lower insulations 5 hours.Namely get reaction solution.
In another reaction flask, add 1000ml water, start and stir, be cooled to 10 ℃, above-mentioned reaction solution slowly is added to the water, the control temperature is at 10 ℃, dropwise, transfer PH=8～8.5 with ammoniacal liquor, collect solid, get the mixture of 2-amino-3-nitro-4-methyl pyridine and 2-amino-4-methyl-5-nitro pyridine.Its mol ratio is: 2-amino-3-nitro-4-methyl pyridine: 2-amino-4-methyl-5-nitro pyridine=100: 3.
With dehydrated alcohol recrystallization said mixture, get 2-amino-3-nitro-4-methyl pyridine sterling 145.0g yield: 95%, content: 99.5%.
(2) 2-hydroxyl-3-nitro-4-methyl pyridine is synthetic
In a reaction flask, add 2-amino-3-nitro-4-methyl pyridine 145g, vitriol oil 260g and water 2000ml, dripping water (240ml) solution of Sodium Nitrite (83g) below 10 ℃, drip and finish, insulation 1h collects solid, the dry 2-hydroxyl-3-nitro-4-methyl pyridine 138g that gets, yield: 95%, content (HPLC): 99.5%
(3) 2-chloro-3-nitro-4-methyl pyridine is synthetic
In a reaction flask, add 2-hydroxyl-3-nitro-4-methyl pyridine 138g and phosphorus oxychloride 450g, be heated to backflow, back flow reaction 4 hours.Normal pressure is slowly poured reaction mixture in the frozen water after reclaiming phosphorus oxychloride, collects solid.Be drying to obtain 2-chloro-3-nitro-4-methyl pyridine 147g, yield: 95%, content: 99.6%
(4) the 2-chlorin-3-amido-4-methyl pyridine is synthetic
In a reaction flask, add 2-chloro-3-nitro-4-methyl pyridine 147g, iron powder 190g and ethanol 800ml, 20 ℃ of stirrings, and under this temperature, slowly drip 10% dilute sulphuric acid, until emerge without bubble, can end.It is confused to filter removal iron, and the normal pressure Recycled ethanol adds entry to doing, and transfers PH=8 with ammoniacal liquor, collects solid, and washing is dried and namely got 2-chlorin-3-amido-4-methyl pyridine 118g.Yield: 97%, content: 99.7%.
(5) 2-chloro-N-(2-chloro-4-picoline-3-yl) niacinamide is synthetic
In a reaction flask, add 2-chlorin-3-amido-4-methyl pyridine 118g, toluene (900ml) and anhydrous pyridine (80g), 20 ℃ of stirrings splash into 2-chloronicotinoyl chloride (160g) and get toluene (600ml) solution, drip off and continue slowly to be added to the water behind the stirring 20min, collect solid, washing, oven dry namely gets 2-chloro-N-(2-chloro-4-picoline-3-yl) niacinamide 222g.Yield: 95%, content: 99.7%.
Embodiment 5
(1) 2-amino-3-nitro-4-methyl pyridine is synthetic
In a reaction flask, add 100ml toluene and the 1000g vitriol oil, start and stir, and under 65 ℃, slowly add 108g2-amino-4-methylpyridine and 6g potassium ethylate in batches, be stirred to whole dissolvings.Then slowly drip 60% rare nitric acid 110g, dropwise, 25 ℃ of lower insulations 5 hours.Namely get reaction solution.
In another reaction flask, add 1000ml water, start and stir, be cooled to 10 ℃, above-mentioned reaction solution slowly is added to the water, the control temperature is at 10 ℃, dropwise, transfer PH=8～8.5 with ammoniacal liquor, collect solid, get the mixture of 2-amino-3-nitro-4-methyl pyridine and 2-amino-4-methyl-5-nitro pyridine.Its mol ratio is: 2-amino-3-nitro-4-methyl pyridine: 2-amino-4-methyl-5-nitro pyridine=100: 2.
With Virahol recrystallization said mixture, get 2-amino-3-nitro-4-methyl pyridine sterling 149.5g yield: 98%, content: 99.5%.
(2) 2-hydroxyl-3-nitro-4-methyl pyridine is synthetic
In a reaction flask, add 2-amino-3-nitro-4-methyl pyridine 145g, vitriol oil 260g and water 2000ml, dripping water (240ml) solution of Sodium Nitrite (83g) below 10 ℃, drip and finish, insulation 1h collects solid, the dry 2-hydroxyl-3-nitro-4-methyl pyridine 138g that gets, yield: 95%, content (HPLC): 99.5%
(3) 2-chloro-3-nitro-4-methyl pyridine is synthetic
In a reaction flask, add 2-hydroxyl-3-nitro-4-methyl pyridine 138g and phosphorus oxychloride 450g, be heated to backflow, back flow reaction 4 hours.Normal pressure is slowly poured reaction mixture in the frozen water after reclaiming phosphorus oxychloride, collects solid.Be drying to obtain 2-chloro-3-nitro-4-methyl pyridine 147g, yield: 95%, content: 99.6%
(4) the 2-chlorin-3-amido-4-methyl pyridine is synthetic
In a reaction flask, add 2-chloro-3-nitro-4-methyl pyridine 147g, iron powder 190g and ethanol 800ml, 20 ℃ of stirrings, and under this temperature, slowly drip 10% rare nitric acid, until emerge without bubble, can end.It is confused to filter removal iron, and the normal pressure Recycled ethanol adds entry to doing, and transfers PH=8 with ammoniacal liquor, collects solid, and washing is dried and namely got 2-chlorin-3-amido-4-methyl pyridine 118g.Yield: 97%, content: 99.7%.
(5) 2-chloro-N-(2-chloro-4-picoline-3-yl) niacinamide is synthetic
In a reaction flask, add 2-chlorin-3-amido-4-methyl pyridine 118g, toluene (900ml) and anhydrous pyridine (80g), 20 ℃ of stirrings splash into 2-chloronicotinoyl chloride (160g) and get toluene (600ml) solution, drip off and continue slowly to be added to the water behind the stirring 20min, collect solid, washing, oven dry namely gets 2-chloro-N-(2-chloro-4-picoline-3-yl) niacinamide 222g.Yield: 95%, content: 99.7%.
Embodiment 6
(1) 2-amino-3-nitro-4-methyl pyridine is synthetic
In a reaction flask, add 100ml dimethylbenzene and the 1000g vitriol oil, start and stir, and under 75 ℃, slowly add 108g2-amino-4-methylpyridine and 10g potassium tert.-butoxide in batches, be stirred to whole dissolvings.Then slowly drip 80% nitric acid 82.5g, dropwise, 25 ℃ of lower insulations 5 hours.Namely get reaction solution.
In another reaction flask, add 1000ml water, start and stir, be cooled to 10 ℃, above-mentioned reaction solution slowly is added to the water, the control temperature is at 10 ℃, dropwise, transfer PH=8～8.5 with ammoniacal liquor, collect solid, get the mixture of 2-amino-3-nitro-4-methyl pyridine and 2-amino-4-methyl-5-nitro pyridine.Its mol ratio is: 2-amino-3-nitro-4-methyl pyridine: 2-amino-4-methyl-5-nitro pyridine=100: 1.
With propyl carbinol recrystallization said mixture, get 2-amino-3-nitro-4-methyl pyridine sterling 149.5g yield: 98%, content: 99.5%.
(2) 2-hydroxyl-3-nitro-4-methyl pyridine is synthetic
In a reaction flask, add 2-amino-3-nitro-4-methyl pyridine 145g, vitriol oil 260g and water 2000ml, dripping water (240ml) solution of Sodium Nitrite (83g) below 10 ℃, drip and finish, insulation 1h collects solid, the dry 2-hydroxyl-3-nitro-4-methyl pyridine 138g that gets, yield: 95%, content (HPLC): 99.5%
(3) 2-chloro-3-nitro-4-methyl pyridine is synthetic
In a reaction flask, add 2-hydroxyl-3-nitro-4-methyl pyridine 138g and phosphorus oxychloride 450g, be heated to backflow, back flow reaction 4 hours.Normal pressure is slowly poured reaction mixture in the frozen water after reclaiming phosphorus oxychloride, collects solid.Be drying to obtain 2-chloro-3-nitro-4-methyl pyridine 147g, yield: 95%, content: 99.6%
(4) the 2-chlorin-3-amido-4-methyl pyridine is synthetic
In a reaction flask, add 2-chloro-3-nitro-4-methyl pyridine 147g, zinc powder 215g and ethanol 800ml, 20 ℃ of stirrings, and under this temperature, slowly drip 10% dilute sulphuric acid, until emerge without bubble, can end.It is confused to filter removal iron, and the normal pressure Recycled ethanol adds entry to doing, and transfers PH=8 with ammoniacal liquor, collects solid, and washing is dried and namely got 2-chlorin-3-amido-4-methyl pyridine 118g.Yield: 97%, content: 99.7%.
(5) 2-chloro-N-(2-chloro-4-picoline-3-yl) niacinamide is synthetic
In a reaction flask, add 2-chlorin-3-amido-4-methyl pyridine 118g, toluene (900ml) and anhydrous pyridine (80g), 20 ℃ of stirrings splash into 2-chloronicotinoyl chloride (160g) and get toluene (600ml) solution, drip off and continue slowly to be added to the water behind the stirring 20min, collect solid, washing, oven dry namely gets 2-chloro-N-(2-chloro-4-picoline-3-yl) niacinamide 222g.Yield: 95%, content: 99.7%.
Claims (10)
1. the synthetic method of the intermediate 2-amino suc as formula the nevirapine shown in the I-3-nitro-4-methyl pyridine, it is characterized in that comprising the following step: in the organic solvent, under the catalysis of mineral alkali or organic bases, under the effect of the vitriol oil and rare nitric acid, to carry out nitration reaction suc as formula the 2-AMINO-4-PICOLINE shown in the II, get final product; Wherein, described mineral alkali is calcium hydroxide, hydrated barta, sodium hydroxide or zinc hydroxide; Described organic bases is sodium methylate, potassium methylate, sodium ethylate, potassium ethylate, sodium tert-butoxide or potassium tert.-butoxide;
2. synthetic method as claimed in claim 1, it is characterized in that: described organic solvent is toluene and/or dimethylbenzene.
3. synthetic method as claimed in claim 1, it is characterized in that: the mass concentration of the described vitriol oil is 95%～98%; The mol ratio of the described vitriol oil and Compound I I is 10: 1～10.5: 1.
4. synthetic method as claimed in claim 1, it is characterized in that: the mass concentration of described rare nitric acid is 20%～80%; The mol ratio of described rare nitric acid and Compound I I is 1.0: 1～1.2: 1.
5. synthetic method as claimed in claim 1 is characterized in that: the consumption of described mineral alkali or organic bases is 0.05～0.1 times of quality of Compound I I.
6. synthetic method as claimed in claim 5 is characterized in that: the consumption of described mineral alkali or organic bases is 0.08～0.1 times of quality of Compound I I.
7. synthetic method as claimed in claim 1, it is characterized in that: the temperature of described nitration reaction is 20～80 ℃.
8. synthetic method as claimed in claim 1 is characterized in that: till the time of described nitration reaction no longer carries out with detection reaction.
9. the synthetic method of the intermediate 2-chloro-N-of a nevirapine (2-chloro-4-picoline-3-yl) niacinamide is characterized in that: comprise the following step:
(1) synthetic method according to each described 2-amino-3-nitro-4-methyl pyridine of claim 1～8 prepares 2-amino-3-nitro-4-methyl pyridine;
(2) the 2-amino of step (1) gained-3-nitro-4-methyl pyridine is carried out diazotization reaction and hydrolysis reaction, gets 2-hydroxyl-3-nitro-4-methyl pyridine;
(3) the 2-hydroxyl of step (2) gained-3-nitro-4-methyl pyridine is carried out the chlorination of hydroxyl, gets 2-chloro-3-nitro-4-methyl pyridine;
(4) the 2-chloro-3-nitro-4-methyl pyridine of step (3) gained is carried out the reduction reaction of nitro, get the 2-chlorin-3-amido-4-methyl pyridine;
(5) the 2-chlorin-3-amido-4-methyl pyridine and the 2-chloronicotinoyl chloride that step (4) are obtained react, and namely make 2-chloro-N-(2-chloro-4-picoline-3-yl) niacinamide;
10. synthetic method as claimed in claim 9, it is characterized in that: the synthetic method of described 2-chloro-N-(2-chloro-4-picoline-3-yl) niacinamide comprises the following step:
(1) prepares 2-amino-3-nitro-4-methyl pyridine according to the synthetic method according to each described 2-amino-3-nitro-4-methyl pyridine of claim 1～8;
(2) 2-hydroxyl-3-nitro-4-methyl pyridine is synthetic
The 2-amino of step (1) gained-3-nitro-4-methyl pyridine is dissolved in the dilute sulphuric acid, drips the aqueous solution of Sodium Nitrite, obtain faint yellow solid, i.e. 2-hydroxyl-3-nitro-4-methyl pyridine;
(3) 2-chloro-3-nitro-4-methyl pyridine is synthetic
With step (2) gained solid, be dissolved in the phosphorus oxychloride, heating reflux reaction namely gets 2-chloro-3-nitro-4-methyl pyridine;
(4) the 2-chlorin-3-amido-4-methyl pyridine is synthetic
Step (3) gained dissolution of solid in solvent, is added reductive agent, add mineral acid, through aftertreatment, collect solid;
Wherein said solvent is a kind of in ethanol, propyl alcohol, Virahol and the butanols etc.; Selected reductive agent is a kind of in the metal-powders such as iron powder, zinc powder and aluminium powder; Selected mineral acid is a kind of in hydrochloric acid, sulfuric acid, nitric acid and the ammonia chloride;
(5) 2-chloro-N-(2-chloro-4-picoline-3-yl) niacinamide is synthetic
In toluene and anhydrous pyridine, and the condensation of 2-chloronicotinoyl chloride namely gets 2-chloro-N-(2-chloro-4-picoline-3-yl) niacinamide with step (4) gained solid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110249349 CN102952068A (en) | 2011-08-26 | 2011-08-26 | Synthesis method for Nevirapine intermediates |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110249349 CN102952068A (en) | 2011-08-26 | 2011-08-26 | Synthesis method for Nevirapine intermediates |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102952068A true CN102952068A (en) | 2013-03-06 |
Family
ID=47761512
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 201110249349 Pending CN102952068A (en) | 2011-08-26 | 2011-08-26 | Synthesis method for Nevirapine intermediates |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102952068A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115028577A (en) * | 2022-06-24 | 2022-09-09 | 盐城迪赛诺制药有限公司 | Purification method of 2-chloro-N- (2-chloro-4-methylpyridin-3-yl) nicotinamide |
-
2011
- 2011-08-26 CN CN 201110249349 patent/CN102952068A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115028577A (en) * | 2022-06-24 | 2022-09-09 | 盐城迪赛诺制药有限公司 | Purification method of 2-chloro-N- (2-chloro-4-methylpyridin-3-yl) nicotinamide |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102153519B (en) | Preparation method of quinazoline derivative | |
| CN103172571B (en) | New preparation method of insect repellent albendazole | |
| CN103304512A (en) | Preparation method for febuxostat | |
| CN102898361A (en) | Method for preparing 2-chlorine-3-amino-4-picoline | |
| CN104402814A (en) | Method for synthesizing 2-chlorine-N-(2,4-difluorophenyl) nicotinamide by one-pot method | |
| CN105399663A (en) | 2, 3-dichloropyridine preparation method | |
| CN105330598A (en) | Preparing method for pirfenidone | |
| CN103694176B (en) | Preparation method of nilotinib intermediate | |
| CN104860923A (en) | Vonoprazan fumarate preparation method | |
| CN107098822A (en) | A kind of preparation method for preparing the hydroxy acetophenone of 3 amino of Pranlukast key intermediate 2 | |
| CN102952068A (en) | Synthesis method for Nevirapine intermediates | |
| CN106674084B (en) | A kind of preparation method of 2- isopropyl oxygroup -5- methyl -4- (piperidin-4-yl) aniline dihydrochloride | |
| CN102898360A (en) | Synthesis of 3, 5-dibromo-4-iodopyridine | |
| CN101983961A (en) | Preparation method of 5-amino-2-methyl quinoline | |
| CN101967120A (en) | Preparation method of 2-p-chlorobenzyl pyridine | |
| CN102108065B (en) | Method for preparing 2-quinoxalinol | |
| CN107698538A (en) | The intermediate 3 of roxatidine acetate hydrochloride（1 piperidine methyl）The new preparation method of phenol | |
| CN107698501A (en) | The preparation technology of the hydroxy niacin of 5,6 dimethyl 2 | |
| CN101219967B (en) | Process for producing 2-nitryl substituted benzene ethane nitrile compounds | |
| CN106749038A (en) | A kind of preparation method of flibanserin | |
| CN102382100A (en) | Preparation method of imatinib | |
| CN103224452B (en) | 2-bromine-4,6-dichloroaniline preparation method | |
| CN102532010A (en) | Preparation method of 2-chloro-3-aminopyridine | |
| CN102942553B (en) | Preparation method for 6-carboxylfluorescein | |
| CN106243022A (en) | A kind of preparation method of nevirapine intermediate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20130306 |