CN102952133A - Method for preparing nevirapine - Google Patents
Method for preparing nevirapine Download PDFInfo
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- CN102952133A CN102952133A CN 201210492734 CN201210492734A CN102952133A CN 102952133 A CN102952133 A CN 102952133A CN 201210492734 CN201210492734 CN 201210492734 CN 201210492734 A CN201210492734 A CN 201210492734A CN 102952133 A CN102952133 A CN 102952133A
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Abstract
The invention relates to a method for preparing nevirapine. With the method disclosed by the invention, the nevirapine is obtained in four steps of Knoevenagel reaction, amination, copper salt catalytic reaction and cyclizing. The method has the advantages of simple technology and convenience in operation and is suitable for the large scale production of the modern enterprise, and the obtained nevirapine has an important influence on the development of the medicine field, and has a huge economic value and social value.
Description
Technical field
The present invention relates to field of biological pharmacy, be specifically related to a kind of preparation method of nevirapine.
Background technology
Nevirapine (Nevirapine) is called for short NVP, chemical name be 11 – Huan Bing Ji –, 4 – Jia Ji –, 5,11 – dihydro-4-Jia Ji – 6H – dihydro pyrido [3,2 – b:2 ', 3 '-e] [Isosorbide-5-Nitrae] diaza Zhuo – 6 – ketone, molecular formula is C
15H
14N
4O, relative molecular weight 266.30 is the non-nucleoside hiv reverse transcriptase inhibitors by the research and development of German Boehringer Ingelheim company.Its mechanism of action is by directly being connected with the HIV reversed transcriptive enzyme, and the catalysis end of this enzyme is broken, and with the dna polymerase activity that blocking-up RNA relies on and DNA relies on, thereby effectively reduces viral load in the body, the recovery immune function of human body.In September, 1996, nevirapine was gone on the market by drugs approved by FDA, and drugs approved by FDA enlarged indication in 1998.Nevirapine is that present use is treated and one of the medicine that prevents AIDS widely, and it can see through placenta, is used for prevention HIV positive pregnant women and infects ewborn infant.
The synthetic method of nevirapine mainly contains three classes at present:
First kind method: 2-chloro-3-pyridyl nitrile and cyclopropylamine are placed ethanol or 1-propyl alcohol solvent, and add K
3PO
4Or triethylamine refluxes, use again the salt acid for adjusting pH value, add chlorizating agent such as sulfur oxychloride, in the solvent of toluene or THF, reflux, last and CAPIC adds anhydrous K 3PO4 amidation in acetonitrile, add highly basic such as NaH or NaH-MDS cyclization in inert solvent such as Jia Ben ﹑ THF and get nevirapine.
This synthetic method sees US6680383, advantage is to have avoided condition of high voltage, but has used irritating chloride reagent, and environment is easily polluted, NaH or expensive NaH-MDS, the high large-scale industrial production that is unfavorable for of production cost are adopted in the final step cyclization.
Equations of The Second Kind method: with 2; 6-two chlorin-3-amido-4-methyl pyridines and 2-chloronicotinoyl chloride carry out amidation; again with cyclopropylamine condensation in xylene solvent; under nitrogen protection; with NaH as catalyzer; reflux in 2-methyl ethyl ether solvent is carried out the catalytic dehydrogenation deoxidation with Pd/C at last and is obtained nevirapine.
This synthetic method craft step is long, and side reaction is many, and the production cycle is long, and domestic research is less, and method sees Grozinger and is published in J.Heterocycle.chem 1995,32 (1), 259-264.
The 3rd class methods: take 3-amino-2-methoxyl group-4-picoline as raw material; with the 2-chloronicotinoyl chloride at ethyl acetate and N; the N-diisopropylethylamine is 0 ℃ of amidation; with cyclopropylamine condensation in encloses container, be placed down in the dry pyridine in argon shield again and get nevirapine with NaH or NaH-DMS 90 ℃ of cyclizations.
This synthetic method needs low-temp reaction, and processing condition are harsh, and real cost of production is high, is not suitable for suitability for industrialized production, is only suitable for the laboratory preparation.
Since the first acquired immune deficiency syndrome (AIDS) (AIDS) was confirmed by the Center for Disease Control (CDC) in June, 1981, capture greatly a difficult problem as one of medical circle, human life security in serious threat.It is reported, China totally reports the infected/patient 444712 examples from 1985 annual report first case acquired immune deficiency syndrome (AIDS) in by the end of December, 2011, and wherein patient's 174399 examples add up dead 93003 examples that surpass.Nevirapine has significant role as the treatment of infecting for HIV in the non-nucleoside reverse transcriptase inhibitor, in production practice how high yield, it is low that to pollute, prepare nevirapine cheaply be the center that numerous experts and scholars endeavour to study always.
Summary of the invention
Purport of the present invention, is proved by repetition test using for reference on the advanced both at home and abroad technical foundation to solve the shortcoming in the above-mentioned background technology; a kind of preparation method of nevirapine is provided, and this technological operation is simple, the low pollution; high yield is fit to large-scale production, can satisfy the requirement of field of medicaments.
For the foregoing invention purpose, the preparation method of a kind of nevirapine of the present invention, concrete technical scheme is:
The preparation method of a kind of nevirapine of the present invention is characterized in that the method comprises Knoevenagel reaction, amination reaction, mantoquita catalyzed reaction, cyclisation four steps.
The present invention take 2-chlorine 3-amino-4-methylpyridine as raw material and the 2-chloronicotinoyl chloride make solvent with toluene, K
2CO
3Make acid binding agent, 75 ℃~80 ℃ amidations get 2-chloro-N-(2-chloro-4-methyl-3-pyridyl) cigarette methane amide, get N-(2-chloro-4-methyl-3-pyridyl)-2-cyclopropyl amino niacinamide with cyclopropylamine 120~130 ℃ of condensations again, adding the potassium tert.-butoxide closed loop in toluene solvant is nevirapine.
The preparation method of a kind of nevirapine of the present invention is characterized in that the method concrete steps are:
(1) be that raw material reacts through Knoevenagel with 4,4-dimethoxy-2-butanone and propane dinitrile, closed loop, chlorination, hydrolysis, the Hofmann 2-chlorine 3-amino-4-methylpyridine of degrading to get then;
(2) under the certain temperature condition, with raw material 2-chlorine 3-amino-4-methylpyridine and 2-chloronicotinoyl chloride, make solvent with toluene, K
2CO
3Make acid binding agent, amination obtains 2-chloro-N-(2-chloro-4-methyl-3-pyridyl) cigarette methane amide;
(3) under the condition of mantoquita catalysis, 2-chloro-N-(2-chloro-4-methyl-3-pyridyl) cigarette methane amide and cyclopropylamine reaction are obtained intermediate N (2-chloro-4-methyl-3-pyridyl)-2-cyclopropyl amino niacinamide;
(4) under alkaline condition, intermediate N (2-chloro-4-methyl-3-pyridyl)-2-cyclopropyl amino niacinamide cyclisation is obtained nevirapine.
A kind of nevirapine preparation method of the present invention is characterized in that the preparation Knoevenagel reaction of 2-chlorine 3-amino-4-methylpyridine, and reaction solvent is one or more in toluene, benzene, methylene dichloride, DMF, THF, the acetone, preferred toluene.
The preparation method of a kind of nevirapine of the present invention is characterized in that the reaction conditions of 2-chlorine 3-amino-4-methylpyridine and 2-chloronicotinoyl chloride, and temperature control is specially 70 ℃~80 ℃, 6~8 hours reaction times.
The preparation method of a kind of nevirapine of the present invention, it is characterized in that the preparation of N-(2-chloro-4-methyl-3-pyridyl)-2-cyclopropyl amino niacinamide, solvent is tetrahydrofuran (THF), and catalyzer is cuprous chloride, temperature of reaction is room temperature, 12~14 hours reaction times.
The preparation method of a kind of nevirapine of the present invention is characterized in that the alkaline condition of intermediate N (2-chloro-4-methyl-3-pyridyl)-2-cyclopropyl amino niacinamide cyclisation is the environment of salt of wormwood.
The present invention has the following advantages:
1. technique is simple, and is easy and simple to handle, pollution-free.
2. product yield is high, and quality is good, and cost is low, is fit to large-scale production.
3. the products production prospect is good, and Social benefit and economic benefit is large.
Embodiment
Following enforcement can illustrate in greater detail the present invention, but does not limit in any form the present invention.
Embodiment:
The preparation of (1) 2,6-dihydroxyl-3-cyano group-4-picoline:
In the 1L three-necked bottle, add Malonamide nitrile (84g, lmol), methyl aceto acetate (130g, lmol) and methyl alcohol (200ml), 68 ℃ splash into potassium hydroxide (68.4g, 1.2mol) methyl alcohol (200ml) solution, drip in the 2h and finish equality of temperature back flow reaction 8h.Be chilled to room temperature, filter, filtrate goes in the 3L flask, adds 70 ℃ water (1.2L), and is complete molten rear with concentrated hydrochloric acid (80ml) acidifying, separates out a large amount of white solids.Filter, the filter cake oven dry gets white powder 2,6-dihydroxyl-3-cyano group-4-picoline (144.5g, 96.3%).
The preparation of (2) 2,6-two chloro-3-cyano group-4-picolines:
In the 2L autoclave, add 2,6-dihydroxyl-3-cyano group-4-picoline (150g, lmol) and phosphorus oxychloride (485ml, 5.3mo1), decompression post-heating to 130 ℃ stirring reaction 8h.Reaction is finished material is poured in the frozen water (3L), suction filtration, and filter cake gets white powder 2 through washing, drying, 6-two chloro-3-cyano group-4-picolines (155.8g, 83.3%), mp106~107 ℃.
The preparation of (3) 2,6-two chloro-4-methyl-Niacinamides:
In the 1L three-necked bottle, add 2,6-, two chloro-3-cyano group-4-picoline (187g, lmol) and dense sulphur (170ml, 2.8mol), pour into behind 105 ℃ of stirring reaction 4h in the frozen water (1.4L), transfer to neutrality with 50% sodium hydroxide solution under stirring.Filter, filter cake gets cream-coloured powdery 2,6-two chloro-4-methyl-Niacinamides (195.7g, 95.4%), 173.5~174.8 ℃ of mp through washing, oven dry.
The preparation of (4) 2,6-two chlorin-3-amido-4-methyl pyridines:
Add entry (700ml) and sodium hydroxide (76.3g, 1.9mol) in the 1L three-necked bottle, 0~5 ℃ of stirring splashes into bromine (29.4ml, 0.6mo1), slowly gradation adds 2,6-, two chloro-4-methyl-Niacinamides (102.5g, 0.5mo1).Finish and slowly be warming up to 70 ℃ of stirring 1.5h, be down to stirred overnight at room temperature.Suction filtration, filter cake gets yellow needle-like crystal 2,6-two chlorin-3-amido-4-methyl pyridines (82.5g, 93.2%), 81~84 ℃ of mp through washing, 60 ℃ of oven dry.
(5) preparation of 3-amino-4-methylpyridine:
In the 2L autoclave, add entry (65m1), methyl alcohol (200m1), 10%Pd/C (1.2g) and 2,6-two chlorin-3-amido-4-methyl pyridine (35.4g, 0.2mo1), slowly pass into hydrogen after the decompression, be warming up to 70 ℃ of reaction 5h under the pressure 700kPa.Filter, filtrate is steamed except methyl alcohol, and residuum transfers to pH 9~10 with the 6mol/L potassium hydroxide solution, suction filtration, and the filter cake hot wash, filtrate and washing lotion leave standstill cooling after merging, and separate out white needle-like crystals.Filter, filtrate extracts with methylene dichloride (30ml * 4), the extraction liquid evaporate to dryness, and residuum and filter cake merge, and get 3-amino-4-methylpyridine (20.3g, 94.0%), 102~104 ℃ of mp.
(6) preparation of 2-chlorin-3-amido-4-methyl pyridine:
In the 1L three-necked bottle, add 3-amino-4-methylpyridine (108g, 1mo1) and the vitriol oil (360m1), be stirred to and be warming up to 40 ℃ after clear and bright, slowly drip freshly prepared 1.15g/ml hydrogen peroxide (105m1) in the 30min, and temperature control is in about 75 ℃.Finish equality of temperature reaction 6~8h.With toluene (40ml * 4) extraction, the extraction liquid evaporate to dryness obtains unreacted 3-amino-4-methylpyridine (4.9g).Water transfers to pH 3 with 45% sodium hydroxide solution, separates out a large amount of precipitations, suction filtration, and the filter cake oven dry gets yellow solid 2-chlorin-3-amido-4-methyl pyridine (133.2g, 93.4%), 70~80 ℃ of mp.
(7) preparation of 2-chloro-N-(2-chloro-4-methyl-3-pyridyl) cigarette methane amide:
In the 3L three-necked bottle, add 2-chlorin-3-amido-4-methyl pyridine (142.5g, 1mo1), toluene (900m1) and anhydrous pyridine (80g), 20 ℃ of stirrings splash into toluene (600m1) solution of 2-chloronicotinoyl chloride (193.6g, 1.1mo1), approximately finish in the 1.5h.Slowly add entry (900m1) after continuing to stir 20min, separate out a large amount of white precipitates.Continue to stir 2h, filter, 60 ℃ of drying under reduced pressure of filter cake get white powdery 2-chloro-N-(2-chloro-4-methyl-3-pyridyl) cigarette methane amide (244g, 86.8%), 190~192 ℃ of mp.
(8) preparation of nevirapine:
In the 2L autoclave, add 2-chloro-N-(2-chloro-4-methyl-3-pyridyl) cigarette methane amide (282g, lmo1), salt of wormwood (56g), cyclopropylamine (142.5g, 2.5mo1) and tetrahydrofuran (THF) 500m1).135~145 ℃ of stirring reactions 12~14 hours.Let cool rear suction filtration, filter cake washs with tetrahydrofuran (THF) (50ml * 3), and filtrate and washing lotion merge, and removes unreacted cyclopropylamine and (approximately 370m1) under reduced pressure, and residuum goes in the separating funnel stand-by.In addition under nitrogen protection with 60%NaH (152g; 3.8mo1) add in the tetrahydrofuran (THF) (1L); splash into the liquid in the separating funnel in the time of 130 ℃; temperature control is in 145~150 ℃ in the dropping process; approximately lh drips completely, continues to remove solvent (approximately 800m1) under reduced pressure after the reaction 1h cooling, and residuum is poured in the water (1.5L) under stirring; be chilled to room temperature, transfer to pH 7 with glacial acetic acid behind the adding hexanaphthene (650m1).Continue to stir 1.5h, filter, filter cake is water (200ml * 4) and ethanol (200ml * 2) washing successively, 70 ℃ of drying under reduced pressure, and getting buff powder is nevirapine (182.3g, 68.5%), 245~247 ℃ of mp.
Claims (6)
1. a method for preparing nevirapine is characterized in that the method comprises Knoevenagel reaction, amination reaction, mantoquita catalyzed reaction, cyclisation four steps.
2. described a kind of method for preparing nevirapine according to claim 1 is characterized in that the method concrete steps are:
Be that raw material reacts through Knoevenagel with 4,4-dimethoxy-2-butanone and propane dinitrile, closed loop, chlorination, hydrolysis, the Hofmann 2-chlorine 3-amino-4-methylpyridine of degrading to get then;
Under the certain temperature condition, with raw material 2-chlorine 3-amino-4-methylpyridine and 2-chloronicotinoyl chloride, make solvent with toluene, K
2CO
3Make acid binding agent, amination obtains 2-chloro-N-(2-chloro-4-methyl-3-pyridyl) cigarette methane amide;
Under the condition of mantoquita catalysis, 2-chloro-N-(2-chloro-4-methyl-3-pyridyl) cigarette methane amide and cyclopropylamine reaction are obtained intermediate N (2-chloro-4-methyl-3-pyridyl)-2-cyclopropyl amino niacinamide;
Under alkaline condition, intermediate N (2-chloro-4-methyl-3-pyridyl)-2-cyclopropyl amino niacinamide cyclisation is obtained nevirapine.
3. a kind of method for preparing nevirapine according to claim 2, it is characterized in that the preparation Knoevenagel reaction of 2-chlorine 3-amino-4-methylpyridine, reaction solvent is one or more in toluene, benzene, methylene dichloride, DMF, THF, the acetone, preferred toluene.
4. a kind of method for preparing nevirapine according to claim 2 is characterized in that the reaction conditions of 2-chlorine 3-amino-4-methylpyridine and 2-chloronicotinoyl chloride, and temperature control is specially 70 ℃~80 ℃, 6~8 hours reaction times.
5. a kind of method for preparing nevirapine according to claim 2, it is characterized in that the preparation of N-(2-chloro-4-methyl-3-pyridyl)-2-cyclopropyl amino niacinamide, solvent is tetrahydrofuran (THF), and catalyzer is cuprous chloride, temperature of reaction is room temperature, 12~14 hours reaction times.
6. described a kind of method for preparing nevirapine according to claim 2 is characterized in that the alkaline condition of intermediate N (2-chloro-4-methyl-3-pyridyl)-2-cyclopropyl amino niacinamide cyclisation is the environment of salt of wormwood.
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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CN114835639A (en) * | 2022-05-30 | 2022-08-02 | 南京红太阳生物化学有限责任公司 | Preparation method of nevirapine intermediate |
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 |
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
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CN114835639A (en) * | 2022-05-30 | 2022-08-02 | 南京红太阳生物化学有限责任公司 | Preparation method of nevirapine intermediate |
CN114835639B (en) * | 2022-05-30 | 2023-12-15 | 南京红太阳生物化学有限责任公司 | Preparation method of nevirapine intermediate |
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 |
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Application publication date: 20130306 |