CN102898361A - Method for preparing 2-chlorine-3-amino-4-picoline - Google Patents
Method for preparing 2-chlorine-3-amino-4-picoline Download PDFInfo
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- CN102898361A CN102898361A CN2012104152771A CN201210415277A CN102898361A CN 102898361 A CN102898361 A CN 102898361A CN 2012104152771 A CN2012104152771 A CN 2012104152771A CN 201210415277 A CN201210415277 A CN 201210415277A CN 102898361 A CN102898361 A CN 102898361A
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Abstract
The invention relates to a novel synthetic method for preparing 2-chlorine-3-amino-4-picoline, and belongs to a production process and corresponding various process conditions for preparing the 2-chlorine-3-amino-4-picoline by using 4-picoline as raw materials sequentially through four-step reaction: concentrated nitric acid nitration, sodium pyrosulfite nitro migration, catalyst catalytic hydrogenation and hydrogen peroxide and concentrated hydrochloric acid chlorination. The method has the beneficial effects that industrial products of 4-picoline are used as raw materials, the raw materials are easily obtained, the price is proper, the reaction condition is mild, and a novel and efficient new path is provided for the industrial production of the 2-chlorine-3-amino-4-picoline.
Description
Technical field
The present invention relates to a kind of new synthetic method of the 2-of preparation chlorin-3-amido-4-methyl pyridine, be specifically take the 4-picoline as raw material successively, Sodium Pyrosulfite nitrated through concentrated nitric acid make nitro migration, catalyst hydrogenation, hydrogen peroxide and concentrated hydrochloric acid chlorination, four-step reaction prepares production technique and corresponding every processing condition of 2-chlorin-3-amido-4-methyl pyridine.
Background technology
The 2-chlorin-3-amido-4-methyl pyridine is the crucial medicine intermediate of synthesizing anti-AIDS pharmaceutical nevirapine, is widely used in the synthetic and research and development of medicine, agricultural chemicals, veterinary drug, has very high using value and marketable value.Existing synthetic 2-chlorin-3-amido-4-methyl pyridine has following method:
The synthetic 2-chlorin-3-amido-4-methyl pyridine of report is in 1980 the earliest, the people such as Chapman have reported take 2-chloro-3-nitro-4-methyl pyridine as raw material, obtain 2-chlorin-3-amido-4-methyl pyridine (Chapman D through reduction, Hurst J.Pyrazolopyridines.Part 5.Preparation and reactions of pyrazolo[3,4-c] pyridines.J Chem Soc, Perkin Trans 1,1980, (11): 2398-2404).
The people such as Grozinger K G had reported in 1993, adopting β-carbonyl ethyl butyrate and malonamide nitrile is starting raw material, obtain the 2-chlorin-3-amido-4-methyl pyridine through closed loop, chlorination, hydrolysis, Hoffman degraded, hydrogenation, chlorination, thick productive rate 43.2-52.7%.This method raw material is not easy to obtain, and step is more loaded down with trivial details, need by intermediate 2, and 2 of 6-dihydroxyl-4-methyl-3-itrile group pyridine, the chlorination of 6-position, again dechlorination reduction will optionally use chlorine in 2-position again chlorination at last.The reduction of the chlorination of 2,6-position and dechlorination and 2-position chlorinating step optionally, equipment requirements is also higher, somewhat expensive, yield is unstable.(Grozinger?K?G，Hargrave?K?D，Grozinger?K?G.Method?for?preparing?3-amino-2-chloro-4-alkylpyridines.US?5200522，1993-04-06.)
The people such as Hargrave K D had reported the synthetic of Nevirapine in 1994, and the synthetic of important intermediate 2-chlorin-3-amido-4-methyl pyridine wherein arranged, and take 2-hydroxyl-3-nitro-4-methyl pyridine as raw material, obtained through chlorination, reduction, and this method raw material is not easy to obtain.，
(Hargrave?K?D，Proudfoot?J?R，Adams?J，et?al.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.US?5366972，1994-11-22.)
The people such as nineteen ninety-five Grozinger K G have reported, in the laboratory take 2-AMINO-4-PICOLINE or 2-hydroxy-4-methyl pyridine as raw material through the step such as nitrated, synthesized the 2-chlorin-3-amido-4-methyl pyridine, but that this reaction can be 3 or 5 non-selectivities is nitrated.(Grozinger?K?G.，Fuchs?V.，Hargrave?K?D，et?al.Synthesis?of?Nevirapine?and?its?Major?Metabolite.J.Heterocyclic?Chem.，1995，32(11)：259-263.)
The people such as nineteen ninety-five Zhang TY have reported from ethyl cyanoacetate, obtain the 2-chlorin-3-amido-4-methyl pyridine through class Michael reaction, closed loop, ammonification, Hofmann degraded.This method Michael addition step reaction time is longer, and closed loop step productive rate is lower.(Zhang?T?Y，Stout?J?R，Keay?J?G，et?al.Regioselective?synthesis?of?2-chloro-3-pyridinecarboxylates.Tetrahedron，1995，51(48)：13177-13184(8).)
The people such as Grozinger K G in 1997 have improved the reaction of report in 1993, adopting β-carbonyl ethyl butyrate and malonamide nitrile is starting raw material, obtain the 2-chlorin-3-amido-4-methyl pyridine, productive rate 19.6-26.1% through closed loop, chlorination, hydrogenation, hydrolysis, Hoffman degraded, chlorination.This method yield is lower and unstable, and step is more loaded down with trivial details, need to remove the chlorine on 2-and the 6-position, and the back is again in the chlorination of 2-position, and in the end chlorinating step 2-position and 6-position all are chlorinated easily, bad control, and equipment requirements is also higher, somewhat expensive.(Grozinger?K?G，Hargrave?K?D，Adams?J.Method?for?the?preparation?of?3-amino-2-chloro-4-methylpyridines.US?5668287，1997-09-16.)
Schenider H had reported from 2 in 1997,6-two chloro-3-amido-4-alkyls or aryl set out and obtain the synthesis route of 2-chloro-3-amido-4-alkyl or aryl-pyridine through dechlorination, chlorination reaction, this method does not need separation of intermediates 3-amido-4-alkyl or aryl-pyridine, directly at H
2O
2With the synthetic target compound of chlorination among the HCl, yield 78.9-80.0%.This chlorination method can effectively substitute the method that the people such as Grozinger K G use chlorinated with chlorine at last, has avoided simultaneously the high request to equipment.(Schenider?H.Methodfor?preparing?3-amino-2-chloro-4-alkylpyridine?or-4-arylpyridine.US?5686618，1997-11-11.)
Nummy L J had reported with the 2-chlorine-3-aminopyridine and has set out in 1997, through becoming sulfosalt with thioether reactant, obtained the substituted pyridines of 4-position alkyl through rearrangement reaction again, obtained the 2-chlorin-3-amido-4-methyl pyridine through reduction reaction again, productive rate 44%.The first step becomes the sulfosalt condition relatively harsher in this reaction, and temperature requirement is lower, and needs nitrogen protection; Final step needs Raney Ni to make catalyzer, and is expensive.(Nummy?L?J.Method?for?the?preparation?of?3-amino-2-chloro-4-alkylpyridines.US?5654429，1997-08-05.)
Grozinger Karl had reported in 2000, take acetone and propane dinitrile as raw material, obtain the 2-chlorin-3-amido-4-methyl pyridine through Knoevenagel reaction, addition reaction, closed loop, sandmeyer reaction, chlorination, hydrolysis, Hofmann degraded, productive rate only has 8.7% (Grozinger K.Synthesis of 3-amino-2-chloro-4-methylpyridine from malononitrile and acetone.WO 0043365.2000-07-27.).
The same year; Grozinger Karl is raw material from acetone and ethyl cyanoacetate; obtain the 2-chlorin-3-amido-4-methyl pyridine through Knoevenagel reaction, class Michael reaction, closed loop, hydrolysis, acidylate, ammonification, Hofmann degraded, productive rate is brought up to 17.4% (in ethyl cyanoacetate).This method yield is still lower, key is that one step of closed loop productive rate is very low, be 30.4% (GrozingerK.Synthesis of 3-amino-2-chloro-4-methylpyridine from acetone and ethyl cyanoacetate.WO0043364,2000-07-27.).
Gupton B F had reported in 2002, from 4,4-dimethoxy-2-butanone and propane dinitrile are that raw material obtains the 2-chlorin-3-amido-4-methyl pyridine through Knoevenagel reaction, closed loop, chlorination, hydrolysis, Hofmann degraded, productive rate 48.7% (in propane dinitrile), and each goes on foot reaction product and all passes through
1HNMR,
13The sign such as C NMR, IR, MS, HPLC (Gupton B F.Process for making3-amino-2-chloro-4-methylpyridine.US 2002052507,2002-05-02.).
In sum, although the synthetic method of preparation 2-chlorin-3-amido-4-methyl pyridine has many, but mostly all only in the laboratory, prepare, particularly each the synthetic method productive rate before 2000 is all lower, raw material should not get, higher to equipment requirements, all be unfavorable for realizing large-scale industrial production, now only rest on the lab scale stage.Gupton B F in 2002 report with 4,4-dimethoxy-2-butanone and propane dinitrile are that the method yield of the synthetic 2-chlorin-3-amido-4-methyl pyridine of raw material is higher, each synthesis condition is relatively gentleer, is fit to suitability for industrialized production, the industrialized production of its that realized at home.But raw material 4, the price of 4-dimethoxy-2-butanone is higher, and should not deposit for a long time, has increased difficulty to suitability for industrialized production.
Summary of the invention
The object of the invention is to for above-mentioned shortcoming, provide a kind of raw material to be easy to get, productive rate is higher, cost is suitable, be fit to the method for preparing the 2-chlorin-3-amido-4-methyl pyridine of large-scale industrial production.
The object of the present invention is achieved like this:
The present invention is take industrialization product 4-picoline as raw material,, Sodium Pyrosulfite nitrated through concentrated nitric acid makes nitro migration, catalyst hydrogenation, hydrogen peroxide and concentrated hydrochloric acid chlorination successively, four-step reaction prepares the 2-chlorin-3-amido-4-methyl pyridine, and concrete preparation process is as follows:
(1) adds first trifluoroacetic anhydride in the reactor, drip the 4-picoline under the cooling conditions, reacted 1-6 hour, drip again concentrated nitric acid, reacted 4-24 hour, make N-nitro-4-methyl pyridine;
(2) reaction solution that (1) is obtained is added drop-wise in the aqueous solution of freezing Sodium Pyrosulfite or S-WAT or sodium bisulfite or V-Brite B, stirring at room reaction 12-48 hour, transfer system pH=6-7 with alkaline solution, extraction makes 3-nitro-4-methyl pyridine;
(3) add 3-nitro-4-methyl pyridine in reactor, methyl alcohol, water or its mixture are made solvent, and palladium carbon is done catalyst hydrogenation, and temperature is controlled between 20-100 ℃, and reaction 1-24h makes the 3-amino-4-methylpyridine;
(4) in reactor, add the 3-amino-4-methylpyridine, in cooling bath to wherein slowly dripping concentrated hydrochloric acid, be warming up to 40 ℃ after stirring to clarify, slowly drip 30% hydrogen peroxide, reacted 1-6 hour, with concentrated alkali solution regulation system pH=3, a large amount of pale precipitations are separated out, recrystallization obtains faint yellow or white needle-like crystals, is product 2-chlorin-3-amido-4-methyl pyridine.
Preparation method of the present invention is characterized in that used reagent of one step of nitro migration is any one or a few the mixture in Sodium Pyrosulfite, S-WAT, sodium bisulfite, the V-Brite B.
Concrete reaction equation is as follows:
Beneficial effect of the present invention is as follows:
Selecting industrialization product 4-picoline is raw material, and raw material is easy to get, and price is suitable, and reaction conditions is gentle, the invention provides a kind of novel, can be used for the new way of suitability for industrialized production 2-chlorin-3-amido-4-methyl pyridine efficiently.
Embodiment
Following exemplifying embodiment will better illustrate the present invention, but it is emphasized that the present invention never only limits to the represented content of these several exemplifying embodiments.
Following examples have shown not ipsilateral of the present invention, and given data comprise concrete operations and reaction response condition and product, and product purity is passed through high-performance liquid chromatogram determination.
Embodiment 1
(1) preparation of N-nitro-4-methyl pyridine: at first add 200mL trifluoroacetic anhydride (0.84mol) in the reactor, stirring is cooled to 0 ℃, slowly drips 33mL 4-picoline (0.34mol), produces yellow solid, after adding, at 0 ℃ of lower stirring reaction 2h that continues.Afterwards, drip 38mL concentrated nitric acid (0.72mol), temperature of reaction rises to room temperature gradually, continues stirring reaction 10h, obtains the solution of N-nitro-4-methyl pyridine, need not further processing, directly enters next step reaction.
(2) preparation of 3-nitro-4-methyl pyridine: the N-nitro-4-methyl pyridine reaction solution that the upper step was obtained is added drop-wise in the aqueous solution of freezing 64g sodium pyrosulfate (0.34mol) and 500mL, stirring at room 24h, transfer system pH=6-7, CH with the 25%NaOH aqueous solution
2Cl
2Extraction product, extraction liquid is dry, filters, and is spin-dried for solvent, gets the crude product of sundown liquid 3-nitro-4-methyl pyridine, purity 81.0%, productive rate 65.9% (in the 4-picoline).
(3) preparation of 3-amino-4-methylpyridine: add successively 34.0g3-nitro-4-methyl pyridine (81.0% in the reactor, 0.2mol), 200mL methyl alcohol, 1.9g5% palladium charcoal (water ratio 54.13%), envelope still, high-purity hydrogen ventilation still Air, pressure 0.4MPa, heated and stirred, temperature are controlled at 70 ℃, reaction 5h is when pressure needs hydrogen make-up during less than 0.15MPa.React complete after, cool to room temperature is driven still, suction filtration reclaims palladium carbon, the filtrate decompression precipitation, add the 50mL water dissolution, be alkalescence with 30% potassium hydroxide solution regulator solution pH value, use organic solvent extraction, merge organic phase, drying is filtered, the decompression precipitation, get faint yellow solid 3-amino-4-methylpyridine, purity 98.1%, productive rate 93.5%.
(4) preparation of 2-chlorin-3-amido-4-methyl pyridine: in reactor, add first 21.6g 3-amino-4-methylpyridine (0.2mol), in cooling bath, slowly drip the concentrated hydrochloric acid of 72mL, be warming up to 40 ℃ after stirring to clarify, slowly drip the hydrogen peroxide of 30mL 30% in the 30-60min, temperature control reaction 2h.React complete, the sodium hydroxide solution regulation system pH=3 with 45% uses chloroform extraction, drying, and precipitation can obtain crude product.With sherwood oil or normal hexane recrystallization, obtain white or faint yellow needle-like crystal, be the 2-chlorin-3-amido-4-methyl pyridine, purity 99.0%, productive rate 83.2%, fusing point 68-69 ℃.
Embodiment 2
Method and condition such as embodiment 1 are synthetic, and (1), (3), (4) step react constant, only sodium pyrosulfate in (2) step are changed to S-WAT, obtain the crude product of product 3-nitro-4-methyl pyridine, purity 75.4%, productive rate 60.3%.
Embodiment 3
Method and condition such as embodiment 1 are synthetic, and (1), (3), (4) step react constant, only sodium pyrosulfate in (2) step are changed to sodium bisulfite, obtain the crude product of product 3-nitro-4-methyl pyridine, purity 79.2%, productive rate 62.5%.
Embodiment 4
Method and condition such as embodiment 1 are synthetic, (1), (3), (4) step reaction is constant, only sodium pyrosulfate in (2) step is changed to V-Brite B, obtains the crude product of product 3-nitro-4-methyl pyridine, purity 85.5%, productive rate 71.2%.
Embodiment 5
Method and condition such as embodiment 1 are synthetic, and (1), (3), (4) step react constant, only reaction times 24h in (2) step are extended to 48h, obtain the crude product of product 3-nitro-4-methyl pyridine, purity 83.8%, productive rate 71.6%.
Embodiment 6
Method and condition such as embodiment 1 are synthetic, (1), (2), (4) step reaction is constant, only solvent 200mL methyl alcohol in (3) step is changed to the mixed solvent of 100mL methyl alcohol and 100mL water, gets product 3-amino-4-methylpyridine, purity 96.9%, productive rate 95.7%.
Embodiment 7
Method and condition such as embodiment 1 are synthetic, and (1), (2), (4) step react constant, only temperature 70 C in (3) step are reduced to 50 ℃, get product 3-amino-4-methylpyridine, purity 97.4%, productive rate 90.8%.
Embodiment 8
Method and condition such as embodiment 1 are synthetic, and (1), (2), (4) step react constant, only reaction times 5h in (3) step are extended to 24h, get product 3-amino-4-methylpyridine, purity 95.9%, productive rate 92.8%.
Embodiment 9
Method and condition such as embodiment 1 are synthetic, and (1), (2), (3) step react constant, only reaction times 2h in (4) step are extended to 6h, get product 2-chlorin-3-amido-4-methyl pyridine, purity 99.2%, productive rate 83.5%, fusing point 68-69 ℃.
Claims (2)
1. synthetic method for preparing the 2-chlorin-3-amido-4-methyl pyridine, it is characterized in that take the 4-picoline as raw material,, Sodium Pyrosulfite nitrated through concentrated nitric acid makes nitro migration, catalyst hydrogenation, hydrogen peroxide and concentrated hydrochloric acid chlorination successively, four-step reaction prepares the 2-chlorin-3-amido-4-methyl pyridine, and concrete preparation process is as follows:
(1) adds first trifluoroacetic anhydride in the reactor, drip the 4-picoline under the cooling conditions, reacted 1-6 hour, drip again concentrated nitric acid, reacted 4-24 hour, make N-nitro-4-methyl pyridine;
(2) reaction solution that (1) is obtained is added drop-wise in the aqueous solution of freezing Sodium Pyrosulfite or S-WAT or sodium bisulfite or V-Brite B, stirring at room reaction 12-48 hour, transfer system pH=6-7 with alkaline solution, extraction makes 3-nitro-4-methyl pyridine;
(3) add 3-nitro-4-methyl pyridine in reactor, methyl alcohol, water or its mixture are made solvent, and palladium carbon is done catalyst hydrogenation, and temperature is controlled between 20-100 ℃, and reaction 1-24h makes the 3-amino-4-methylpyridine;
(4) in reactor, add the 3-amino-4-methylpyridine, in cooling bath to wherein slowly dripping concentrated hydrochloric acid, be warming up to 40 ℃ after stirring to clarify, slowly drip 30% hydrogen peroxide, reacted 1-6 hour, with concentrated alkali solution regulation system pH=3, a large amount of pale precipitations are separated out, recrystallization obtains faint yellow or white needle-like crystals, is product 2-chlorin-3-amido-4-methyl pyridine.
2. preparation method according to claim 1 is characterized in that used reagent of one step of nitro migration is any one or a few the mixture in Sodium Pyrosulfite, S-WAT, sodium bisulfite, the V-Brite B.
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Cited By (8)
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| CN103819398A (en) * | 2014-01-24 | 2014-05-28 | 河北科技大学 | Method for synthesizing 4-amino-2-chlorine-3-nitro pyridine |
| CN104356057A (en) * | 2014-11-12 | 2015-02-18 | 江苏中邦制药有限公司 | Preparation method of 3-amino-4-methylpyridine |
| CN104945314A (en) * | 2015-06-19 | 2015-09-30 | 洪帅金 | Method for preparing 3-bromo-4-methylpyridine |
| CN107417603A (en) * | 2017-05-17 | 2017-12-01 | 江苏斯威森生物医药工程研究中心有限公司 | A kind of Crizotinib intermediate preparation method |
| CN108675955A (en) * | 2018-06-27 | 2018-10-19 | 安徽星宇化工有限公司 | A kind of preparation method of -5 chloropyridine of 2- amino |
| CN110015988A (en) * | 2018-01-10 | 2019-07-16 | 新发药业有限公司 | A kind of simple and convenient process for preparing of low cost 3- amino-4-methylpyridine |
| CN113527128A (en) * | 2021-07-16 | 2021-10-22 | 淮阴工学院 | Method for continuously synthesizing 2-methoxy-4-nitroacetanilide |
| 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 |
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| WO2016118586A1 (en) * | 2015-01-20 | 2016-07-28 | Virginia Commonwealth University | Lowcost, high yield synthesis of nevirapine |
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| CN103819398A (en) * | 2014-01-24 | 2014-05-28 | 河北科技大学 | Method for synthesizing 4-amino-2-chlorine-3-nitro pyridine |
| CN103819398B (en) * | 2014-01-24 | 2016-05-04 | 河北科技大学 | The synthetic method of the chloro-3-nitropyridine of 4-amino-2- |
| CN104356057A (en) * | 2014-11-12 | 2015-02-18 | 江苏中邦制药有限公司 | Preparation method of 3-amino-4-methylpyridine |
| CN104945314A (en) * | 2015-06-19 | 2015-09-30 | 洪帅金 | Method for preparing 3-bromo-4-methylpyridine |
| CN107417603A (en) * | 2017-05-17 | 2017-12-01 | 江苏斯威森生物医药工程研究中心有限公司 | A kind of Crizotinib intermediate preparation method |
| CN107417603B (en) * | 2017-05-17 | 2020-08-11 | 张家港威胜生物医药有限公司 | Preparation method of crizotinib intermediate |
| CN110015988A (en) * | 2018-01-10 | 2019-07-16 | 新发药业有限公司 | A kind of simple and convenient process for preparing of low cost 3- amino-4-methylpyridine |
| CN110015988B (en) * | 2018-01-10 | 2020-06-23 | 新发药业有限公司 | Preparation method of 3-amino-4-methylpyridine |
| CN108675955A (en) * | 2018-06-27 | 2018-10-19 | 安徽星宇化工有限公司 | A kind of preparation method of -5 chloropyridine of 2- amino |
| CN113527128A (en) * | 2021-07-16 | 2021-10-22 | 淮阴工学院 | Method for continuously synthesizing 2-methoxy-4-nitroacetanilide |
| CN113527128B (en) * | 2021-07-16 | 2024-03-26 | 淮阴工学院 | Method for continuously synthesizing 2-methoxy-4-nitroacetanilide |
| 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 |
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