CN102898361B - Method for preparing 2-chlorine-3-amino-4-picoline - Google Patents

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

A kind of method of preparing 2-chlorin-3-amido-4-methyl pyridine

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 to take 4-picoline to make nitro migration, catalyst hydrogenation, hydrogen peroxide and concentrated hydrochloric acid chlorination as raw material successively, Sodium Pyrosulfite nitrated through concentrated nitric acid specifically, four-step reaction is prepared production technique and corresponding every processing condition of 2-chlorin-3-amido-4-methyl pyridine.

Background technology

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 that take the chloro-3-nitro-4-methyl of 2-pyridine is raw material, through reduction, obtain 2-chlorin-3-amido-4-methyl pyridine (Chapman D, 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 in 1993 have reported, adopting β-carbonyl ethyl butyrate and malonamide nitrile is starting raw material, through closed loop, chlorination, hydrolysis, Hoffman degraded, hydrogenation, chlorination, obtain 2-chlorin-3-amido-4-methyl pyridine, 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, then dechlorination reduction, finally will optionally use chlorine in 2-position again chlorination.The chlorination of 2,6-position and dechlorination reduction and optionally 2-position chlorinating step, 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 in 1994 have reported the synthetic of Nevirapine, wherein have the synthetic of important intermediate 2-chlorin-3-amido-4-methyl pyridine, and 2-hydroxyl-3-nitro-4-methyl pyridine of take is raw material, through chlorination, reduction, obtain, 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 laboratory, take 2-AMINO-4-PICOLINE or 2-hydroxy-4-methyl pyridine as raw material is through the step such as nitrated, synthesized 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, through class Michael reaction, closed loop, ammonification, Hofmann degraded, obtain 2-chlorin-3-amido-4-methyl pyridine.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, through closed loop, chlorination, hydrogenation, hydrolysis, Hoffman degraded, chlorination, obtain 2-chlorin-3-amido-4-methyl pyridine, productive rate 19.6-26.1%.This method yield is lower and unstable, and step is more loaded down with trivial details, need to remove the chlorine on 2-and 6-position, after again in the chlorination of 2-position, and in the end chlorinating step 2-position and 6-position are all easily chlorinated, bad control, 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.)

Within 1997, Schenider H has reported from 2, the chloro-3-amido-4-alkyl of 6-bis-or aryl set out and through dechlorination, chlorination reaction, obtain the synthesis route of the chloro-3-amido-4-alkyl of 2-or aryl-pyridine, 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 in HCl, yield 78.9-80.0%.This chlorination method can effectively substitute the method that the people such as Grozinger K G finally use chlorinated with chlorine, has avoided the high request to equipment simultaneously.(Schenider?H.Methodfor?preparing?3-amino-2-chloro-4-alkylpyridine?or-4-arylpyridine.US?5686618，1997-11-11.)

Within 1997, Nummy L J has reported with 2-chlorine-3-aminopyridine and has set out, and through becoming sulfosalt with thioether reactant, then through rearrangement reaction, obtains the substituted pyridines of 4-position alkyl, then through reduction reaction, obtains 2-chlorin-3-amido-4-methyl pyridine, productive rate 44%.In this reaction, the first step becomes sulfosalt condition harsher, and temperature requirement is lower, and needs nitrogen protection; Final step needs Raney Ni to make catalyzer, expensive.(Nummy?L?J.Method?for?the?preparation?of?3-amino-2-chloro-4-alkylpyridines.US?5654429，1997-08-05.)

Within 2000, Grozinger Karl has reported, take acetone and propane dinitrile as raw material, through Knoevenagel reaction, addition reaction, closed loop, sandmeyer reaction, chlorination, hydrolysis, Hofmann degraded, obtain 2-chlorin-3-amido-4-methyl pyridine, 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; through Knoevenagel reaction, class Michael reaction, closed loop, hydrolysis, acidylate, ammonification, Hofmann degraded, obtain 2-chlorin-3-amido-4-methyl pyridine, productive rate is brought up to 17.4% (in ethyl cyanoacetate).This method yield is still lower, key is that closed loop one step 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.).

Within 2002, Gupton B F has reported, from 4,4-dimethoxy-2-butanone and propane dinitrile are that raw material obtains 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 walks 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 laboratory, prepare, particularly each synthetic method productive rate before 2000 is all lower, raw material should not obtain, 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 gentleer, is applicable to suitability for industrialized production, its industrialized production having realized at home.But raw material 4, the price of 4-dimethoxy-2-butanone is higher, and should not deposit for a long time, to suitability for industrialized production, has increased difficulty.

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 applicable to the method for preparing 2-chlorin-3-amido-4-methyl pyridine of large-scale industrial production.

The object of the present invention is achieved like this:

It is raw material that industrialization product 4-picoline is take in the present invention,, Sodium Pyrosulfite nitrated through concentrated nitric acid makes nitro migration, catalyst hydrogenation, hydrogen peroxide and concentrated hydrochloric acid chlorination successively, four-step reaction is prepared 2-chlorin-3-amido-4-methyl pyridine, and concrete preparation process is as follows:

(1) in reactor, first add trifluoroacetic anhydride, under cooling conditions, drip 4-picoline, reaction 1-6 hour, then drip concentrated nitric acid, reaction 4-24 hour, makes N-nitro-4-methyl pyridine;

(2) reaction solution (1) being 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, with alkaline solution, adjust system pH=6-7, extraction, makes 3-nitro-4-methyl pyridine;

(3) in reactor, add 3-nitro-4-methyl pyridine, 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 3-amino-4-methylpyridine;

(4) in reactor, add 3-amino-4-methylpyridine, in cooling bath, slowly drip wherein concentrated hydrochloric acid, after stirring to clarify, be warming up to 40 ℃, slowly drip 30% hydrogen peroxide, reaction 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 it is any one or a few the mixture in Sodium Pyrosulfite, S-WAT, sodium bisulfite, V-Brite B that nitro moves step reagent used.

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 new way novel, that can be used for efficiently suitability for industrialized production 2-chlorin-3-amido-4-methyl pyridine.

Embodiment

Exemplifying embodiment below will better illustrate the present invention, but it is emphasized that the present invention never only limits to the represented content of these 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: first add 200mL trifluoroacetic anhydride (0.84mol) in reactor, stirring is cooled to 0 ℃, slowly drips 33mL 4-picoline (0.34mol), produces yellow solid, after adding, at 0 ℃, continue stirring reaction 2h.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, without further processing, directly enters next step reaction.

(2) preparation of 3-nitro-4-methyl pyridine: the N-nitro-4-methyl pyridine reaction solution that upper step is obtained is added drop-wise in the aqueous solution of freezing 64g sodium pyrosulfate (0.34mol) and 500mL, stirring at room 24h, with the 25%NaOH aqueous solution, adjust system pH=6-7, CH ₂cl ₂extraction product, extraction liquid is dry, filters, and is spin-dried for solvent, obtains the crude product of sundown liquid 3-nitro-4-methyl pyridine, purity 81.0%, productive rate 65.9% (in 4-picoline).

(3) preparation of 3-amino-4-methylpyridine: add successively 34.0g3-nitro-4-methyl pyridine (81.0% in reactor, 0.2mol), 200mL methyl alcohol, 1.9g5% palladium charcoal (water ratio 54.13%), envelope still, air in high-purity hydrogen ventilation still, pressure 0.4MPa, heated and stirred, temperature is controlled at 70 ℃, reaction 5h needs hydrogen make-up when pressure is less than 0.15MPa.After completion of the reaction, cool to room temperature, drives still, suction filtration, reclaims palladium carbon, filtrate decompression precipitation, add 50mL water dissolution, by 30% potassium hydroxide solution regulator solution pH value, be alkalescence, with organic solvent extraction, merge organic phase, dry, filter, decompression precipitation, obtain faint yellow solid 3-amino-4-methylpyridine, purity 98.1%, productive rate 93.5%.

(4) preparation of 2-chlorin-3-amido-4-methyl pyridine: first add 21.6g 3-amino-4-methylpyridine (0.2mol) in reactor, in cooling bath, slowly drip the concentrated hydrochloric acid of 72mL, after stirring to clarify, be warming up to 40 ℃, in 30-60min, slowly drip the hydrogen peroxide of 30mL 30%, temperature control reaction 2h.React complete, the sodium hydroxide solution regulation system pH=3 with 45%, with chloroform extraction, dry, precipitation can obtain crude product.With sherwood oil or normal hexane recrystallization, obtain white or faint yellow needle-like crystal, be 2-chlorin-3-amido-4-methyl pyridine, purity 99.0%, productive rate 83.2%, fusing point 68-69 ℃.

Embodiment 2

As synthetic in the method for embodiment 1 and condition, (1), (3), the reaction of (4) step are 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

As synthetic in the method for embodiment 1 and condition, (1), (3), the reaction of (4) step are 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

As synthetic in the method for embodiment 1 and condition, (1), the reaction of (3), (4) step 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

As synthetic in the method for embodiment 1 and condition, (1), (3), the reaction of (4) step are 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

As synthetic in the method for embodiment 1 and condition, (1), the reaction of (2), (4) step is constant, only solvent 200mL methyl alcohol in (3) step is changed to the mixed solvent of 100mL methyl alcohol and 100mL water, obtains product 3-amino-4-methylpyridine, purity 96.9%, productive rate 95.7%.

Embodiment 7

As synthetic in the method for embodiment 1 and condition, (1), (2), the reaction of (4) step are constant, only temperature 70 C in (3) step are reduced to 50 ℃, obtain product 3-amino-4-methylpyridine, purity 97.4%, productive rate 90.8%.

Embodiment 8

As synthetic in the method for embodiment 1 and condition, (1), (2), the reaction of (4) step are constant, only reaction times 5h in (3) step are extended to 24h, obtain product 3-amino-4-methylpyridine, purity 95.9%, productive rate 92.8%.

Embodiment 9

As synthetic in the method for embodiment 1 and condition, (1), (2), the reaction of (3) step are constant, only reaction times 2h in (4) step are extended to 6h, obtain product 2-chlorin-3-amido-4-methyl pyridine, purity 99.2%, productive rate 83.5%, fusing point 68-69 ℃.

Claims (2)

1. a synthetic method of preparing 2-chlorin-3-amido-4-methyl pyridine, it is characterized in that take that 4-picoline is as raw material,, Sodium Pyrosulfite nitrated through concentrated nitric acid or S-WAT or sodium bisulfite or V-Brite B make nitro migration, catalyst hydrogenation, hydrogen peroxide and concentrated hydrochloric acid chlorination successively, four-step reaction is prepared 2-chlorin-3-amido-4-methyl pyridine, and concrete preparation process is as follows:

(1) in reactor, first add trifluoroacetic anhydride, under cooling conditions, drip 4-picoline, reaction 1-6 hour, then drip concentrated nitric acid, reaction 4-24 hour, makes N-nitro-4-methyl pyridine solution;

(2) reaction solution (1) being 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, with alkaline solution, adjust system pH=6-7, extraction, makes 3-nitro-4-methyl pyridine;

(3) in reactor, add 3-nitro-4-methyl pyridine, 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 3-amino-4-methylpyridine;

(4) in reactor, add 3-amino-4-methylpyridine, in cooling bath, slowly drip wherein concentrated hydrochloric acid, after stirring to clarify, be warming up to 40 ℃, slowly drip 30% hydrogen peroxide, reaction 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 it is any one in Sodium Pyrosulfite, S-WAT, sodium bisulfite, V-Brite B that nitro moves step reagent used.