CN108863917A - A kind of preparation method of 2,5- dimethoxy-pyridine - Google Patents
A kind of preparation method of 2,5- dimethoxy-pyridine Download PDFInfo
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- CN108863917A CN108863917A CN201710340647.2A CN201710340647A CN108863917A CN 108863917 A CN108863917 A CN 108863917A CN 201710340647 A CN201710340647 A CN 201710340647A CN 108863917 A CN108863917 A CN 108863917A
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- GHUGQICXYXAICG-DVBIZMGNSA-N C/C(/Br)=C\N=C(/C)\OC Chemical compound C/C(/Br)=C\N=C(/C)\OC GHUGQICXYXAICG-DVBIZMGNSA-N 0.000 description 1
- SQCCGXPQVBNAFP-UHFFFAOYSA-N COC(C=C1)NC=C1OC Chemical compound COC(C=C1)NC=C1OC SQCCGXPQVBNAFP-UHFFFAOYSA-N 0.000 description 1
- LKBKDKVMHWPZDB-UHFFFAOYSA-N COc(cc1)ncc1O Chemical compound COc(cc1)ncc1O LKBKDKVMHWPZDB-UHFFFAOYSA-N 0.000 description 1
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/69—Two or more oxygen atoms
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Abstract
The invention discloses the preparation methods of one kind 2,5- dimethoxy-pyridine, belong to technical field of medicine synthesis, include the following steps：Step 1, in the presence of alcoholic solvent, formula A compound and sodium methoxide haptoreaction are to form formula B compound；Step 2, in the presence of metallic catalyst, so that step 1 Chinese style B compound is reacted to obtain 2,5- dimethoxy-pyridine, post-processing, purifying obtain product.This method route is short, step is few, without using expensive palladium metal catalyst and acid reagent, reduce preparation cost, it avoids using inflammable and explosive lithium reagent and peroxide, reaction condition is mild, post-processing operation is easy, improves total recovery and purity, and product quality is easy to control, industrial amplification prospect is good.
Description
Technical field
The present invention relates to a kind of methods for preparing 2,5- dimethoxy-pyridine, belong to technical field of organic synthesis.
Background technique
2,5- dimethoxy-pyridines, molecular formula C7H9NO2, a kind of chemical synthesis or pharmaceutical synthesis intermediate or
Raw material, structure are shown in formula I.
Pyridine and its derivatives are the important foundation raw materials of medicine, pesticide, are of wide application.At present known to pyridine and its
Derivative is mainly used in medicine intermediate, pesticide intermediate, feedstuff and other many fields.Such as pyridine can produce
The number such as pharmaceuticals Cefalexin, prednisone, dexamethasone acetate, sulfamido sulfuric acid piperazine acid, hydrocortisone, iodoxuridine, progesterone
Ten kinds of drugs.Pyridine can also synthesize bromopentylpyridine, for producing penicillin deemulsifying agent and fermentation precipitating reagent etc..
The scale of global drug market rapidly increases in recent years, and the molecular structure of pharmaceutical chemicals is generally relatively more multiple
Miscellaneous, synthesis step is also more.Recently in some medical new varieties efficient, performance is good of foreign countries' exploitation, heterocycle is mostly introduced
Structure.After pyridine ring, significantly improve the bioactivity of medical kind or performance.For example, public recently in Bayer
In the patent CN105849109 opened, a series of oxo pyridine derivant structure is disclosed, has inhibiting factor Xia and blood plasma to swash
Peptide releasing enzyme activity can be used to treat or prevent cardiovascular disorder, especially thrombosis or thromboembolic disorders, in the literature
It mentions and can be also used for oedema or ophthalmology disease.Oxo pyridine derivative is with 2,5- dimethoxy-pyridine for original in document
Material synthesizes series using methoxypyridine as the new pharmacy structural compounds of nuclear structure.
Due to the special chemical property of pyridine ring, in several isomers of dimethoxy-pyridine, 2,5- dimethoxies
Yl pyridines are more difficult to be synthetically prepared due to containing 5 special methoxyl groups.Document report 2,5- dimethoxy-pyridine at present
2 bromines are reacted under alkaline condition be converted into methoxyl group first, then by preparation method with 2,5- dibromo pyridine for raw material
Boric acid is converted with lithium reagent reaction under ultralow temperature by 5 bromines or is converted into boron using palladium catalyst reaction at relatively high temperatures
Acid esters further aoxidizes boric acid or borate group using peroxide and is converted to hydroxyl, and the hydrogen on last hydroxyl is by first
Base replaces to obtain final products 2,5- dimethoxy-pyridine；Alternatively, 5- dibromo pyridine is raw material with 2,5 bromines are existed first
It is converted into boric acid with lithium reagent reaction under ultralow temperature or is reacted at relatively high temperatures using palladium catalyst and be converted into borate, then into
One step makes boric acid or borate group oxidation be converted to hydroxyl using peroxide, then again that 2 bromines are anti-under alkaline condition
It should be converted into methoxyl group, the hydrogen on last 5 hydroxyls is replaced to obtain final products 2,5- dimethoxy-pyridine by methyl.
Their synthetic route is as follows：
Route one：
Route two：
Route three：
The preparation method of above-mentioned existing 2,5- dimethoxy-pyridine is required to 5 bromines being converted into boric acid or borate
Group, further oxidation generates hydroxyl, and the hydrogen of last hydroxyl, which is substituted, obtains final methoxy group, and general line needs 4 steps to obtain
To final products 2,5- dimethoxy-pyridine.Therefore existing 2,5- dimethoxy-pyridine preparation method step is more, reaction condition
Harshness, total recovery are low.Also, the palladium catalyst and acid reagent of inflammable and explosive lithium reagent or valuableness are used in preparation,
Increase existing preparation method cost, risk is big, feeds intake and post-processing operation is cumbersome, be unfavorable for industrializing.
In view of the defect of above-mentioned existing synthetic route preparation, to developing, a kind of synthetic route is short, cost is relatively low, is easy to industry
There are demands for the 2,5- dimethoxy-pyridine preparation method of change.
Summary of the invention
In order to solve the problems in the existing technology, the object of the present invention is to provide a kind of new 2,5- dimethoxy pyrroles
Pyridine preparation method.The features such as this method has route short, and yield is high, low in cost, and operation is simple, safe, environmentally protective.
One aspect of the present invention provides the synthetic method of one kind 2,5- dimethoxy-pyridine (Formulas I) compound,
It includes：
In the presence of a catalyst, formula B compound reacts to obtain 2,5- dimethoxy-pyridine (Formulas I),
The formula B compound is：
X is selected from halogen；
Further, X is selected from fluorine, chlorine, bromine, iodine；
Preferably, X is selected from chlorine, bromine, iodine；
The catalyst is metallic catalyst, and wherein metal is selected from palladium metal, copper metal, nickel metal；Preferably copper metal
Catalyst；
Further, copper metal catalyst is selected from copper powder, copper sulphate, copper acetate, copper chloride, stannous chloride, cupric iodide, iodine
Change cuprous, copper bromide, cuprous bromide, copper fluoride, copper fluoride, copper oxide, cuprous oxide；It is preferred that cupric iodide, cuprous iodide；
The reaction is：Under reaction temperature, formula B compound is dissolved in organic solvent, be added methoxy carbanionic reagent and
Above-mentioned metallic catalyst reacts 4~24 hours, and post-processing, purifying obtain compound of formula I.
Wherein, in the reaction organic solvent be aprotic solvent and alcoholic solvent mixed solvent；
Further, aprotic solvent is selected from DMF, DME, acetonitrile, toluene, Isosorbide-5-Nitrae-dioxane, DMSO, N, N- dimethyl
Acetamide, N-Methyl pyrrolidone；Preferably DMF；Alcoholic solvent is selected from methanol, ethyl alcohol, propyl alcohol, butanol, isopropanol, ethylene glycol；
It is preferred that methanol；Methoxy carbanionic reagent is selected from sodium methoxide, potassium methoxide, sodium hydride and methanol and matches agents, hydrofining and methanol
With agents；It is preferred that sodium methoxide；
Further, the weight (gram) of aprotic solvent and alcoholic solvent is than being 1:0~1:1；Preferably 1:0~1:
0.66；More preferably 1:0.3~1:0.5；
The weight (gram) of the methoxy carbanionic reagent and formula B compound is than being 1:1~1:4；It is preferred that 1:1~1:2；
The weight (gram) of the metallic catalyst and formula B compound is than being 1:10~1:200, preferably 1:40~1:80；
The reaction temperature is 80~110 DEG C.
In better embodiment of the invention, it is crucial intermediate that the present invention provides preparation 2,5- dimethoxy-pyridine (Formulas I)
The synthetic method of compound (formula B),
It includes formula A compound is exposed under reaction condition to form the formula B compound.
The formula A compound is：
X is selected from halogen；
Further, X is selected from fluorine, chlorine, bromine, iodine；
Preferably, X is selected from chlorine, bromine, iodine；
The reaction condition includes：
In the presence of alcoholic solvent, formula A compound and methoxy carbanionic reagent haptoreaction are to form formula B compound.
Wherein, methoxy carbanionic reagent be selected from sodium methoxide, potassium methoxide, sodium hydride and methanol with agents, hydrofining with
Methanol matches agents；It is preferred that sodium methoxide；
The weight (gram) of methoxy carbanionic reagent and formula A compound is than being 1:1~1：4；Preferably 1:1.5~1:2；
The alcoholic solvent is selected from methanol, ethyl alcohol, propyl alcohol, butanol, isopropanol, ethylene glycol；It is preferred that methanol；
The reaction at the reaction temperatures, by formula A compound and methoxy carbanionic reagent reacts 10 in alcoholic solvent~
It 36 hours, post-processes and purifies to obtain formula B compound.
Wherein, reaction temperature is 40~70 DEG C.
On the other hand, the present invention provides the method for preparation 2,5- dimethoxy-pyridine (Formulas I) compound, it includes：
Step 1：In the presence of alcoholic solvent, formula A compound and methoxy carbanionic reagent haptoreaction are to form formula B chemical combination
Object；
The formula A compound is：
The formula B compound is：
Wherein, X is selected from halogen；
Further, X is selected from fluorine, chlorine, bromine, iodine；
Preferably, X is selected from chlorine, bromine, iodine；
Methoxy carbanionic reagent is selected from sodium methoxide, potassium methoxide, sodium hydride and methanol and matches with agents, hydrofining and methanol
Agents；It is preferred that sodium methoxide；
The weight (gram) of methoxy carbanionic reagent and formula A compound is than being 1:1.5~1:2；
The alcoholic solvent is selected from methanol, ethyl alcohol, propyl alcohol, butanol, isopropanol, ethylene glycol；It is preferred that methanol；
Further, the reaction is at the reaction temperatures, by formula A compound and methoxy carbanionic reagent in alcoholic solvent
Reaction 10~36 hours, post-processes and purifies to obtain formula B compound；
Wherein, reaction temperature is 40~70 DEG C；
Step 2：In the presence of metallic catalyst, step 1 Chinese style B compound is made to react to obtain 2,5- dimethoxy-pyridine
(Formulas I)；
Wherein, metal is selected from palladium metal, copper metal, nickel metal；Metallic catalyst is preferably copper metal catalyst；
Further, copper metal catalyst is selected from copper powder, copper sulphate, copper acetate, copper chloride, stannous chloride, cupric iodide, iodine
Change cuprous, copper bromide, cuprous bromide, copper fluoride, copper fluoride, copper oxide, cuprous oxide；It is preferred that cupric iodide, cuprous iodide；
The reaction is：Under reaction temperature, formula B compound is dissolved in organic solvent, be added methoxy carbanionic reagent and
Above-mentioned metallic catalyst reacts 4~24 hours, and post-processing, purifying obtain compound of formula I.
Wherein, in the reaction organic solvent be aprotic solvent and alcoholic solvent mixed solvent；
Further, aprotic solvent is selected from DMF, DME, acetonitrile, toluene, Isosorbide-5-Nitrae-dioxane, DMSO, N, N- dimethyl
Acetamide, N-Methyl pyrrolidone；Preferably DMF；Alcoholic solvent is selected from methanol, ethyl alcohol, propyl alcohol, butanol, isopropanol, ethylene glycol；
It is preferred that methanol；Methoxy carbanionic reagent is selected from sodium methoxide, potassium methoxide, sodium hydride and methanol and matches agents, hydrofining and methanol
With agents；It is preferred that sodium methoxide；
Further, the weight (gram) of aprotic solvent and alcoholic solvent is than being 1:0~1:1；Preferably 1:0~1:
0.66；More preferably 1:0.3~1:0.5；
The weight (gram) of the methoxy carbanionic reagent and formula B compound is than being 1:1~1:4；It is preferred that 1:1~1:2；
The weight (gram) of the metallic catalyst and formula B compound is than being 1:10~1:200, preferably 1:40~1:80；
The reaction temperature is 80~110 DEG C.
In aforesaid operations, post-processing, purifying include but is not limited to stirring, the transfer of liquid or solid, washing, alkali cleaning,
The operation such as pickling, filtering, ultrafiltration, loop ultrafiltration, dilution, concentration, drying, freeze-drying, or turn of stirring, liquid or solid
Shifting, washing, alkali cleaning, pickling, filtering, ultrafiltration, loop ultrafiltration, dilution, concentration, drying, freeze-drying, air-distillation, vacuum distillation etc.
The combination of one or more of operation.
Step, solvent, reagent in the synthetic method of above-mentioned 2,5- dimethoxy-pyridine (Formulas I) compound of the present invention, after
Processing, recrystallization etc. described in can in any combination/split, can be achieved the object of the invention.
Compared with prior art, the preparation method route of 2,5- dimethoxy-pyridine (Formulas I) compound of the invention is short, step
Rapid few, reaction condition is mildly easy to operate, reduces costs, and improves total recovery.
The present invention prepares the method for 2,5- dimethoxy-pyridine (Formulas I) without using expensive palladium metal catalyst and boric acid
Reagent not only greatly reduces reagent cost；Moreover, the drawbacks of acid reagent should not be removed when post-processing purifying is avoided,
Keep improved preparation method post-processing easy, it is easy to operate, reduce post processing cost.Be conducive to industrial amplification production.
The method that the present invention prepares 2,5- dimethoxy-pyridine (Formulas I) avoids using ultralow temperature and high temperature control in synthesis process
The condition for making reaction, keeps preparation method synthesis process easy to operate, energy saving, reduces cost.It avoids using inflammable and explosive lithium
Reagent and peroxidic reagents are advantageously implemented industrial amplification production while reducing catalyst cost.
In conclusion preparation method route of the present invention by change 2,5- dimethoxy-pyridine (Formulas I), shortens synthesis road
The step of line, optimizes preparation method condition, avoids reducing the cost of raw materials and reagents using expensive and inflammable and explosive reagent
Meanwhile being conducive to feed intake and post-processing operation, it realizes and simplifies preparation method, reduce cost, improve preparation 2,5- dimethoxy
The total recovery of yl pyridines (Formulas I) method, obtained product 2,5- dimethoxy-pyridine purity is high are advantageously implemented industrialization.
Specific embodiment
If background technique is discussed, compound of formula I is 2,5- dimethoxy-pyridine, is commonly used in new drug structural compounds
Component units structure.The present invention includes the improvement synthetic method of compound of formula I.
1. terminology used in the present invention defines
As used in the specification and claims, unless the context clearly dictates otherwise, otherwise singular "
One " with " is described " to refer to object including multiple.
As used herein, term " including " refers to that method includes cited element, but is not excluded for other elements.
As used herein, term " contact " be instigate two or more chemical molecular close so that both or
It can react between two or more chemical moleculars.For example, contact may include mixing and continuous mixed chemical substance.Contact
It can be by the way that two or more chemical substance be dissolved completely or partially or is suspended in one or more kinds of solvents, by one
Chemical substance of the kind in solvent mixes or mixes two or more solid with the chemical substance of another solid phase or gas phase
Chemical substance or the commonly known other methods of those skilled in the art carry out.
As used herein, term " reaction condition " refers to details locating when being chemically reacted.React item
The example of part includes but is not limited to one or more following factors:When reaction temperature, solvent, pH value, pressure, reaction
Between, the presence of the molar ratio of reactant, alkali or acid or catalyst etc..Reaction condition can be according to the specialization for using these conditions
Learn reaction name, coupling conditions, hydrogenation conditions, acylation condition, reducing condition, salt formation condition etc..
As used herein, term " metallic catalyst ", which refers to, can be used for urging for this paper technical solution containing metal
Agent, including but not limited to metal simple-substance, metal salt, metal oxide, metal complex or metal complex；It can be block
Shape, particle, powder, aluminium oxide or tripolite loading or other load forms etc..
For example, the copper metal catalyst refers to the catalyst containing copper when metallic catalyst is copper metal catalyst, wrap
Include but be not limited to copper simple substance (such as copper powder), mantoquita (such as copper sulphate, copper acetate, copper chloride, stannous chloride, cupric iodide, iodate
Cuprous, copper bromide, cuprous bromide, copper fluoride, copper fluoride), Cu oxide (such as copper oxide, cuprous oxide), copper complex
Or copper complex (such as cupric tetramminosulfate).
As used herein, term " methoxy carbanionic reagent " refers to containing in methyl negative oxygen ion or reaction process
The reagent of methyl negative oxygen ion can be provided, be a kind of sensu lato reagent, can be a kind of compound (such as sodium methoxide, first
Potassium alcoholate), it is also possible to two or more compounds or solvent with the use of (such as sodium hydride and methanol or hydrofining and first
Alcohol).
2. the detailed description of 2,5- dimethoxy-pyridine compound (Formulas I) preparation method of the present invention
According to the present invention, the preparation method of 2, the 5- dimethoxy-pyridine compound (Formulas I),
It includes：
In the presence of a catalyst, formula B-1 compound reacts to obtain 2,5- dimethoxy-pyridine (Formulas I),
The formula B-1 compound is：
The catalyst is metallic catalyst, and wherein metal is selected from palladium metal, copper metal, nickel metal；Preferably copper metal
Catalyst；
Further, copper metal catalyst is selected from copper powder, copper sulphate, copper acetate, copper chloride, stannous chloride, cupric iodide, iodine
Change cuprous, copper bromide, cuprous bromide, copper fluoride, copper fluoride copper oxide, cuprous oxide；It is preferred that cupric iodide, cuprous iodide；
The reaction is：Under reaction temperature, formula B-1 compound is dissolved in organic solvent, sodium methoxide is added and above-mentioned is urged
Agent is reacted 4~24 hours, and post-processing, purifying obtain compound of formula I.
Wherein, in the reaction organic solvent be aprotic solvent and alcoholic solvent mixed solvent；
Further, aprotic solvent is selected from DMF, DME, acetonitrile, toluene, Isosorbide-5-Nitrae-dioxane, DMSO, N, N- dimethyl
Acetamide, N-Methyl pyrrolidone；Preferably DMF；Alcoholic solvent is selected from methanol, ethyl alcohol, propyl alcohol, butanol, isopropanol, ethylene glycol；
It is preferred that methanol；
Further, the weight (gram) of aprotic solvent and alcoholic solvent is than being 1:0~1:1；It is preferred that 1:0~1:0.66；
More preferably 1:0.3~1:0.5；
The weight (gram) of the sodium methoxide and formula B-1 compound is than being 1:1~1:4；It is preferred that 1:1~1:2；
The weight (gram) of the metallic catalyst and formula B-1 compound is than being 1:10~1:200, preferably 1:40~1:
80；
The reaction temperature is 80~110 DEG C.
In better embodiment of the invention, it is crucial intermediate that the present invention provides preparation 2,5- dimethoxy-pyridine (Formulas I)
The synthetic method of compound (formula B-1),
It includes formula A-1 compound is exposed under reaction condition to form the formula B-1 compound.
The formula A-1 compound is：
The reaction condition includes：
In the presence of alcoholic solvent, formula A-1 compound and sodium methoxide haptoreaction are to form formula B-1 compound.
Wherein, the weight ratio (gram) of sodium methoxide and formula A-1 compound is 1:1~1：4；Preferably 1:1.5~1:2；
The alcoholic solvent is selected from methanol, ethyl alcohol, propyl alcohol, butanol, isopropanol, ethylene glycol；It is preferred that methanol；
The reaction is that at the reaction temperatures, formula A-1 compound is reacted in alcoholic solvent 10~36 hours with sodium methoxide,
Post-processing, purifying obtain formula B-1 compound.
Wherein, reaction temperature is 40~70 DEG C.
In better embodiment of the invention, the preparation method packet of 2, the 5- dimethoxy-pyridine compound (Formulas I)
Include following steps,
Step 1：In the presence of methanol solvate, by the weight (gram) of sodium methoxide and formula A-1 compound than being 1:1.5~1:2
Material dissolution, reaction solution reaction temperature be 40~70 DEG C stir 10~36 hours；Solvent is removed, vacuum distillation purifying obtains
Formula B-1 compound
The formula A-1 compound is：
The formula B-1 compound is：
Step 2：Step 1 Chinese style B-1 compound is dissolved in organic solvent, the alcoholic solvent and copper metal that sodium methoxide is added are urged
Agent heats 80~110 DEG C and reacts 4~24 hours；Cooling filtering, vacuum distillation purifying obtains 2,5- bis- after filtrate removes solvent
Methoxypyridine (Formulas I)；
The copper metal catalyst is selected from copper powder, copper sulphate, copper acetate, copper chloride, stannous chloride, cupric iodide, iodate Asia
Copper, copper bromide, cuprous bromide, copper fluoride, copper fluoride, copper oxide, cuprous oxide；It is preferred that cupric iodide, cuprous iodide；
Organic solvent is the mixed solvent of aprotic solvent and alcoholic solvent in the reaction；
Further, the weight (gram) of the metallic catalyst and formula B compound is than being 1:10~1:200, preferably 1:
40~1:80；
The aprotic solvent is selected from DMF, DME, acetonitrile, toluene, Isosorbide-5-Nitrae-dioxane, DMSO, N, N- dimethylacetamide
Amine, N-Methyl pyrrolidone；Preferably DMF；Alcoholic solvent is selected from methanol, ethyl alcohol, propyl alcohol, butanol, isopropanol, ethylene glycol；It is preferred that
Methanol；
Further, the weight (gram) of aprotic solvent and alcoholic solvent is than being 1:0~1:1；It is preferred that 1:0~1:0.66；
More preferably 1:0.3~1:0.5；
The weight (gram) of the sodium methoxide and formula B compound is than being 1:1~1:4；It is preferred that 1:1~1:2；
Sodium methoxide can be the solid sodium methylate either alcoholic solution of sodium methoxide that feeds intake and feed intake；Sodium methoxide is in alcoholic solvent
Weight (gram) percentage composition be preferably 20%~30%.
3. in conventional synthetic method and embodiment, intermediate synthesis example, the meaning respectively abridged is such as in description of the invention
Shown in lower：
DMF n,N-Dimethylformamide
DME glycol dimethyl ether
DMSO dimethyl sulfoxide
NaOMe sodium methoxide
EtOH ethyl alcohol
MeOH methanol
CuI cuprous iodide
4. example
Below in conjunction with specific embodiment to the preparation synthesis side of 2,5- dimethoxy-pyridine compound (Formulas I) of the invention
Method is described further.
The preparation of embodiment 1,2- methoxyl group -5- chloropyridine (formula B-2)
The aqueous isopropanol (30%, 150 grams) of formula A-2 (50 grams), sodium methoxide is fed intake in reaction vessel, reaction solution stirs
It mixes and is heated to about 70 DEG C, continue stirring 20 hours.
Reaction solution is cooled to room temperature removing solvent, and ethyl acetate and water extraction is added, and organic phase dries, filters, and filtrate is removed
Solvent is removed, vacuum distillation purifies to obtain formula B-2 compound (34 grams, yield 70%).
The preparation of embodiment 2,2- methoxyl group -5- bromopyridine (formula B-1)
The methanol solution (30%, 333 grams) of formula A-1 (150 grams), sodium methoxide is fed intake in reaction vessel, reaction solution stirs
It mixes and is heated to about 70 DEG C, continue stirring 20 hours.
Reaction solution is cooled to room temperature removing solvent, and ethyl acetate and water extraction is added, and organic phase dries, filters, and filtrate is removed
Solvent is removed, vacuum distillation purifies to obtain formula B-1 compound (102 grams, yield 85.7%).
The preparation of embodiment 3,2- methoxyl group -5- bromopyridine (formula B-1)
The methanol solution (30%, 150 grams) of formula A-3 (100 grams), sodium methoxide is fed intake in reaction vessel, reaction solution stirs
It mixes and is heated to about 50 DEG C, continue stirring 10 hours.
Reaction solution is cooled to room temperature removing solvent, and ethyl acetate and water extraction is added, and organic phase dries, filters, and filtrate is removed
Solvent is removed, vacuum distillation purifies to obtain formula B-1 compound (57 grams, yield 86.0%).
The preparation of embodiment 4,2- methoxyl group -5- iodine pyridine (formula B-4)
The methanol solution (30%, 60 grams) of formula A-4 (80 grams), sodium methoxide is fed intake in reaction vessel, reaction solution stirring
40 DEG C are heated to about, stirring 36 hours is continued.
Reaction solution is cooled to room temperature removing solvent, and ethyl acetate and water extraction is added, and organic phase dries, filters, and filtrate is removed
Solvent is removed, vacuum distillation purifies to obtain formula B-4 compound (47 grams, yield 82.7%).
The preparation of embodiment 5, Formulas I
By formula B-2 (30 grams), the methanol solution (30%, 100 grams) of DMSO (140 grams) and sodium methoxide feeds intake in reaction vessel
In, logical argon gas displacement is vacuumized, is added CuI (3 grams), reaction solution continues stirring 24 hours after being heated with stirring to about 110 DEG C.
Reaction solution, which is cooled to room temperature, is filtered to remove solid impurity, water and ethyl acetate is added in filtrate, extraction is collected organic
It is mutually washed, is dried, filtered, filtrate removes solvent, and vacuum distillation purifying obtains product compound of formula I (25g, yield
85.7%).
The preparation of embodiment 6, Formulas I
By formula B-2 (30 grams), toluene (200 grams) and solid sodium methylate (30 grams) feed intake in reaction vessel, vacuumize logical
Argon gas displacement, is added CuI (2 grams), and reaction solution continues stirring 24 hours after being heated with stirring to about 110 DEG C.
Reaction solution, which is cooled to room temperature, is filtered to remove solid impurity, water and ethyl acetate is added in filtrate, extraction is collected organic
It is mutually washed, is dried, filtered, filtrate removes solvent, and vacuum distillation purifying obtains product compound of formula I (25.6g, yield
87.8%).
The preparation of embodiment 7, Formulas I
By formula B-1 (50 grams), the methanol solution (30%, 83 grams) of DMF (145 grams) and sodium methoxide feeds intake in reaction vessel
In, logical argon gas displacement is vacuumized, is added CuI (1.25 grams), reaction solution continues stirring 6 hours after being heated with stirring to about 110 DEG C.
Reaction solution, which is cooled to room temperature, is filtered to remove solid impurity, water and ethyl acetate is added in filtrate, extraction is collected organic
It is mutually washed, is dried, filtered, filtrate removes solvent, and vacuum distillation purifying obtains product compound of formula I (26.8g, yield
90.6% purity 97.5%).
The preparation of embodiment 8, Formulas I
By formula B-1 (50 grams), the methanol solution (30%, 166 grams) of DME (350 grams) and sodium methoxide feeds intake in reaction vessel
In, logical argon gas displacement is vacuumized, CuI is added2(0.62 gram), reaction solution continue stirring 15 hours after being heated with stirring to about 80 DEG C.
Reaction solution, which is cooled to room temperature, is filtered to remove solid impurity, water and ethyl acetate is added in filtrate, extraction is collected organic
It is mutually washed, is dried, filtered, filtrate removes solvent, and vacuum distillation purifying obtains product compound of formula I (26g, yield
87.9%).
The preparation of embodiment 9, Formulas I
By formula B-4 (20 grams), the methanol solution (30%, 44 grams) of DMF (46 grams) and sodium methoxide feeds intake in reaction vessel,
Logical argon gas displacement is vacuumized, is added CuBr (0.4 gram), reaction solution is heated with stirring to about, continues stirring 8 hours after 80 DEG C.
Reaction solution, which is cooled to room temperature, is filtered to remove solid impurity, water and ethyl acetate is added in filtrate, extraction is collected organic
It is mutually washed, is dried, filtered, filtrate removes solvent, and vacuum distillation purifying obtains product compound of formula I (7.5g, yield
89.3%).
The preparation of embodiment 10, Formulas I
By formula B-4 (20 grams), the methanol solution (20%, 25 grams) of n,N-dimethylacetamide (20 grams) and potassium methoxide feeds intake
In reaction vessel, logical argon gas displacement is vacuumized, is added CuI (0.1 gram), reaction solution continues to stir after being heated with stirring to about 85 DEG C
4 hours.
Reaction solution, which is cooled to room temperature, is filtered to remove solid impurity, water and ethyl acetate is added in filtrate, extraction is collected organic
It is mutually washed, is dried, filtered, filtrate removes solvent, and vacuum distillation purifying obtains product compound of formula I (7.7g, yield
91.6%).
Formula I obtained to above-described embodiment is carried out1H-NMR analysis, it is as a result as follows：
1H-NMR(400MHz,CDCl3)δ：7.75~7.76 (d, 1H), 7.13~7.16 (dd, 1H), 6.61~6.64 (d,
1H), 3.84 (s, 3H), 3.74 (s, 3H).
In conclusion the synthetic method of 2,5- dimethoxy-pyridine (Formulas I) compound of the invention is synthesized by two steps
To target product 2,5- dimethoxy-pyridine reduces the usage amount of catalysts and solvents, has simplified post-processing operation, reduces
Production cost；Each step intermediate easy purification of the method for the present invention, 97% or more, quality is easy to control finished product purity；This hair
Bright method avoids avoiding the safe operation etc. for reducing production using inflammable and explosive reagent using expensive reagent, catalyst
Grade is advantageously implemented industrialization amplification while totle drilling cost is effectively reduced.
The invention is not limited to specific embodiments above-mentioned.The present invention, which expands to, any in the present specification to be disclosed
New feature or any new combination, and disclose any new method or process the step of or any new combination.
Claims (10)
1. a kind of the method for preparing compound of formula I：
It includes,
In the presence of a catalyst, formula B compound reacts to obtain compound of formula I,
The formula B compound is：
X is selected from halogen；
The catalyst is metallic catalyst, and wherein metal is selected from palladium metal, copper metal, nickel metal.
2. method according to claim 1, which is characterized in that X is chlorine, bromine, iodine；Metallic catalyst is copper metal catalyst,
Selected from copper powder, copper sulphate, copper acetate, copper chloride, stannous chloride, cupric iodide, cuprous iodide, copper bromide, cuprous bromide, fluorination
Copper, copper fluoride, copper oxide, cuprous oxide；It is preferred that cupric iodide, cuprous iodide.
3. method according to claim 1, which is characterized in that the reaction is：Under reaction temperature, formula B compound is dissolved in
In organic solvent, methoxy carbanionic reagent is added and metallic catalyst reacts 4~24 hours, post-processing, purifying obtain Formulas I chemical combination
Object；
Wherein, organic solvent is the mixed solvent of aprotic solvent and alcoholic solvent.
4. method according to claim 3, which is characterized in that the aprotic solvent is selected from DMF, DME, acetonitrile, toluene, 1,
4- dioxane, DMSO, n,N-dimethylacetamide, N-Methyl pyrrolidone；Preferably DMF；Alcoholic solvent is selected from methanol, second
Alcohol, propyl alcohol, butanol, isopropanol, ethylene glycol；It is preferred that methanol；Methoxy carbanionic reagent be selected from sodium methoxide, potassium methoxide, sodium hydride with
Methanol matches agents with agents, hydrofining and methanol；Preferably sodium methoxide.
5. method according to claim 4, which is characterized in that
The weight ratio of the aprotic solvent and alcoholic solvent is 1:0~1:1；
The weight ratio of the methoxy carbanionic reagent and formula B compound is 1:1~1:4；
The weight ratio of the metallic catalyst and formula B compound is 1:10~1:200.
6. according to claim 1 to any one of 5 the methods, which is characterized in that the synthetic method of the formula B compound is will
Formula A compound is exposed under reaction condition to form the formula B compound；
The formula B compound is：
The formula A compound is：
X is selected from halogen；
Preferably, X is selected from chlorine, bromine, iodine；
Wherein, reaction condition includes：
In the presence of alcoholic solvent, formula A compound and methoxy carbanionic reagent haptoreaction are to form formula B compound.
7. a kind of the method for preparing compound of formula I, it includes following steps：
Step 1：In the presence of alcoholic solvent, formula A compound and methoxy carbanionic reagent haptoreaction are to form formula B compound；
The formula A compound is：
The formula B compound is：
Wherein, X is selected from halogen；
Preferably, X is selected from chlorine, bromine, iodine；
It is small that the reaction at the reaction temperatures, by formula A compound with methoxy carbanionic reagent reacts 10~36 in alcoholic solvent
When, post-processing, purifying obtain formula B compound；
The methoxy carbanionic reagent is selected from sodium methoxide, potassium methoxide, sodium hydride and methanol and matches with agents, hydrofining and methanol
Agents；Preferably sodium methoxide；
The weight ratio of methoxy carbanionic reagent and formula A compound is 1:1.5~1:2；
The alcoholic solvent is selected from methanol, ethyl alcohol, propyl alcohol, butanol, isopropanol, ethylene glycol；Preferably methanol；
Step 2：In the presence of metallic catalyst, step 1 Chinese style B compound is made to react to obtain compound of formula I；
Wherein, metallic catalyst is copper metal catalyst, is selected from copper powder, copper sulphate, copper acetate, copper chloride, stannous chloride, iodate
Copper, cuprous iodide, copper bromide, cuprous bromide, copper fluoride, copper fluoride, copper oxide, cuprous oxide；It is preferred that cupric iodide, iodate Asia
Copper.
8. method according to claim 7, which is characterized in that in step 2, the reaction is：Under reaction temperature, by formula Bization
It closes object to be dissolved in organic solvent, methoxy carbanionic reagent is added and metallic catalyst reacts 4~24 hours, post-processes, purify
To compound of formula I；
Wherein, in the reaction organic solvent be aprotic solvent and alcoholic solvent mixed solvent；
Aprotic solvent is selected from DMF, DME, acetonitrile, toluene, Isosorbide-5-Nitrae-dioxane, DMSO, n,N-dimethylacetamide, N- methyl
Pyrrolidones；Preferably DMF；Alcoholic solvent is selected from methanol, ethyl alcohol, propyl alcohol, butanol, isopropanol, ethylene glycol；It is preferred that methanol；Methoxy
Carbanionic reagent is selected from sodium methoxide, potassium methoxide, sodium hydride and methanol and matches agents with agents, hydrofining and methanol；It is excellent
Select sodium methoxide.
9. method according to claim 8, which is characterized in that
The weight ratio of the aprotic solvent and alcoholic solvent is 1:0~1:1；
The weight ratio of the methoxy carbanionic reagent and formula B compound is 1:1~1:4；
The weight ratio of the metallic catalyst and formula B compound is 1:10~1:200.
10. a kind of the method for preparing compound of formula I, it includes following steps：
Step 1：It is 1 by the weight ratio of sodium methoxide and formula A-1 compound in the presence of methanol solvate:1.5~1:2 material is molten
Solution, reaction solution are 40~70 DEG C in reaction temperature and stir 10~36 hours；Solvent is removed, vacuum distillation purifying obtains formula B-1ization
Close object；
The formula A-1 compound is：
The formula B-1 compound is：
Step 2：Step 1 Chinese style B-1 compound is dissolved in organic solvent, sodium methoxide and copper metal catalyst, heating 80 is added
~110 DEG C are reacted 4~24 hours；Cooling filtering, vacuum distillation purifying obtains compound of formula I after filtrate removes solvent；
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