CN106588758A - Synthetic process for 2-hydrazinylpyridine derivative - Google Patents
Synthetic process for 2-hydrazinylpyridine derivative Download PDFInfo
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- CN106588758A CN106588758A CN201610980696.8A CN201610980696A CN106588758A CN 106588758 A CN106588758 A CN 106588758A CN 201610980696 A CN201610980696 A CN 201610980696A CN 106588758 A CN106588758 A CN 106588758A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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
- C07D213/72—Nitrogen atoms
- C07D213/76—Nitrogen atoms to which a second hetero atom is attached
- C07D213/77—Hydrazine radicals
Abstract
The invention discloses a synthetic process for a 2-hydrazinylpyridine derivative. The process includes the steps that a pyridine halide A, hydrazine hydrate and a solvent I are mixed for a reaction; and after the reaction and aftertreatment, a reaction product, namely the 2-hydrazinylpyridine derivative P is obtained. According to the process, the pyridine halide A can be obtained through a hydrogen substitution reaction of a precursor compound B under the conditions of bases and catalysts. N,N-dimethylpropanolamine in the solvent I plays the role of an acid-binding agent to a certain extent, and the reaction is promoted to the product generating direction; and in the hydrogen substitution reaction, the mixed catalysts are combined with compounding use of the strong base and the weak base, so that the selectivity of the hydrogen substitution reaction is improved, and the reaction speed of the hydrogen substitution reaction is increased.
Description
Technical field
The present invention relates to field of fine chemical, more particularly to a kind of synthesis technique of 2- hydrazino pyridines derivant.
Background technology
2- hydrazino pyridines derivant is widely used in the fields such as medicine, pesticide, rubber and dyestuff as intermediate.With me
The fast development of state's fine chemistry industry, particularly China medicine, the fast development of pesticide industry, to 2- hydrazino pyridines derivant such as 3-
The demand of chloride-2-hydrazinopyridine increasingly increases.
At present, it is less to the report of the industrial preparative method of 2- hydrazino pyridine derivants, only 2- diazanyls chloro- to 3- on a small quantity
The research of pyridine preparation method.As in Chinese patent CN103588705A, the fluoro- 3- chloropyridines of 2- and hydrazine hydrate are mixed, with second
Alcohol is solvent, is reacted at normal temperatures.The fluoro- 3- chloropyridines of the method reaction raw materials 2- prepare difficulty, using hydration hydrazine reaction
When without security protection, and be not directed to the recovery of solvent.3- chloride-2-hydrazinopyridines also can be by 2,3- dichloropyridines and hydration hydrazine reaction
Preparation, but reaction raw materials 2, the preparation of 3- dichloropyridines is generally obtained using nicotiamide with sodium hypochlorite Jing hoffman degradation reactions
Obtain to 3- aminopyridines, then Jing chlorination reactions, diazotising and Sang Demaier reaction, this course of reaction step is more, cause to produce
Product yield expends more extracting operation in a large amount of costs of labor, and diazotising, chlorination and course of reaction while not high
A large amount of waste liquids can be produced and given up admittedly, environmental pollution is serious, constrains the industrial production scale of the product, not meet China's section
Can reduction of discharging, the requirement of green production.
Therefore, it is necessary to a kind of new synthesis process of the 2- hydrazino pyridine derivants that can be used for industrialized production is researched and developed, with
Simplified flowsheet condition, reduction pollutant emission and raising product yield.
The content of the invention
In order to solve the above problems, present inventor has performed studying with keen determination, the hydrogen occurred using hydrogen and precursor compound B
Substitution reaction prepares pyridinium halide A, greatly reduces the generation of the three wastes, by the choosing for selecting specific catalyst to replace hydrogen
Selecting property and yield are high, and pyridinium halide A and hydrazine hydrate react under conditions of using tertiary amines as solvent I, are conducive to reaction
Carrying out, reaction rate and yield are greatly improved, so as to complete the present invention.
It is an object of the invention to provide a kind of synthesis technique of 2- hydrazino pyridines derivant, comprises the following steps：
Step 1, pyridinium halide A, hydrazine hydrate and solvent I are mixed, and are reacted；
Step 2, it is post-treated after reaction terminates, obtain product 2- hydrazino pyridine derivant P；
The structure of the pyridinium halide A is：
The structure of 2- hydrazino pyridines derivant P is：
Wherein, X is halogen atom, is preferably selected from any one in F, Cl or Br；
R is selected from one or more of hydrogen atom, halogen, alkyl, alkoxyl and ester group.
In a preferred embodiment, in step 1, the solvent I be selected from alcohols, in amide or hydramine any one
Or it is various, the alcohols is C1～C4 small molecular alcohols, such as methanol, ethanol or n-butyl alcohol, and the amide is selected from N, N- dimethyl methyls
In amide, N,N-dimethylacetamide or N, N- dimethylpropionamide any one or more, the hydramine be selected from 2- hydroxyl second
Amine, N, N- dimethyl propanol amines, N, in N- diethyl ethylene diamines, triethanolamine or monoisopropanolamine any one or more,
Preferably, the solvent I be hydramine, more preferably N, N- dimethyl propanol amines.
Reaction is carried out under an inert atmosphere, and the inert atmosphere is nitrogen or argon, preferably nitrogen；Reaction temperature is
100～150 DEG C, preferably 125～130 DEG C.
In another preferred embodiment, in step 1, when R bases are 3 and/or 4 bit substituent, pyridinium halide A
Can be commercially available or prepared by following methods：
Precursor compound B, solvent II, alkali and catalyst are added in reaction vessel, being passed through hydrogen carries out hydrogen substitution reaction,
Pyridinium halide A is obtained,
The structure of the precursor compound B is：
Wherein, X is halogen atom, is preferably selected from F, Cl and Br；
Y is halogen atom, is preferably selected from F, Cl and Br；
R is selected from hydrogen, halogen, alkyl, alkoxyl or ester group.
Wherein, the solvent II in alcohols, amide or the hydramine any one or more, preferably alcohols, more preferably
For methanol；
The alkali selected from organic base and/or inorganic base, preferably pyridine and sodium hydroxide compounding use, it is highly preferred that pyrrole
Pyridine is added before the reaction in reaction vessel, and sodium hydroxide solvent II is slowly added during the course of the reaction after disperseing in the way of Deca
Enter；
The catalyst selected from carried catalyst and/or skeleton type catalyst, preferably carried catalyst, more preferably with
Activated carbon is the catalyst of carrier, most preferably palladium/carbon and platinum/carbon mixed catalyst.
The synthesis technique of the 2- hydrazino pyridine derivants provided according to the present invention, has the advantages that：
(1) selection of solvent I N, N- dimethyl propanol amines in synthesis technique, it not only meets the dissolubility need of reaction raw materials
Ask；Meanwhile, used as tertiary amine compound, it can to a certain extent play a part of acid binding agent, and the acid-base value of stabilising system promotes
React is carried out to the direction for generating product；
(2) the synthesis technique reaction condition of 2- hydrazino pyridines derivant P is gentle, low temperature is carried out under inert gas shielding and is returned
Stream reaction, increased the safety of reaction；
(3) pyridinium halide A can be prepared by the hydrogen substitution reaction of precursor compound B, and Pd/C or Pt/C is adopted in preparation
Mixed catalyst, greatly improves the selectivity and reaction rate of hydrogen substitution reaction；
(4) in hydrogen substitution reaction, alkali selects highly basic and weak base compound use, in particular pyridine and sodium hydroxide to be combined and make
With and limit its order of addition, the pH for controlling reaction system avoids the situation that peracid crosses alkali between 6～9, not only, to body
Be acid-base value control more accurately, it is rapid, and then ensure that the selectivity and efficiency of hydrogen substitution reaction；
(5) hydrogen substitution reaction is reduced useless compared to the wide method with nicotiamide as reaction raw materials is used at present
The discharge capacity of thing, improves yield.
Description of the drawings
Fig. 1 is the gas chromatogram of the not purified 2,3- dichloropyridines prepared in embodiment 1；
Fig. 2 is the liquid chromatogram of chloro- 2 hydrazino pyridines of 3- prepared in embodiment 1；
Fig. 3 is the gas chromatogram of the not purified 2,3- dichloropyridines prepared in embodiment 2；
Fig. 4 is the liquid chromatogram of chloro- 2 hydrazino pyridines of 3- prepared in embodiment 2；
Fig. 5 is the gas chromatogram of the not purified 2,3- dichloropyridines prepared in comparative example 1；
Fig. 6 is the liquid chromatogram of chloro- 2 hydrazino pyridines of 3- prepared in comparative example 1；
Fig. 7 is the gas chromatogram of the not purified 2,3- dichloropyridines prepared in comparative example 2；
Fig. 8 is the liquid chromatogram of chloro- 2 hydrazino pyridines of 3- prepared in comparative example 2.
Specific embodiment
Below by the present invention is described in detail, the features and advantages of the invention will become more with these explanations
For clear, clear and definite.
It is an object of the invention to provide a kind of synthesis technique of 2- hydrazino pyridines derivant, the synthesis technique includes following step
Suddenly：
Step 1, pyridinium halide A, hydrazine hydrate and solvent I are mixed, and are reacted；
Step 2, it is post-treated after reaction terminates, obtain product 2- hydrazino pyridine derivant P；
The structure of the pyridinium halide A is：
The structure of 2- hydrazino pyridines derivant P is：
Wherein, X is halogen atom, is preferably selected from any one in F, Cl or Br, preferably Cl；
R is any one or more in 3,4,5 or 6 bit substituents, selected from hydrogen, halogen, alkyl, alkoxyl and ester group, i.e.,
Pyridinium halide A is not limited to two replacements, can also replace for multidigit.The halogen be selected from F, Cl and Br, the alkyl as-
CH3、-CH2CH3、-CH(CH3)2、-C(CH3)3, the alkoxyl such as-OCH3、-OCH2CH3、-OCH(CH3)2, the ester group as-
CH3COOCH3、-CH3COOCH2CH3With-CH2CH3COOCH3.The pyridinium halide A can be 2,3- dichloropyridines, chloro- uncles 4- of 2-
Butyl-pyridinium, 2- chloro-5-methoxyl pyridines, the bromo- 5- methoxypyridines of 2-, the bromo- 2- chloro-4-methoxies pyridines of 5- etc..
In step 1, pyridinium halide A, hydrazine hydrate and solvent I are mixed in a kettle., adjust reaction temperature, carried out back
Stream reaction.Reaction equation is as shown in following formula 1：
In the present invention, the mass fraction of hydrazine hydrate is 70%～80%, unsuitable too low, in order to avoid introduce excessive water, shadow
Ring the dissolubility of reaction raw materials pyridinium halide A.
From formula 1, on the premise of R group is not involved in reaction, in theory pyridinium halide A and hydration hydrazine reaction are generated
X group during 2- hydrazino pyridine derivants P is 1 with the mol ratio of hydrazine hydrate:1.Carry out to react fully, select hydrazine hydrate mistake
The mol ratio of amount, pyridinium halide A and hydrazine hydrate is set to 1:1.5～1:1.8.The amount ratio of pyridinium halide A and hydrazine hydrate is tight
Lattice are limited, and in mol ratio 1 is more than:When 1.8, reaction terminates the presence of more hydrazine hydrate in rear system, causes the wasting of resources or hydration
Hydrazine recovery difficult is larger；And be the machine for reducing R group and hydration hydrazine reaction such as ester group in the case where R group may participate in reaction
The mol ratio of rate, pyridinium halide A and hydrazine hydrate also should be less than 1:1.8.In particular cases, determine that R group needs and hydrazine hydrate
When reacting, the mol ratio of pyridinium halide A and hydrazine hydrate can be repeatedly fed intake or adjusted.
Consider dissolubility of the reaction raw materials in solvent I, solvent I is selected from alcohols, in amide or hydramine any one or it is many
Kind.The alcohols is C1～C4 small molecular alcohols, such as methanol, ethanol or n-butyl alcohol, the amide selected from DMF,
In N,N-dimethylacetamide or N, N- dimethylpropionamide any one or more, the hydramine be selected from 2 hydroxy ethylamine, N,
N- dimethyl propanol amines, N, in N- diethyl ethylene diamines, triethanolamine or monoisopropanolamine any one or more.
From formula 1, because pyridinium halide A and hydration hydrazine reaction generate hydrogen halides, the removal to hydrogen halides in system
Would be even more beneficial to the carrying out reacted.Selection solvent I be hydramine, preferably N, N- dimethyl propanol amines.N, N- dimethyl propanol amine
It is not only miscible with water, and gas chromatography is can dissolve, meet basic dissolubility demand；Meanwhile, used as tertiary amine compound, it can
Play a part of acid binding agent, and then the acid-base value of stabilising system to a certain extent, promote reaction to enter to the direction for generating product
OK.
Further to remove chlorination halogen, reactor connection device for absorbing tail gas in step 1, absorption plant adopts water absorbing halogen
Change hydrogen, obtain hydrochloric acid side-product.Thus, almost non-exhaust emission in whole reaction system, environmental protection, the water of absorbing acid gases
Other purposes are can be additionally used in, secondary benefit is produced.
The weight ratio of hydrazine hydrate and solvent I is 1:25～1:50, back flow reaction requirement is met, while it is former not result in reaction
Material concentration is too low, reduces reaction rate.
The reflux temperature of hydrazine hydrate and solvent I is 100～150 DEG C, and in this temperature range, substitution reaction can be rapidly
Carry out, and by-product is few in obtained product, and preferable reaction temperature is 125～130 DEG C.Further, using noble gases
Air in replacement reaction kettle, makes the reaction carry out under an inert atmosphere, and the inert atmosphere is nitrogen or argon, preferably nitrogen
Gas.Inert atmosphere avoids absorption of the hydrazine hydrate to Carbon Dioxide in Air.If the noble gases being filled with are more than atmospheric pressure, promoting
The gasification of hydrazine hydrate is reduced while entering reaction rate, reduces hydrazine hydrate steam risk of toxicity.
In the present invention, pyridinium halide A can be obtained for commercially available or self-control, when R bases are 3 and/or 4 bit substituent,
Pyridinium halide A is prepared by following methods：Precursor compound B, solvent II, alkali and catalyst are added in reaction vessel, is led to
Entering hydrogen carries out hydrogen substitution reaction, obtains pyridinium halide A,
The structure of the precursor compound B is：
Wherein, X is halogen atom, is preferably selected from F, Cl and Br；
Y is halogen atom, is preferably selected from F, Cl and Br；
R is selected from hydrogen, halogen, alkyl, alkoxyl or ester group.
This reaction is hydrogen substitution reaction, and reaction equation is as shown in following formula 2：
In this reaction, catalyst is selected from work selected from carried catalyst and/or skeleton type catalyst, the carried catalyst
Property charcoal, Calcium Carbonate, aluminium oxide or Graphene for carrier palladium or platinum catalyst in any one or more, the matrix type is urged
Agent is selected from any one or more in Raney's nickel, thunder Buddhist nun's cobalt, thunder Buddhist nun ruthenium or Lei Nitong.
Improve as one kind of above-mentioned embodiment, the catalyst is selected from carried catalyst, is preferably with activated carbon
The catalyst of carrier, more preferably palladium/carbon (Pd/C) and platinum/carbon (Pt/C) mixed catalyst.Production practices show, mixed catalytic
Pd/C the or Pt/C catalyst that agent is relatively used alone on catalytic efficiency and selectivity is improved.
Used as the further improvement of above-mentioned embodiment, the load capacity of Pt is 7～8%, Pd/C catalysis in Pt/C catalyst
The load capacity of Pd is 10 for the weight ratio of 7～8%, Pt/C catalyst and Pd/C catalyst in agent:1～1:10.
Improve as the another kind of above-mentioned embodiment, be the effective catalysis for ensureing catalyst, the catalyst and precursor
The weight ratio of compound B is 1:15～1:30, preferably 1:20～1:25.
In this reaction, alkali and the hydrogen halides reaction for producing are added, to avoid the large change of reaction system acid-base value.Acidity
Metal in Pd/C or Pt/C catalyst is easily set to come off greatly, and halogen ion (the especially Cl departed from precursor compound B-) easily make to urge
Agent is poisoned, and affects catalytic efficiency；Alkalescence is excessive, and the alkali compoundss of addition are excessive, and more polymictic introducing affects product
Purity.Alkali is selected from pyridine, triethylamine, Feldalat NM, potassium ethoxide or the tert-butyl alcohol selected from organic base and/or inorganic base, the organic base
In potassium any one or more, the inorganic base is selected from alkali metal hydroxide and/or alkaline earth metal hydroxide, such as hydroxide
In sodium, potassium hydroxide or calcium hydroxide any one or more.
Improve as one kind of above-mentioned embodiment, the alkali selects the mode of highly basic and weak base compound use, preferably
Pyridine and sodium hydroxide are used in mixed way.
Used as the further improvement of above-mentioned embodiment, pyridine is added before the reaction with precursor compound B and solvent
In reaction vessel, sodium hydroxide solvent II is slowly added to during the course of the reaction after disperseing in the way of Deca.
Pyridine is alkalescence, and now it provides suitable initial soda acid equivalent to the pH buffer of reaction system for reaction
Degree.When using methanol as reaction dissolvent, pyridine has bigger dissolubility compared to triethylamine, preferably to use.With anti-
The carrying out answered, hydrogen halides are constantly produced, pyridine it is alkaline limited, need the alkaline sodium hydroxide solution of Deca be allowed to it is rapid with it is sour
Reaction, the pH of control reaction system is between 6～9.By the way of the weak base and highly basic compound use, it is to avoid peracid crosses alkali
Situation, to the control of system acid-base value more accurately, it is rapid, and then ensure that the selectivity and efficiency of hydrogen substitution reaction.
Used as the further improvement of above-mentioned embodiment, weak base is 1 with the weight ratio of precursor compound B:8～1:14,
Preferably 1:10～1:12.
Solvent II is selected from any one or more in alcohols, amide or hydramine, wherein the alcohols is C1～C4 small molecules
Alcohol, such as methanol, ethanol or n-butyl alcohol, the amide is selected from DMF, N,N-dimethylacetamide or N, N- bis-
In methyl propanamide any one or more, the hydramine be selected from 2 hydroxy ethylamine, N, N- dimethyl propanol amines, N, N- diethyl
In ethanolamine, triethanolamine or monoisopropanolamine any one or more.
Improve as one kind of above-mentioned embodiment, the solvent II is selected from alcohols, preferred methanol.C1～C4 small molecules
Alcohol, especially methanol, have preferably dissolving compared to amide or hydramine to pyridinium halide A and as the pyridine of pH buffer
Property, and methanol prices are cheap, reduce production cost.
Add in reaction vessel after precursor compound B, solvent II, pH buffer (alkali) and catalyst, adjust temperature simultaneously
Being passed through hydrogen carries out hydrogen substitution reaction.The temperature of hydrogen substitution reaction is 20～40 DEG C, and reaction can be completed under room temperature；It is passed through hydrogen
The pressure in reaction vessel is maintained to be 0.2Mpa～0.4Mpa afterwards.
After the completion of hydrogen substitution reaction, reactant liquor is filtered, the solid for obtaining is cleaned with water, remove the salt that mixes or
Alkali, reclaims catalyst.Filtrate to obtaining carries out air-distillation, you can reclaim reaction dissolvent, adds in leftover materials after distillation
Water decrease temperature crystalline, obtains product.Separating-purifying is carried out to hydrogen substitution reaction product, after obtaining pyridinium halide A so as to use
In the synthesis of 2- hydrazino pyridine derivants P, or separating-purifying is not carried out to product, the pyridine halogenation of a small amount of by-product will be contained
Thing A is directly used in the synthesis of 2- hydrazino pyridine derivants P, carries out product purification after reaction again.The former increased processing step, but
Beneficial to the purity for improving reactant in subsequent reactions, and the latter is simple to operate, but is generating the reaction of 2- hydrazino pyridine derivants P
The middle response magnitude that can increase hydrazine hydrate, reduces the purity of reaction rate and product.According to practical situations such as product requirements when using
Selected, preferably the former is i.e. using front advance to pyridinium halide A separating-purifyings.
It is post-treated after reaction terminates in step (2), obtain product 2- hydrazino pyridine derivant P.In the present invention
In, the post processing includes crystallisation by cooling, the separation of product, purification and drying.
The temperature of crystallisation by cooling is determined according to specific 2- hydrazino pyridines derivant P, the temperature of crystallisation by cooling typically sets
For 20～30 DEG C.Solid-liquid separation is carried out to system after crystallization, separate mode is for centrifugation or filters, and is preferably centrifuged.To collecting
Crystalline solid carry out purification, way of purification is recrystallization or washing, is preferably washed, and is non-in 2- hydrazino pyridines derivant P
Under the premise of water miscible, selection water is cleaning solvent.
Centrifugation or crystalline solid after purification are dried, and drying mode is that constant pressure and dry or low pressure are dried, preferably low
Press dry it is dry, baking temperature be 55 DEG C～65 DEG C.In the industrial production, product can be delivered in double cone dryer and is dried, make product
Uniform drying is abundant.
If the 2- hydrazino pyridines derivant for obtaining is at normal temperatures liquid, 2- hydrazino pyridines can be carried out by extraction mode and be spread out
Biological P is separated with reaction system, then distills out extract, obtains product 2- hydrazino pyridine derivants P.
In step 2, also including the recovery of solvent, the removal process is comprised the following steps：Adjust molten after product is separated
Agent is distilled under an inert atmosphere to neutrality, and the inert atmosphere is nitrogen or argon, preferred nitrogen atmosphere.
Because of the aobvious acidity containing hydrogen chloride in solvent after reaction, if solvent is also possible to and hydrogen chloride for tertiary amines
With reference to, thus it is to neutrality and anti-with the hydrogen chloride that tertiary amines solvent is combined that appropriate bases can be added to adjust solvent before being distilled
Should, it is to avoid hydrogen chloride gas are steamed therewith or cannot Distillation recovery with reference to the tertiary amines solvent of hydrogen chloride during distillation.
As above-mentioned embodiment one kind improve, distilled under an inert atmosphere, the inert atmosphere be nitrogen or
Argon, preferred nitrogen atmosphere.Due to containing various ingredients in solvent, different solvents component can be at different temperatures separately recovered.
With N, as a example by N- dimethyl propanol amines are as solvent I, the rectification process of solvent is after reaction：Under agitation, to dress
Have after reaction and put into appropriate piece alkali (sodium hydroxide) in the distillating still of solvent, control temperature below 50 DEG C, the piece into distillating still
Alkali is completely dissolved, and adjusts material liquid pH to neutrality, then logical nitrogen displacement air three times in distillating still, in normal pressure, 120 DEG C of conditions
Under steam N, N- dimethyl propanol amines go rectification.
The N of rectification will be treated, N- dimethyl propanol amines proceed to rectifying still, -0.09MPa ,≤101 DEG C under the conditions of water is evaporated off；
Water is evaporated off terminating, and remaining main fraction in rectifying still, i.e. N, N- dimethyl propanol amines (remain hydrazine hydrate), returns production and applies mechanically.
Embodiment
Below by taking the synthesis technique of chloro- 2 hydrazino pyridines of 3- as an example, the present invention is further described by instantiation.But
These examples are only exemplary, do not constitute any restriction to protection scope of the present invention.
Embodiment 1
(1) synthesis (with 2,3,6- trichloropyridines as raw material) of 2,3- dichloropyridines
By 500g 2.3.6- trichloropyridines, 1800g methanol, 20g mixed catalyst (8%Pt/C:8%Pd/C=1:10)
It is added in reactor with 45g pyridines, is passed through hydrogen, while being slowly added dropwise 5 (weight) % sodium hydrate methanol solutions, remains anti-
Pressure in kettle is answered to be 0.3Mpa, temperature is 30 DEG C, and after the completion of hydrogenation, replacing hydrogen filters out Pt/C and Pd/C catalyst and applies mechanically,
Filtrate air-distillation recovery methanol is received to obtain, adds water, decrease temperature crystalline, centrifugation, purification to obtain 2,3- dichloropyridines in leftover materials.
The purity of 2,3- dichloropyridines is 97.6% in step (), and yield is not purified seasonal epidemic pathogens phase after 88.5% crystallization
Chromatogram is as shown in Figure 1.
(2) synthesis of chloro- 2 hydrazino pyridines of 3-
By 148g 2,3- dichloropyridines and 3700g N, N- dimethyl propanol amine mix homogeneously in a kettle. is added
The hydrazine hydrates of 105g 80%, with air in nitrogen displacement kettle three times, then heat to 130 DEG C, insulation back flow reaction 10 hours, instead
Should terminate, be cooled to 25 DEG C of crystallizations, then turn material to centrifuge, and wash centrifugal solids with water, centrifuge mother liquor enters N, N-
Dimethyl propanol amine mother liquor tank in case rectification, deliver to and be dried in double cone dryer (- 0.09MPa, 60 DEG C) after centrifugation, must produce by solid
Product 3- chloride-2-hydrazinopyridines.
The purity of 3- chloride-2-hydrazinopyridines is 99.7% in step (two), and yield is 95%, liquid chromatogram such as Fig. 2 institutes
Show.
Embodiment 2
(1) synthesis of 2,3- dichloropyridines
By 450g 2.3.6- trichloropyridines, 1600g ethanol, 20g mixed catalyst (8%Pt/C:8%Pd/C=10:1)
It is added in reactor with 45g triethylamines, is passed through hydrogen, while being slowly added dropwise 5 (weight) % sodium hydroxide ethanol solution, maintains
Pressure is 0.25Mpa in reactor, and temperature is 25～30 DEG C, and after the completion of hydrogenation, replacing hydrogen filters out Pt/C and Pd/C catalysis
Agent is applied mechanically, and receives to obtain filtrate air-distillation recovery methanol, adds water, decrease temperature crystalline, centrifugation, purification to obtain 2,3- bis- in leftover materials
Chloropyridine.
The purity of 2,3- dichloropyridines is 96.8% in step (), and yield is 85%, not purified seasonal epidemic pathogens phase after crystallization
Chromatogram is as shown in Figure 3.
(2) synthesis of chloro- 2 hydrazino pyridines of 3-
By 148g 2,3- dichloropyridines and 4500g DMFs mix homogeneously in a kettle. is added
The hydrazine hydrates of 110g 80%, with air in nitrogen displacement kettle three times, then heat to 130 DEG C, insulation back flow reaction 10 hours, instead
Should terminate, be cooled to 25 DEG C of crystallizations, then turn material to centrifuge, and wash centrifugal solids with water, centrifuge mother liquor enters N, N-
Dimethylformamide mother liquor tank in case rectification, deliver to and be dried in double cone dryer (- 0.09MPa, 60 DEG C) after centrifugation, must produce by solid
Product 3- chloride-2-hydrazinopyridines.
The purity of 3- chloride-2-hydrazinopyridines is 99.2% in step (two), and yield is 90%, liquid chromatogram such as Fig. 4 institutes
Show.
Comparative example 1
(1) synthesis of 2,3- dichloropyridines
500g 2.3.6- trichloropyridines, 1800g methanol, 20g single catalysts (8%Pt/C) and 45g pyridines are added to
In reactor, hydrogen is passed through, while being slowly added dropwise 5 (weight) % sodium hydrate methanol solutions, pressure is in maintenance reactor
0.3Mpa, temperature is 25～30 DEG C, and after the completion of hydrogenation, replacing hydrogen filters out Pt/C and Pd/C catalyst and applies mechanically, and receives to obtain filtrate
Methanol is reclaimed in air-distillation, adds water, decrease temperature crystalline, centrifugation, purification to obtain 2,3- dichloropyridines in leftover materials.
The purity of 2,3- dichloropyridines is 89.2% in step (), and yield is 65%, not purified seasonal epidemic pathogens phase after crystallization
Chromatogram is as shown in Figure 5.
(2) synthesis of chloro- 2 hydrazino pyridines of 3-
By 148g 2,3- dichloropyridines and 3700g n-butyl alcohol mix homogeneously in a kettle. adds 105g 70% to be hydrated
Hydrazine, with air in nitrogen displacement kettle three times, then heats to 100 DEG C, insulation back flow reaction 10 hours, and reaction terminates, and is cooled to
25 DEG C of crystallizations, then turn material to centrifuge, and wash centrifugal solids with water, and centrifuge mother liquor enters mother liquor tank in case rectification, from
Solid is delivered in double cone dryer (- 0.09MPa, 60 DEG C) and is dried after the heart, obtains product 3- chloride-2-hydrazinopyridines.
The purity of 3- chloride-2-hydrazinopyridines is 96.0% in step (two), and yield is 80%, liquid chromatogram such as Fig. 6 institutes
Show.
Comparative example 2
(1) synthesis of 2,3- dichloropyridines
It is identical with process conditions in embodiment 1, differ only in catalysts conditions by mixed catalyst (8%Pt/C:
8%Pd/C=1:2) condition becomes single catalyst (8%Pd/C).
The purity of 2,3- dichloropyridines is 85.4% in step (), and yield is 68%, not purified seasonal epidemic pathogens phase after crystallization
Chromatogram is as shown in Figure 7.
(2) synthesis of chloro- 2 hydrazino pyridines of 3-
It is identical with process conditions in embodiment 1, differ only in solvent I by N, N- dimethyl propanol amines become dioxy six
Ring, reflux temperature is changed into 100 DEG C from 130 DEG C.
The purity of 3- chloride-2-hydrazinopyridines is 93.7% in step (two), and yield is 79%, liquid chromatogram such as Fig. 8 institutes
Show.The product of embodiment 1～2 and comparative example 1～2 the results are shown in Table 1.
Table 1
From embodiment 1～2 in table 1, highly basic and weak base compound use are adopted during synthesis 2,3- dichloropyridines and is mixed
Close catalyst reaction, purity >=95% of 2,3- dichloropyridines, yield >=85%；Chloro- 2 hydrazino pyridines of synthesis 3- are from conjunction
Suitable solvent, purity >=99% of chloro- 2 hydrazino pyridines of 3-, yield >=90%.
From comparative example 1～2 in table 1, single catalyst, and synthesis 3- chloro- 2 are adopted during synthesis 2,3- dichloropyridines
Hydrazino pyridine select non-tertiary amine class solvent, purity≤90% of 2,3- dichloropyridines, yield≤70%, chloro- 2 hydrazino pyridines of 3-
Purity≤97%, yield≤80%, the economic benefit of product is far below the product prepared using preferred embodiment.
The present invention has been described in detail above in association with specific embodiment and exemplary example, but these explanations are simultaneously
It is not considered as limiting the invention.It will be appreciated by those skilled in the art that without departing from the spirit and scope of the invention,
Various equivalencings, modification can be carried out to technical solution of the present invention and embodiments thereof or is improved, these each fall within the present invention
In the range of.Protection scope of the present invention is defined by claims.
Claims (10)
1. a kind of synthesis technique of 2- hydrazino pyridines derivant, comprises the following steps：
Step 1, pyridinium halide A, hydrazine hydrate and solvent I are mixed, and are reacted；
Step 2, it is post-treated after reaction terminates, obtain product 2- hydrazino pyridine derivant P.
2. technique according to claim 1, it is characterised in that
The structure of the pyridinium halide A is：
Wherein, X is halogen atom, is preferably selected from F, Cl and Br；
The structure of 2- hydrazino pyridines derivant P is：
Wherein, R is selected from one or more of hydrogen, halogen, alkyl, alkoxyl and ester group.
3. technique according to claim 1 and 2, it is characterised in that in step 1,
The mass fraction of hydrazine hydrate is 70%～80%；And/or
The mol ratio of pyridinium halide A and hydrazine hydrate is 1:1.5～1:1.8；And/or
The weight ratio of hydrazine hydrate and solvent I is 1:25～1:50；And/or
The solvent I be selected from alcohols, in amide or hydramine any one or more, the alcohols be C1～C4 small molecular alcohols, such as
Methanol, ethanol or n-butyl alcohol, the amide is selected from DMF, N,N-dimethylacetamide or N, N- dimethyl propylene
In amide any one or more, the hydramine be selected from 2 hydroxy ethylamine, N, N- dimethyl propanol amines, N, N- diethylaluminum ethoxides
In amine, triethanolamine or monoisopropanolamine any one or more,
Preferably, the solvent I be hydramine, more preferably N, N- dimethyl propanol amines.
4. the technique according to one of claims 1 to 3, it is characterised in that the reaction in step 1 is entered under an inert atmosphere
OK, the inert atmosphere is nitrogen or argon, preferably nitrogen；And/or,
Reaction temperature is 100～150 DEG C, preferably 125～130 DEG C.
5. the synthesis technique according to one of claim 2 to 4, it is characterised in that in step 1, when R takes for 3 and/or 4
During for base, pyridinium halide A can be prepared by following methods：
Precursor compound B, solvent II, alkali and catalyst are added in reaction vessel, being passed through hydrogen carries out hydrogen substitution reaction, obtains
Pyridinium halide A, wherein,
The structure of the precursor compound B is：
X is halogen atom, is preferably selected from F, Cl and Br；
Y is halogen atom, is preferably selected from F, Cl and Br；
R is selected from hydrogen, halogen, alkyl, alkoxyl or ester group.
6. synthesis technique according to claim 5, it is characterised in that
The solvent II is selected from any one or more in alcohols, amide or hydramine, wherein the alcohols is C1～C4 small molecules
Alcohol, such as methanol, ethanol or n-butyl alcohol, the amide is selected from DMF, N,N-dimethylacetamide or N, N- bis-
In methyl propanamide any one or more, the hydramine be selected from 2 hydroxy ethylamine, N, N- dimethyl propanol amines, N, N- diethyl
In ethanolamine, triethanolamine or monoisopropanolamine any one or more；And/or
The alkali is selected from pyridine, triethylamine, Feldalat NM, potassium ethoxide or tertiary fourth selected from organic base and/or inorganic base, the organic base
In potassium alcoholate any one or more, the inorganic base is selected from alkali metal hydroxide and/or alkaline earth metal hydroxide, such as hydrogen-oxygen
Change any one or more in sodium, potassium hydroxide or calcium hydroxide；And/or
The catalyst is selected from activated carbon, carbonic acid selected from carried catalyst and/or skeleton type catalyst, the carried catalyst
Calcium, aluminium oxide or Graphene are one or more in the palladium or platinum catalyst of carrier, and the skeleton type catalyst is selected from thunder Buddhist nun
In nickel, thunder Buddhist nun's cobalt, thunder Buddhist nun ruthenium or Lei Nitong any one or more.
7. the synthesis technique according to claim 5 or 6, it is characterised in that
The solvent II is selected from alcohols, preferred methanol；And/or
The alkali is pyridine and sodium hydroxide compounding use, it is preferable that pyridine is added before the reaction in reaction vessel, sodium hydroxide
It is slowly added in the way of Deca during the course of the reaction after being disperseed with solvent II；And/or
The catalyst be selected from carried catalyst, the catalyst preferably with activated carbon as carrier, more preferably palladium/carbon and platinum/
Carbon mixed catalyst.
8. the synthesis technique according to one of claim 5 to 7, it is characterised in that the reaction temperature of hydrogen substitution reaction is 20
～40 DEG C, the pressure being passed through after hydrogen in reaction vessel is 0.2Mpa～0.4Mpa.
9. the synthesis technique according to one of claim 1 to 8, it is characterised in that in step 2,
The post processing includes crystallisation by cooling, the separation of product, purification and drying,
The separate mode is for centrifugation or filters, and is preferably centrifuged, and/or
The way of purification is recrystallization or washing, is preferably washed, and/or
The drying is that constant pressure and dry or low pressure are dried, and preferably low pressure is dried, and baking temperature is 55 DEG C～65 DEG C.
10. the synthesis technique according to one of claim 1 to 9, it is characterised in that in step 2, also returning including solvent
Receive, the removal process is comprised the following steps：
The solvent after product is separated is adjusted to neutrality, is distilled under an inert atmosphere, the inert atmosphere is nitrogen or argon,
Preferably nitrogen.
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| CN107721913A (en) * | 2017-11-28 | 2018-02-23 | 利尔化学股份有限公司 | A kind of preparation method of 2,3 dichloropyridine |
| CN110041252A (en) * | 2019-05-22 | 2019-07-23 | 南京合巨药业有限公司 | A kind of preparation method of the chloro- 4- hydrazino pyridine of 2- |
| CN110551062A (en) * | 2019-09-16 | 2019-12-10 | 西安凯立新材料股份有限公司 | Method for preparing 2,3, 5-trichloropyridine by adopting 2,3,5, 6-tetrachloropyridine |
| CN112694438A (en) * | 2020-12-11 | 2021-04-23 | 江苏优普生物化学科技股份有限公司 | Improved process of 2-hydrazino-3-chloropyridine |
| CN113683558A (en) * | 2021-09-14 | 2021-11-23 | 西安思科赛实业有限公司 | Preparation method for increasing yield of 2, 3-dichloropyridine |
| CN114057631A (en) * | 2022-01-14 | 2022-02-18 | 苏州开元民生科技股份有限公司 | Synthetic method of 3-chloro-2-hydrazinopyridine |
| CN115403577A (en) * | 2022-09-21 | 2022-11-29 | 凤翔万生源医药科技有限公司 | Synthesis method of carboxyl azaindole |
| CN115403577B (en) * | 2022-09-21 | 2024-04-26 | 西安宇特邦医药科技有限公司 | Synthesis method of carboxyl azaindole |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107721913A (en) * | 2017-11-28 | 2018-02-23 | 利尔化学股份有限公司 | A kind of preparation method of 2,3 dichloropyridine |
| CN107721913B (en) * | 2017-11-28 | 2019-10-18 | 利尔化学股份有限公司 | A kind of preparation method of 2,3- dichloropyridine |
| CN110041252A (en) * | 2019-05-22 | 2019-07-23 | 南京合巨药业有限公司 | A kind of preparation method of the chloro- 4- hydrazino pyridine of 2- |
| CN110551062A (en) * | 2019-09-16 | 2019-12-10 | 西安凯立新材料股份有限公司 | Method for preparing 2,3, 5-trichloropyridine by adopting 2,3,5, 6-tetrachloropyridine |
| CN112694438A (en) * | 2020-12-11 | 2021-04-23 | 江苏优普生物化学科技股份有限公司 | Improved process of 2-hydrazino-3-chloropyridine |
| CN113683558A (en) * | 2021-09-14 | 2021-11-23 | 西安思科赛实业有限公司 | Preparation method for increasing yield of 2, 3-dichloropyridine |
| CN114057631A (en) * | 2022-01-14 | 2022-02-18 | 苏州开元民生科技股份有限公司 | Synthetic method of 3-chloro-2-hydrazinopyridine |
| CN114057631B (en) * | 2022-01-14 | 2022-10-25 | 苏州开元民生科技股份有限公司 | Synthetic method of 3-chloro-2-hydrazinopyridine |
| CN115403577A (en) * | 2022-09-21 | 2022-11-29 | 凤翔万生源医药科技有限公司 | Synthesis method of carboxyl azaindole |
| CN115403577B (en) * | 2022-09-21 | 2024-04-26 | 西安宇特邦医药科技有限公司 | Synthesis method of carboxyl azaindole |
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