CN106588758B - Synthesis process of 2-hydrazinopyridine derivative - Google Patents
Synthesis process of 2-hydrazinopyridine derivative Download PDFInfo
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Abstract
The invention discloses a synthesis process of 2-hydrazinopyridine derivatives, which comprises the steps of mixing pyridine halide A, hydrazine hydrate and a solvent I for reaction; after the reaction is finished, carrying out post-treatment to obtain a reaction product 2-hydrazinopyridine derivative P; wherein, the pyridine halide A can be prepared by hydrogen substitution reaction of a precursor compound B under the conditions of alkali and catalyst. The N, N-dimethylpropanolamine selected as the solvent I plays a role of an acid binding agent to a certain extent to promote the reaction to proceed towards the direction of a generated product, and in the hydrogen substitution reaction, a mixed catalyst is combined with the combined use of strong base and weak base, so that the selectivity and the reaction rate of the hydrogen substitution reaction are improved.
Description
Technical Field
The invention relates to the field of fine chemical engineering, and particularly relates to a synthesis process of a 2-hydrazinopyridine derivative.
Background
The 2-hydrazinopyridine derivative as intermediate is used widely in medicine, pesticide, rubber, dye and other fields. With the rapid development of fine chemical industry in China, particularly the rapid development of medical and pesticide industries in China, the demand of 2-hydrazinopyridine derivatives such as 3-chloro-2-hydrazinopyridine is increasing day by day.
Currently, few reports are made on industrial synthesis methods of 2-hydrazinopyridine derivatives, and only a few studies are made on preparation methods of 3-chloro-2-hydrazinopyridine. For example, in chinese patent CN103588705A, 2-fluoro-3-chloropyridine and hydrazine hydrate are mixed, and reacted at room temperature with ethanol as a solvent. The method has the advantages that the preparation of the reaction raw material 2-fluoro-3-chloropyridine is difficult, no safety protection is realized when hydrazine hydrate is adopted, and the recovery of a solvent is not involved. The 3-chloro-2-hydrazinopyridine can also be prepared by reacting 2, 3-dichloropyridine with hydrazine hydrate, however, the reaction raw material 2, 3-dichloropyridine is generally prepared by carrying out Hofmann degradation reaction on nicotinamide and sodium hypochlorite to obtain 3-aminopyridine and then carrying out chlorination reaction, diazotization and Sandmeyer reaction, and the reaction process has more steps, so that the product yield is not high, a large amount of labor cost is consumed, and a large amount of waste liquid and waste solids can be generated by more extraction operations in the diazotization, chlorination and reaction processes, so that the environmental pollution is serious, the industrial production scale of the product is restricted, and the requirements of energy conservation, emission reduction and green production in China are not met.
Therefore, there is a need to develop a new synthesis process of 2-hydrazinopyridine derivatives that can be used in industrial production to simplify process conditions, reduce pollutant emissions, and increase product yield.
Disclosure of Invention
In order to solve the above problems, the present inventors have made intensive studies, and have completed the present invention by preparing pyridine halide a through a hydrogen substitution reaction of hydrogen and a precursor compound B, greatly reducing the generation of three wastes, making the selectivity and yield of hydrogen substitution extremely high by selecting a specific catalyst, reacting pyridine halide a with hydrazine hydrate under the condition that a tertiary amine is used as a solvent i, facilitating the reaction, and greatly improving the reaction rate and yield.
The invention aims to provide a synthesis process of a 2-hydrazinopyridine derivative, which comprises the following steps:
step 1, mixing pyridine halide A, hydrazine hydrate and solvent I for reaction;
step 2, after the reaction is finished, carrying out post-treatment to obtain a reaction product 2-hydrazinopyridine derivative P;
the structure of the pyridine halide A is as follows:
the structure of the 2-hydrazinopyridine derivative P is as follows:
wherein, X is a halogen atom, preferably selected from any one of F, Cl or Br;
r is selected from one or more of hydrogen atom, halogen, alkyl, alkoxy and ester group.
In a preferred embodiment, in step 1, the solvent I is selected from any one or more of alcohols, amides or alcohol amines, the alcohols are C1-C4 small molecule alcohols, such as methanol, ethanol or N-butanol, the amides are selected from any one or more of N, N-dimethylformamide, N-dimethylacetamide or N, N-dimethylpropanamide, the alcohol amines are selected from any one or more of 2-hydroxyethylamine, N-dimethylpropanolamine, N-diethylethanolamine, triethanolamine or monoisopropanolamine,
preferably, the solvent i is an alcohol amine, more preferably N, N-dimethylpropanolamine.
The reaction is carried out under an inert atmosphere, wherein the inert atmosphere is nitrogen or argon, and nitrogen is preferred; the reaction temperature is 100-150 ℃, preferably 125-130 ℃.
In another preferred embodiment, in step 1, when the R group is a substituent at the 3 and/or 4 position, the pyridine halide A may be commercially available or prepared by the following method:
adding a precursor compound B, a solvent II, alkali and a catalyst into a reaction vessel, introducing hydrogen to carry out hydrogen substitution reaction to obtain pyridine halide A,
the structure of the precursor compound B is:
wherein X is a halogen atom, preferably selected from F, Cl and Br;
y is a halogen atom, preferably selected from F, Cl and Br;
r is selected from hydrogen, halogen, alkyl, alkoxy or ester group.
Wherein the solvent II is selected from any one or more of alcohols, amides or alcohol amines, preferably alcohols, and more preferably methanol;
the alkali is selected from organic alkali and/or inorganic alkali, preferably pyridine and sodium hydroxide are compounded for use, more preferably, pyridine is added into a reaction container before reaction, and sodium hydroxide is slowly added in a dropwise manner in the reaction process after being dispersed by a solvent II;
the catalyst is selected from a supported catalyst and/or a skeleton type catalyst, preferably a supported catalyst, more preferably a catalyst taking activated carbon as a carrier, and most preferably a palladium/carbon and platinum/carbon mixed catalyst.
According to the synthesis process of the 2-hydrazinopyridine derivative provided by the invention, the following beneficial effects are achieved:
(1) in the synthesis process, N-dimethylpropanolamine is selected as a solvent I, so that the solubility requirement of reaction raw materials is met; meanwhile, as a tertiary amine compound, the tertiary amine compound can play a role of an acid binding agent to a certain extent, stabilize the pH value of a system and promote the reaction to proceed towards the direction of generating a product;
(2) the reaction conditions of the synthesis process of the 2-hydrazinopyridine derivative P are mild, and the low-temperature reflux reaction is carried out under the protection of inert gas, so that the reaction safety is improved;
(3) the pyridine halide A can be prepared by the hydrogen substitution reaction of a precursor compound B, and a Pd/C or Pt/C mixed catalyst is adopted in the preparation, so that the selectivity and the reaction rate of the hydrogen substitution reaction are greatly improved;
(4) in the hydrogen substitution reaction, alkali is selected from strong alkali and weak alkali for composite use, particularly pyridine and sodium hydroxide for composite use, the addition sequence is limited, and the pH of the reaction system is controlled to be between 6 and 9, so that the condition of over-acid and over-alkali is avoided, the pH value of the system is controlled more accurately and rapidly, and the selectivity and the efficiency of the hydrogen substitution reaction are further ensured;
(5) compared with the method which takes nicotinamide as a reaction raw material and is widely used at present, the hydrogen substitution reaction reduces the discharge amount of waste and improves the yield.
Drawings
FIG. 1 is a gas chromatogram of unpurified 2, 3-dichloropyridine prepared in example 1;
FIG. 2 is a liquid chromatogram of 3-chloro-2-hydrazinopyridine prepared in example 1;
FIG. 3 is a gas chromatogram of unpurified 2, 3-dichloropyridine prepared in example 2;
FIG. 4 is a liquid chromatogram of 3-chloro-2-hydrazinopyridine prepared in example 2;
FIG. 5 is a gas chromatogram of unpurified 2, 3-dichloropyridine prepared in comparative example 1;
FIG. 6 is a liquid chromatogram of 3-chloro-2-hydrazinopyridine prepared in comparative example 1;
FIG. 7 is a gas chromatogram of unpurified 2, 3-dichloropyridine prepared in comparative example 2;
FIG. 8 is a liquid chromatogram of 3-chloro-2 hydrazinopyridine prepared in comparative example 2.
Detailed Description
The features and advantages of the present invention will become more apparent and appreciated from the following detailed description of the invention.
The invention aims to provide a synthesis process of a 2-hydrazinopyridine derivative, which comprises the following steps:
step 1, mixing pyridine halide A, hydrazine hydrate and solvent I for reaction;
step 2, after the reaction is finished, carrying out post-treatment to obtain a reaction product 2-hydrazinopyridine derivative P;
the structure of the pyridine halide A is as follows:
the structure of the 2-hydrazinopyridine derivative P is as follows:
wherein, X is a halogen atom, preferably selected from any one of F, Cl or Br, preferably Cl;
and R is any one or more of 3, 4, 5 or 6-position substituent groups and is selected from hydrogen, halogen, alkyl, alkoxy and ester groups, namely the pyridine halide A is not limited to two-position substitution and can also be multi-position substitution. The halogen is selected from F, Cl and Br, and the alkyl is-CH3、-CH2CH3、-CH(CH3)2、-C(CH3)3Said alkoxy is-OCH3、-OCH2CH3、-OCH(CH3)2The ester group is such as-CH3COOCH3、-CH3COOCH2CH3and-CH2CH3COOCH3. The pyridine halide A may be 2, 3-dichloropyridine, 2-chloro-4-tert-butylpyridine, 2-chloro-5-methoxypyridine, 2-bromo-5-methoxypyridine, 5-bromo-2-chloro-4-methoxypyridine, and the like.
In the step 1, pyridine halide A, hydrazine hydrate and a solvent I are mixed in a reaction kettle, the reaction temperature is adjusted, and reflux reaction is carried out. The reaction formula is shown as the following formula 1:
in the invention, the mass fraction of hydrazine hydrate is 70-80%, and the hydrazine hydrate is not too low so as to avoid introducing too much water to influence the solubility of the pyridine halide A serving as a reaction raw material.
As can be seen from formula 1, the molar ratio of X groups to hydrazine hydrate in the reaction of pyridine halide A with hydrazine hydrate to form 2-hydrazinopyridine derivative P is theoretically 1:1, without the R groups participating in the reaction. In order to fully carry out the reaction, hydrazine hydrate is selected to be excessive, and the molar ratio of the pyridine halide A to the hydrazine hydrate is 1: 1.5-1: 1.8. The dosage ratio of the pyridine halide A to the hydrazine hydrate is strictly limited, and when the molar ratio is more than 1:1.8, more hydrazine hydrate exists in the system after the reaction is finished, so that resource waste is caused or the recovery difficulty of the hydrazine hydrate is higher; and in the case where the R group can participate in the reaction, such as an ester group, to reduce the probability of reaction of the R group with hydrazine hydrate, the molar ratio of the pyridine halide A to hydrazine hydrate should also be less than 1: 1.8. In special cases, multiple charges or adjustments of the molar ratio of pyridine halide A to hydrazine hydrate may be made to determine the reaction of the R group with hydrazine hydrate.
The solvent I is selected from any one or more of alcohols, amides or alcohol amines in consideration of the solubility of the reaction raw materials in the solvent I. The alcohol is C1-C4 small molecular alcohol, such as methanol, ethanol or N-butanol, the amide is selected from one or more of N, N-dimethylformamide, N-dimethylacetamide or N, N-dimethylpropionamide, and the alcohol amine is selected from one or more of 2-hydroxyethylamine, N-dimethylpropanolamine, N-diethylethanolamine, triethanolamine or monoisopropanolamine.
As can be seen from formula 1, the removal of the hydrogen halide from the system is more favorable for the reaction, since the pyridine halide A reacts with hydrazine hydrate to generate hydrogen halide. The solvent I is selected to be alcohol amine, preferably N, N-dimethyl propanol amine. The N, N-dimethyl propanolamine is not only miscible with water, but also can dissolve various organic matters, thereby meeting the basic solubility requirement; meanwhile, as a tertiary amine compound, the tertiary amine compound can play a role of an acid binding agent to a certain extent, so that the pH value of a system is stabilized, and the reaction is promoted to be carried out towards the direction of generating a product.
In order to further remove the chlorine halide, the reaction kettle in the step 1 is connected with a tail gas absorption device, and the absorption device adopts water to absorb the hydrogen halide to obtain a hydrochloric acid byproduct. Therefore, the whole reaction system almost has no waste gas emission, is green and environment-friendly, and the water for adsorbing the acid gas can be used for other purposes, thereby generating secondary benefit.
The weight ratio of hydrazine hydrate to the solvent I is 1: 25-1: 50, so that the requirement of reflux reaction is met, the concentration of reaction raw materials is not too low, and the reaction rate is not reduced.
The reflux temperature of hydrazine hydrate and the solvent I is 100-150 ℃, the substitution reaction can be rapidly carried out within the temperature range, the by-products in the prepared product are few, and the preferable reaction temperature is 125-130 ℃. Further, the reaction is carried out under an inert atmosphere, which is nitrogen or argon, preferably nitrogen, by replacing the air in the reaction vessel with an inert gas. The inert atmosphere avoids absorption of carbon dioxide in the air by hydrazine hydrate. If the filled inert gas is higher than the atmospheric pressure, the gasification of the hydrazine hydrate is reduced while the reaction rate is promoted, and the toxicity risk of hydrazine hydrate steam is reduced.
In the invention, the pyridine halide A can be obtained commercially or by self, and when the R group is a substituent at the 3-position and/or the 4-position, the pyridine halide A is prepared by the following method: adding a precursor compound B, a solvent II, alkali and a catalyst into a reaction vessel, introducing hydrogen to carry out hydrogen substitution reaction to obtain pyridine halide A,
the structure of the precursor compound B is:
wherein X is a halogen atom, preferably selected from F, Cl and Br;
y is a halogen atom, preferably selected from F, Cl and Br;
r is selected from hydrogen, halogen, alkyl, alkoxy or ester group.
This reaction is a hydrogen substitution reaction, and the reaction formula is shown in the following formula 2:
in the reaction, the catalyst is selected from a carrier catalyst and/or a skeleton type catalyst, the carrier catalyst is selected from any one or more of palladium or platinum catalysts taking active carbon, calcium carbonate, alumina or graphene as carriers, and the skeleton type catalyst is selected from any one or more of raney nickel, raney cobalt, raney ruthenium or raney copper.
As a modification of the above embodiment, the catalyst is selected from the group consisting of a supported catalyst, preferably a catalyst supported on activated carbon, more preferably a palladium/carbon (Pd/C) and platinum/carbon (Pt/C) mixed catalyst. Production practice shows that the mixed catalyst has higher catalytic efficiency and selectivity than Pd/C or Pt/C catalyst used independently.
As a further improvement of the above embodiment, the supported amount of Pt in the Pt/C catalyst is 7-8%, the supported amount of Pd in the Pd/C catalyst is 7-8%, and the weight ratio of the Pt/C catalyst to the Pd/C catalyst is 10: 1-1: 10.
In another improvement of the above embodiment, in order to ensure effective catalysis of the catalyst, the weight ratio of the catalyst to the precursor compound B is 1:15 to 1:30, preferably 1:20 to 1: 25.
In this reaction, an alkali is added to react with the hydrogen halide produced to avoid the pH value of the reaction systemA large variation. The acidity is so high that the metal in the Pd/C or Pt/C catalyst is easily removed, and the halide ions (especially Cl) are removed from the precursor compound B-) The catalyst is easy to be poisoned, and the catalytic efficiency is influenced; too much alkalinity, too much added alkaline compound and introduction of more impurities affect the purity of the product. The base is selected from organic base and/or inorganic base, the organic base is selected from any one or more of pyridine, triethylamine, sodium methoxide, potassium ethoxide or potassium tert-butoxide, and the inorganic base is selected from any one or more of alkali metal hydroxide and/or alkaline earth metal hydroxide, such as sodium hydroxide, potassium hydroxide or calcium hydroxide.
As a modification of the above embodiment, the alkali is selected from a combination of a strong alkali and a weak alkali, and preferably pyridine and sodium hydroxide are used in combination.
As a further improvement of the above embodiment, pyridine is added to the reaction vessel before the reaction together with the precursor compound B and the solvent, and sodium hydroxide is slowly added dropwise during the reaction after being dispersed with the solvent II.
Pyridine is weakly basic, which in this case corresponds to the pH buffer of the reaction system, providing the appropriate initial pH for the reaction. When methanol is used as a reaction solvent, pyridine has a higher solubility than triethylamine and is preferably used. With the reaction, hydrogen halide is continuously generated, the alkalinity of pyridine is limited, a strong alkaline sodium hydroxide solution is required to be dripped to rapidly react with acid, and the pH of a reaction system is controlled to be between 6 and 9. The method of using weak base and strong base in a combined way is adopted, the condition of over-base of peracid is avoided, the pH value of the system is controlled more accurately and rapidly, and the selectivity and the efficiency of the hydrogen substitution reaction are further ensured.
In a further improvement of the above embodiment, the weight ratio of the weak base to the precursor compound B is 1:8 to 1:14, preferably 1:10 to 1: 12.
The solvent II is selected from one or more of alcohols, amides or alcohol amines, wherein the alcohols are C1-C4 small molecular alcohols, such as methanol, ethanol or N-butyl alcohol, the amides are selected from one or more of N, N-dimethylformamide, N-dimethylacetamide or N, N-dimethylpropanamide, and the alcohol amines are selected from one or more of 2-hydroxyethylamine, N-dimethylpropanolamine, N-diethylethanolamine, triethanolamine or monoisopropanolamine.
As a modification of the above embodiment, the solvent ii is selected from alcohols, preferably methanol. Compared with amide or alcohol amine, C1-C4 small molecular alcohol, especially methanol has better solubility to pyridine halide A and pyridine as pH buffering agent, and methanol is cheap, thus reducing production cost.
Adding precursor compound B, solvent II, pH buffer (alkali) and catalyst into a reaction vessel, adjusting the temperature and introducing hydrogen to carry out hydrogen substitution reaction. The temperature of the hydrogen substitution reaction is 20-40 ℃, and the reaction can be completed at normal temperature; and after introducing hydrogen, maintaining the pressure in the reaction vessel at 0.2-0.4 MPa.
After the hydrogen substitution reaction is completed, the reaction solution is filtered, the obtained solid is washed with water, the mixed salt or alkali is removed, and the catalyst is recovered. And distilling the obtained filtrate at normal pressure to recover the reaction solvent, and adding water into the residual material after distillation to cool and crystallize to obtain a reaction product. And (2) separating and purifying the hydrogen substitution reaction product to obtain the pyridine halide A, then using the pyridine halide A for synthesizing the 2-hydrazinopyridine derivative P, or not separating and purifying the product, directly using the pyridine halide A containing a small amount of by-products for synthesizing the 2-hydrazinopyridine derivative P, and purifying the product after the reaction. The former increases the process steps but is beneficial to improving the purity of reactants in the subsequent reaction, while the latter is simple to operate, but increases the reaction amount of hydrazine hydrate in the reaction for generating the 2-hydrazinopyridine derivative P, and reduces the reaction rate and the purity of the product. The pyridine halide A is preferably separated and purified in advance before use, and the pyridine halide A is preferably used as it is, for example, selected according to the actual conditions such as the product requirements.
In the step (2), after the reaction is finished, post-treatment is carried out to obtain a reaction product 2-hydrazinopyridine derivative P. In the present invention, the post-treatment includes cooling crystallization, separation of the product, purification and drying.
The temperature of cooling crystallization is determined according to the specific 2-hydrazinopyridine derivative P, and the temperature of cooling crystallization is generally set to be 20-30 ℃. And (3) carrying out solid-liquid separation on the system after crystallization, wherein the separation mode is centrifugation or filtration, and centrifugation is preferred. The collected crystalline solid is purified by recrystallization or washing, preferably washing, with water as the washing solvent on the premise that the 2-hydrazinopyridine derivative P is water-insoluble.
And drying the centrifuged or purified crystalline solid in a normal pressure drying mode or a low pressure drying mode, preferably in a low pressure drying mode, wherein the drying temperature is 55-65 ℃. In industrial production, the product can be sent to a double-cone dryer for drying, so that the product is dried uniformly and fully.
If the obtained 2-hydrazinopyridine derivative is liquid at normal temperature, the 2-hydrazinopyridine derivative P can be separated from a reaction system by an extraction mode, and then the extract liquor is distilled to obtain the product 2-hydrazinopyridine derivative P.
In the step 2, the method also comprises the recovery of the solvent, and the recovery process comprises the following steps: adjusting the solvent after the product separation to be neutral, and distilling under an inert atmosphere, wherein the inert atmosphere is nitrogen or argon, and preferably nitrogen.
The solvent may be acidic due to the presence of hydrogen chloride after the reaction, and if the solvent is tertiary amine, the solvent may be combined with hydrogen chloride, so that a proper amount of alkali can be added to adjust the solvent to be neutral before distillation, and the solvent reacts with the hydrogen chloride combined with the tertiary amine solvent, thereby avoiding the problem that hydrogen chloride gas is evaporated out along with distillation or the tertiary amine solvent combined with hydrogen chloride cannot be distilled and recycled.
As a modification of the above embodiment, the distillation is carried out under an inert atmosphere, which is nitrogen or argon, preferably a nitrogen atmosphere. Because the solvent contains a plurality of components, different solvent components can be respectively recovered at different temperatures.
Taking N, N-dimethylpropanolamine as a solvent I as an example, the rectification process of the solvent after the reaction comprises the following steps: adding a proper amount of caustic soda flakes (sodium hydroxide) into a distillation still filled with a solvent after reaction under stirring, controlling the temperature below 50 ℃ until the caustic soda flakes are completely dissolved in the distillation still, adjusting the pH of a feed liquid to be neutral, introducing nitrogen into the distillation still to replace air for three times, and distilling out the N, N-dimethylpropanolamine at the normal pressure and 120 ℃ to be rectified.
Transferring the N, N-dimethylpropanolamine to be rectified into a rectifying still, and evaporating water under the conditions of-0.09 MPa and the temperature of less than or equal to 101 ℃; and (4) after the water evaporation is finished, recycling the residual main fraction in the rectifying still, namely N, N-dimethyl propanolamine (residual hydrazine hydrate) for production and reuse.
Examples
The invention is further described by the following specific examples, taking the synthesis process of 3-chloro-2 hydrazinopyridine as an example. However, these examples are only illustrative and do not set any limit to the scope of the present invention.
Example 1
Synthesis of (I) 2, 3-dichloropyridine (2, 3, 6-trichloropyridine is used as raw material)
Adding 500g of 2.3.6-trichloropyridine, 1800g of methanol, 20g of mixed catalyst (8% Pt/C: 8% Pd/C ═ 1:10) and 45g of pyridine into a reaction kettle, introducing hydrogen, slowly dropwise adding 5% by weight of sodium hydroxide methanol solution at the same time, maintaining the pressure in the reaction kettle at 0.3Mpa and the temperature at 30 ℃, replacing the hydrogen after hydrogenation is finished, filtering out the Pt/C and Pd/C catalyst, recycling the methanol by normal pressure distillation of the obtained filtrate, adding water into the residual material, cooling, crystallizing, centrifuging and purifying to obtain the 2, 3-dichloropyridine.
The gas chromatogram of the 2, 3-dichloropyridine obtained in step (I) without purification after crystallization with the purity of 97.6% and the yield of 88.5% is shown in FIG. 1.
Synthesis of (di) 3-chloro-2 hydrazinopyridine
148g of 2, 3-dichloropyridine and 3700g N, N-dimethylpropanolamine are uniformly mixed in a reaction kettle, 105g of 80% hydrazine hydrate is added, the air in the kettle is replaced by nitrogen for three times, then the temperature is raised to 130 ℃, the reflux reaction is carried out under the condition of heat preservation for 10 hours, the reaction is finished, the reaction is cooled to 25 ℃ for crystallization, then the materials are transferred to a centrifuge for centrifugation, the centrifuged solid is washed by water, the centrifuged mother liquor is put into an N, N-dimethylpropanolamine mother liquor tank for rectification, and the centrifuged solid is sent to a bipyramid dryer (-0.09MPa, 60 ℃) for drying to obtain the product of the 3-chloro-2-hydrazinopyridine.
In the step (II), the purity of the 3-chloro-2-hydrazinopyridine is 99.7 percent, the yield is 95 percent, and a liquid chromatogram is shown in figure 2.
Example 2
Synthesis of (mono) 2, 3-dichloropyridine
Adding 2.3.6-trichloropyridine 450g, ethanol 1600g, mixed catalyst 20g (8% Pt/C: 8% Pd/C is 10:1) and triethylamine 45g into a reaction kettle, introducing hydrogen, slowly dropwise adding 5% by weight of sodium hydroxide ethanol solution while maintaining the pressure in the reaction kettle at 0.25Mpa and the temperature at 25-30 ℃, replacing the hydrogen after hydrogenation is completed, filtering out the Pt/C and Pd/C catalysts for use, recovering methanol from the filtrate by normal pressure distillation, adding water into the residual material, cooling for crystallization, centrifuging and purifying to obtain 2, 3-dichloropyridine.
In the step (I), the purity of the 2, 3-dichloropyridine is 96.8 percent, the yield is 85 percent, and a gas chromatogram when the 2, 3-dichloropyridine is not purified after crystallization is shown in figure 3.
Synthesis of (di) 3-chloro-2 hydrazinopyridine
148g of 2, 3-dichloropyridine and 4500g N, N-dimethylformamide are uniformly mixed in a reaction kettle, 110g of 80% hydrazine hydrate is added, air in the kettle is replaced by nitrogen for three times, then the temperature is raised to 130 ℃, the reflux reaction is carried out for 10 hours under the condition of heat preservation, the reaction is finished, the temperature is cooled to 25 ℃ for crystallization, then the materials are transferred to a centrifuge for centrifugation, the centrifuged solid is washed by water, the centrifuged mother liquor is put into an N, N-dimethylformamide mother liquor tank for rectification, and the centrifuged solid is sent to a bipyramid dryer (-0.09MPa, 60 ℃) for drying to obtain the product of 3-chloro-2-hydrazino pyridine.
In the step (II), the purity of the 3-chloro-2-hydrazinopyridine is 99.2 percent, the yield is 90 percent, and a liquid chromatogram is shown in figure 4.
Comparative example 1
Synthesis of (mono) 2, 3-dichloropyridine
Adding 2.3.6-trichloropyridine 500g, methanol 1800g, a single catalyst 20g (8% Pt/C) and pyridine 45g into a reaction kettle, introducing hydrogen, slowly dropwise adding 5 wt% of sodium hydroxide methanol solution at the same time, maintaining the pressure in the reaction kettle at 0.3Mpa and the temperature at 25-30 ℃, replacing the hydrogen after hydrogenation is completed, filtering out the Pt/C catalyst for use, recovering the methanol by normal pressure distillation of filtrate, adding water into the residual material, cooling for crystallization, centrifuging and purifying to obtain the 2, 3-dichloropyridine.
In the step (I), the purity of the 2, 3-dichloropyridine is 89.2%, the yield is 65%, and a gas chromatogram when the 2, 3-dichloropyridine is not purified after crystallization is shown in FIG. 5.
Synthesis of (di) 3-chloro-2 hydrazinopyridine
148g of 2, 3-dichloropyridine and 3700g of n-butanol are uniformly mixed in a reaction kettle, 105g of 70% hydrazine hydrate is added, air in the kettle is replaced by nitrogen for three times, then the temperature is raised to 100 ℃, the heat preservation reflux reaction is carried out for 10 hours, the reaction is finished, the temperature is cooled to 25 ℃, the crystallization is carried out, then the material is transferred to a centrifuge for centrifugation, the centrifugal solid is washed by water, the centrifugal mother liquor is put into a mother liquor tank for rectification, the centrifuged solid is sent to a double-cone dryer (-0.09MPa, 60 ℃) for drying, and the product of 3-chloro-2-hydrazinopyridine is obtained.
In the step (II), the purity of the 3-chloro-2-hydrazinopyridine is 96.0 percent, the yield is 80 percent, and a liquid chromatogram is shown in figure 6.
Comparative example 2
Synthesis of (mono) 2, 3-dichloropyridine
The same as the process conditions in example 1, except that the catalyst conditions were changed from mixed catalyst (8% Pt/C: 8% Pd/C ═ 1:10) to single catalyst (8% Pd/C).
In the step (I), the purity of the 2, 3-dichloropyridine is 85.4%, the yield is 68%, and a gas chromatogram when the 2, 3-dichloropyridine is not purified after crystallization is shown in FIG. 7.
Synthesis of (di) 3-chloro-2 hydrazinopyridine
The same process conditions as in example 1 were followed except that the solvent I was changed from N, N-dimethylpropanolamine to dioxane and the reflux temperature was changed from 130 ℃ to 100 ℃.
In the step (II), the purity of the 3-chloro-2-hydrazinopyridine is 93.7 percent, the yield is 79 percent, and a liquid chromatogram is shown in figure 8. The results of the products of examples 1-2 and comparative examples 1-2 are shown in Table 1.
TABLE 1
As can be seen from the examples 1-2 in Table 1, when synthesizing 2, 3-dichloropyridine, strong base and weak base are used in a composite manner and a mixed catalyst is used for catalytic reaction, the purity of the 2, 3-dichloropyridine is more than or equal to 95 percent, and the yield is more than or equal to 85 percent; the 3-chloro-2 hydrazinopyridine is synthesized by selecting a proper solvent, the purity of the 3-chloro-2 hydrazinopyridine is more than or equal to 99 percent, and the yield is more than or equal to 90 percent.
As can be seen from comparative examples 1-2 in Table 1, a single catalyst is used in the synthesis of 2, 3-dichloropyridine, and a non-tertiary amine solvent is used for the synthesis of 3-chloro-2-hydrazinopyridine, the purity of 2, 3-dichloropyridine is less than or equal to 90%, the yield is less than or equal to 70%, the purity of 3-chloro-2-hydrazinopyridine is less than or equal to 97%, the yield is less than or equal to 80%, and the economic benefit of the product is far lower than that of the product prepared by the preferred embodiment.
The invention has been described in detail with reference to specific embodiments and illustrative examples, but the description is not intended to be construed in a limiting sense. Those skilled in the art will appreciate that various equivalent substitutions, modifications or improvements may be made to the technical solution of the present invention and its embodiments without departing from the spirit and scope of the present invention, which fall within the scope of the present invention. The scope of the invention is defined by the appended claims.
Claims (1)
1. A synthesis process of 3-chloro-2-hydrazinopyridine comprises the following steps:
synthesis of (mono) 2, 3-dichloropyridine
Adding 2.3.6-trichloropyridine 500g, methanol 1800g and mixed catalyst 20g, Pt/C8% and Pd/C8% 1:10 8 and pyridine 45g into a reaction kettle, introducing hydrogen gas while slowly dropwise adding 5 wt% sodium hydroxide methanol solution, maintaining the pressure in the reaction kettle at 0.3Mpa and the temperature at 30 ℃, replacing hydrogen gas after hydrogenation, filtering out Pt/C and Pd/C catalyst, recycling methanol by normal pressure distillation, adding water into the rest materials, cooling, crystallizing, centrifuging, purifying to obtain 2, 3-dichloropyridine,
in the step (I), the purity of the 2, 3-dichloropyridine is 97.6 percent, the yield is 88.5 percent, and the synthesis of the (di) 3-chloro-2 hydrazinopyridine
Uniformly mixing 148g of 2, 3-dichloropyridine and 3700g N, N-dimethylpropanolamine in a reaction kettle, adding 105g of 80% hydrazine hydrate, replacing air in the kettle with nitrogen for three times, heating to 130 ℃, preserving heat, refluxing for 10 hours, cooling to 25 ℃ for crystallization after the reaction is finished, transferring the materials to a centrifuge for centrifugation, washing the centrifuged solid with water, putting the centrifuged mother liquor into a N, N-dimethylpropanolamine mother liquor tank for rectification, sending the centrifuged solid to a double-cone dryer at-0.09 MPa and 60 ℃ for drying to obtain the product of 3-chloro-2-hydrazinopyridine,
in the step (II), the purity of the 3-chloro-2-hydrazinopyridine is 99.7 percent, and the yield is 95 percent.
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| 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 |
| 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 |
| 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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