CN108003154B - Method for synthesizing paliperidone intermediate by using microchannel reactor - Google Patents
Method for synthesizing paliperidone intermediate by using microchannel reactor Download PDFInfo
- Publication number
- CN108003154B CN108003154B CN201711324153.1A CN201711324153A CN108003154B CN 108003154 B CN108003154 B CN 108003154B CN 201711324153 A CN201711324153 A CN 201711324153A CN 108003154 B CN108003154 B CN 108003154B
- Authority
- CN
- China
- Prior art keywords
- reaction
- module
- microchannel reactor
- pyrido
- preheating
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Catalysts (AREA)
Abstract
The invention discloses a method for synthesizing a paliperidone intermediate by using a microchannel reactor, belonging to the technical field of synthesis of psychotropic drugs in organic synthesis. Adding a paliperidone hydrogenation reaction precursor 3- (2-chloroethyl) -2-methyl-9-hydroxy-4H-pyrido [1,2-A ] pyrimidine-4-ketone into an organic solvent, adding a noble metal-supported active carbon catalyst to serve as a material I, and conveying the material I into a preheating module of a microchannel reactor for preheating; respectively conveying the preheated material I and hydrogen to a reaction module group of a microchannel reactor for reaction, collecting reaction liquid flowing out from an outlet of the microchannel reactor, and carrying out post-treatment to obtain a paliperidone intermediate. The synthesis method can effectively shorten the reaction time, greatly reduce the potential safety hazard of hydrogen leakage combustion explosion, and is suitable for synthesizing the paliperidone intermediate.
Description
Technical Field
The invention relates to a method for synthesizing a paliperidone intermediate by using a microchannel reactor, belonging to the technical field of synthesis of psychotropic drugs in organic synthesis.
Background
The paliperidone has the Chinese name of 3- [2- [4- (6-fluoro-1, 2-benzisoxazol-3-yl) -1-piperidyl]-ethyl radical]-6,7,8, 9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido [1,2-a]Pyrimidin-4-one of formula: c23H27FN4O3The chemical structural formula is as follows
The drug is approved by the U.S. FDA for acute or maintenance treatment of schizophrenia in 2006, 12 and 19, and researches show that paliperidone can delay the recurrence rate of schizophrenia, is used for acute short-term and long-term maintenance treatment of schizophrenia, relieves diseases, and can effectively stabilize the illness state of patients after long-term use.
The compound 3- (2-chloroethyl) -6,7,8, 9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido [1,2-a ] pyrimidine-4-ketone is a key intermediate for synthesizing paliperidone, and the chemical structural formula is as follows:
the current main synthesis methods of the intermediate mainly comprise two methods:
the method comprises the following steps:
the method takes 2-amino-3-hydroxypyridine as a starting material, and the starting material is cyclized with alpha-acetyl-gamma-butyrolactone after the benzylation protection of hydroxyl to obtain 3- (2-hydroxyethyl) -2-methyl-9-benzyloxy-4H-pyridine [1,2-a ] pyrimidine-4-ketone, and the target product is obtained after chlorination and catalytic hydrogenation reaction.
The second method comprises the following steps:
the method also takes 2-amino-3-hydroxypyridine as a starting material, and directly carries out hydrogenation and chlorination reactions under the unprotected condition to obtain the target product.
The two synthetic routes set forth above are generally similar, and although route two is short and simple, the current route is the primary method for synthesizing paliperidone due to the difficulty in controlling the selectivity of the hydroxychlorination during the final chlorination. The synthesis of target products uses high-temperature high-pressure catalytic hydrogenation in industrial production, the method uses cheap hydrogen as a reducing agent, heavy metals Pd, Pt, Rh and the like as catalysts of reaction, the catalytic hydrogenation reaction belongs to a typical gas-liquid-solid three-phase reaction, the low efficiency of mixing and exchanging among three phases determines that the reaction must be carried out under high temperature and high pressure to ensure the full conversion of raw materials, and the flammable and explosive properties of the hydrogen enable the reaction to have great production safety accidents if the reaction is dangerous, so a conventional stirring high-pressure reaction kettle is often defined as a 'high-risk' chemical reaction when carrying out hydrogenation operation, the operation requirement is extremely high, and the safe examination and approval of equipment are very difficult. In order to overcome the difficulties, the invention utilizes an innovative microchannel or microreactor technology to complete the catalytic hydrogenation reaction of the paliperidone intermediate, and the synthesis method is not reported in documents so far.
Disclosure of Invention
In order to solve the problems of low yield, poor purity, easy generation of danger caused by violent explosion, degradation caused by long reaction time at high temperature, low recycling frequency of a catalyst and the like in the traditional synthesis reaction, the invention provides a catalytic hydrogenation synthesis technology of 3- (2-chloroethyl) -6,7,8, 9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido [1,2-a ] pyrimidine-4-ketone, which is intrinsically safe, green and environment-friendly, and particularly provides a method for synthesizing a paliperidone intermediate by using a microchannel reactor. In order to achieve the above object, the applicant provides the following technical solutions:
the invention aims to provide a method for synthesizing a paliperidone intermediate by using a microchannel reactor, wherein the microchannel reactor comprises a preheating module, a reaction module group and a cooling module, and the method comprises the following steps: the preheating module is connected with the reaction module group in series, the reaction module group is connected with the cooling module in series, and the reaction module group comprises 1 unit reaction module or is formed by connecting more than two unit reaction modules in series; the method for synthesizing the paliperidone intermediate comprises the following steps:
1) adding a paliperidone hydrogenation reaction precursor 3- (2-chloroethyl) -2-methyl-9-hydroxy-4H-pyrido [1,2-A ] pyrimidine-4-ketone into an organic solvent, adding concentrated hydrochloric acid, adding a noble metal-loaded active carbon catalyst, taking the mixture as a material I, and conveying the material I into a preheating module of a microchannel reactor for preheating;
2) conveying the material I preheated in the step 1) to a preheating module of a reactor through a slurry pump, allowing hydrogen to pass through a reaction module group, reacting with the preheated material I in the reaction module group of the microchannel reactor, collecting reaction liquid flowing out of a cooling module, and performing aftertreatment to obtain a paliperidone intermediate, namely 3- (2-chloroethyl) -6,7,8, 9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido [1,2-a ] pyrimidin-4-one.
Preferably, the organic solvent in step 1) is any one or more of methanol, ethanol and isopropanol.
Preferably, the activated carbon supported noble metal catalyst in the step 1) is a composition of one or more of Pd/C, Pt/C, Rh/C; wherein the mass ratio of the noble metal accounts for 1 to 10 percent of the total mass of the catalyst.
Preferably, the concentration of the 3- (2-chloroethyl) -2-methyl-9-hydroxy-4H-pyrido [1,2-A ] pyrimidine-4-ketone in the step 1) in the organic solvent is 0.1 mol/L-0.4 mol/L.
Preferably, the mass ratio of the 3- (2-chloroethyl) -2-methyl-9-hydroxy-4H-pyrido [1,2-A ] pyrimidine-4-ketone in the step 1) to the catalyst with noble metal supported on active carbon is 1 (0.01-0.1).
Preferably, the molar ratio of the 3- (2-chloroethyl) -2-methyl-9-hydroxy-4H-pyrido [1,2-A ] pyrimidine-4-ketone and hydrogen in the step 1) is 1 (3.0-4.0).
Preferably, the pressure of the reaction in the step 2) is 0.5MPa to 1.5 MPa.
Preferably, the total residence time of the material I and the hydrogen in the reaction module group in the step 2) is 10 s-40 s. The total residence time of the material I and the hydrogen in the reaction module group refers to the sum of the residence time of the material I and the hydrogen in all the unit reaction modules, namely the reaction time.
Preferably, the temperature of the reaction of step 2) is from 40 ℃ to 90 ℃, more preferably 60 ℃.
Preferably, the temperature of the cooling module in the step 2) is 20-30 ℃.
Preferably, the mass ratio of the concentrated hydrochloric acid in the step 1) to the 3- (2-chloroethyl) -2-methyl-9-hydroxy-4H-pyrido [1,2-A ] pyrimidine-4-ketone is 1 (1.0-1.5).
The microchannel reactor of the invention is also called a microreactor. The microchannel reactor used by the invention comprises a preheating module, a reaction module group and a cooling module, wherein the preheating module is connected with the reaction module group in series, the reaction module group is connected with the cooling module in series, and unit reaction modules of the reaction module group are randomly connected in series or in parallel according to the feeding speed, the reactant concentration, the reaction time and the like (for example, the reaction module group is formed by randomly connecting 1-8 unit modules in series according to the feeding speed, the reactant concentration, the reaction time and the like); as shown in fig. 1-2, a material I is preheated in a preheating module 1, then enters a first group of unit reaction modules of a reaction module group 2, hydrogen directly enters the first group of unit reaction modules of the reaction module group 2 without preheating, is mixed and reacts in the first group of unit reaction modules, and with continuous entry of hydrogen and the material I, the hydrogen and the material I flow from the first group of unit reaction modules to a last group of unit reaction modules, and reacts in the flowing process, and finally flows out from a cooling module, the effluent reaction solution is a solution containing a paliperidone intermediate, and after purification, a paliperidone intermediate, that is, 3- (2-chloroethyl) -6,7,8, 9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido [1,2-a ] pyrimidin-4-one. The cooling module is used for cooling the high-temperature feed liquid to room temperature through the module so as to be convenient to process.
The preheating module in the microchannel reactor of the present invention may adopt a straight structure or a two-in one-out heart-shaped structure module, as shown in fig. 1, the first group of unit reaction modules in the reaction module may adopt a microchannel unit reaction module having two inlets and one outlet (referred to as a two-in one-out structure module for short), wherein the two inlets are respectively used for the inlet of hydrogen and the inlet of the material I, and the second group of unit modules to the last group of unit modules may adopt a microchannel unit reaction module having one inlet and one outlet (referred to as a single-in one-out structure module for short), wherein: the two-in one-out structure module is mainly used for mixing reaction, and the single-in one-out structure module is used for prolonging the reaction residence time and cooling the high-temperature reaction liquid to room temperature. The connection sequence of the preheating module and the reaction module (two-in one-out structure module + single-in one-out structure module) is as follows: the system comprises a preheating module, a two-in one-out structure module and a single-in single-out structure module. The microchannel reactor also comprises a slurry pump and a gas flowmeter, wherein the slurry pump is used for conveying a material I into the preheating module 1, and hydrogen enters the first group of unit reaction modules of the reaction modules through the gas flowmeter A.
In the invention, the material I and the hydrogen are controlled by a slurry pump and a gas flowmeter. When the reaction is carried out in the microchannel reactor, the preheating module is a straight structure or a two-in one-out heart-shaped structure module; the reaction module is a two-in one-out or single-in single-out heart-shaped structure module, and is connected with a preheating module, a reaction module with a two-in one-out structure and a reaction module with a single-in single-out structure in sequence, the reaction modules with the two-in one-out structure are used for mixed reaction after preheating, and the reaction modules with the single-in single-out structure are used for prolonging the reaction residence time. The used microchannel reactor comprises a preheating module group, a reaction module group and a cooling module, wherein the preheating module is connected with the reaction module group in series, the reaction module group is connected with the cooling module in series, the preheating module group comprises one preheating module or more than two preheating modules connected in parallel, the reaction module group comprises one reaction module or more than two reaction modules connected in series, and the cooling module is a single module with single inlet and single outlet; the material 1 enters a preheating module 1 through a slurry pump, and the preheating module 1 is connected with a reaction module 2 in series; the material 2 enters the reaction module 2 through a gas flowmeter a.
The reaction module can be made of more than one of special glass, silicon carbide ceramic, stainless steel metal coated with a corrosion-resistant layer or polytetrafluoroethylene, and can bear the maximum safe pressure of 1.5-1.8 MPa.
The invention has the beneficial effects that:
the mass transfer efficiency of gas-liquid-solid three phases in the reaction process of the microchannel reactor catalytic hydrogenation is more than 100 times of that of the traditional stirring hydrogenation reaction kettle, the whole process from mixing to reaction can be completed in a very short time, the intrinsic reaction speed is greatly improved, the reaction time can be shortened from more than 10 hours to about 30 seconds, and the shortening of the reaction time has the advantages that the content of high-temperature decomposition and dechlorination impurities can be greatly reduced, and the potential safety hazard of hydrogen leakage, combustion and explosion is reduced due to low liquid holdup.
The industrial production of the pharmaceutical and chemical intermediates is a process from pilot plant research to enlarged production, and the increase of the volume of equipment can bring great influence on temperature conduction, stirring efficiency and the like. The stirring has relatively small influence on the homogeneous reaction process, heterogeneous reactions such as catalytic hydrogenation have great influence, and the stirring speed of large-scale production equipment is limited to a certain extent, so that a high-pressure hydrogenation reaction kettle usually needs extremely high reaction temperature and pressure to ensure the complete conversion of reaction raw materials, which possibly causes side reactions such as degradation, dechlorination and the like caused by high reaction temperature, and the recycling and applying efficiency of the catalyst is greatly reduced due to long-time excessive friction and the like. If hydrogen leaks in the reaction process, serious safety accidents are likely to happen due to the explosive property of the hydrogen.
The invention also produces other beneficial technical effects:
1) the traditional high-pressure reaction kettle has the advantages that the reaction is required to be carried out at high temperature and high pressure due to poor gas-liquid-solid three-phase mixing exchange effect in the stirring process, and a large amount of degradation and dechlorination byproducts are generated in the reaction process due to overlong reaction time and overhigh reaction temperature, so that the yield of the step is generally not more than 80%, the purity is hardly more than 97%, the reaction time of about 10 hours can be shortened to less than 1 minute by the microchannel reactor, the reaction time is shortened, the content of the high-temperature degradation and dechlorination byproducts is greatly reduced, the yield can be increased to more than 90%, the purity is more than 99%, and the properties and the appearance of the product are greatly improved.
2) The liquid holding volume is small, the potential safety hazard possibly generated by large-scale hydrogen leakage is avoided, and meanwhile, the unique cooling module design ensures that even if the reaction is carried out at high temperature, the stable control of the feed liquid can be ensured at about room temperature through online cooling, so that the green and intrinsically safe production is realized.
3) The reaction time is short, the surface structure of the catalyst cannot be greatly changed due to long-time stirring and high temperature, the activity of the catalyst can be retained to the maximum extent, the cyclic application result of the catalyst is considered by taking Pd/C and Pt/C as examples in the proposal, and the experimental data shows that the catalyst still has high activity after 8 cycles.
4) The method has no amplification effect, can be directly used for amplification production after the data optimization in the laboratory stage is completed, shortens the process development period from the pilot test to the production, and greatly reduces the research and development cost.
5) The continuous production device has the advantages that the operability is strong, continuous uninterrupted production can be realized within 24 hours a day or within 360 days a year by matching with electronic terminal equipment, the use efficiency of the equipment is improved, the continuous production is easy, the automatic control is easy to realize, the operation labor can be reduced by 50 to 70 percent, the production cost is reduced, and the production economy is guaranteed.
Drawings
Fig. 1 is a schematic diagram of the shape structure of a module material flow pipeline of an organic glass material microchannel reactor, wherein (a) is a heart-shaped single-in single-out module, (b) is a heart-shaped two-in single-out module, and (c) is a straight module.
FIG. 2 is a schematic diagram showing the connection relationship between the catalytic hydrogenation reaction process and the microchannel reactor, in which A is a gas flowmeter, B is a slurry pump, 1 is a straight preheating module, 2 is a heart-shaped two-in one-out reaction module for mixing reaction after preheating, and 3-6 are respectively a heart-shaped single-in single-out reaction module.
Detailed Description
The present invention will be further illustrated with reference to the following specific examples; it should be understood that the following examples are illustrative of the present invention only and are not intended to limit the scope of the present invention; further, it is to be understood that various modifications or changes may be made by those skilled in the art after reading the description of the present invention, but those equivalents are also within the scope of the invention defined by the appended claims.
Example 1
The present embodiment provides a method for synthesizing a paliperidone intermediate using a microchannel reactor, as shown in fig. 1 and fig. 2, the microchannel reactor includes a preheating module, a reaction module group, and a cooling module, wherein: the preheating module is connected with the reaction module group in series, the reaction module group is connected with the cooling module in series, and the reaction module group comprises 1 unit reaction module or is formed by connecting more than two unit reaction modules in series; the method for synthesizing the paliperidone intermediate comprises the following steps:
1) weighing 200g of paliperidone hydrogenation precursor 3- (2-chloroethyl) -2-methyl-9-hydroxy-4H-pyrido [1,2-A ] pyrimidine-4-ketone, adding 4L of absolute ethyl alcohol and 200g of concentrated hydrochloric acid, stirring uniformly, adding 5g of 10% Pd/C, and fully stirring and mixing to form a material I;
2) respectively conveying the material I preheated in the step 1) and hydrogen to a reaction module group of a microchannel reactor for reaction, wherein: adjusting the flow rate of the slurry pump to make the flow rate of the material I be 40.0g/min, and adjusting the flow rate of the material H2The flow rate of the gas flow meter is 700ml/min, the reaction temperature is 80 ℃, the temperature of the cooling module is 25 ℃, the reaction pressure is 1.5Mpa, and the reaction pressure is 3- (2-chloroethyl) -2-methyl-9-hydroxy-4H-pyrido [1,2-A ]]Pyrimidin-4-ones and H2The molar ratio of (1: 3.2) and the total residence time of the reaction in the reaction module group is 20 s; collecting reaction solution flowing out of cooling module, filtering to recover catalyst, distilling under reduced pressure to remove solvent, adding 500ml of water into residue to dissolve completely, and adding saturated NaHCO3Under the condition of a solution, adding 1.2L of ethyl acetate into a crude product, heating to 60 ℃ for dissolution, slowly dropwise adding 1.2L of n-hexane, cooling to 0-10 ℃, keeping the temperature and stirring for 1H, filtering, washing a filter cake with a small amount of n-hexane, and performing vacuum drying at 50 ℃ for 8H to obtain a paliperidone intermediate 3- (2-chloroethyl) -6,7,8, 9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido [1,2-a ]]128.91g of pyrimidin-4-one, 87.32% yield and 99.28% purity.
Example 2
The present embodiment provides a method for synthesizing a paliperidone intermediate using a microchannel reactor, as shown in fig. 1 and fig. 2, the microchannel reactor includes a preheating module, a reaction module group, and a cooling module, wherein: the preheating module is connected with the reaction module group in series, the reaction module group is connected with the cooling module in series, and the reaction module group comprises 1 unit reaction module or is formed by connecting more than two unit reaction modules in series; the method for synthesizing the paliperidone intermediate comprises the following steps:
1) weighing 200g of paliperidone hydrogenation precursor 3- (2-chloroethyl) -2-methyl-9-hydroxy-4H-pyrido [1,2-A ] pyrimidine-4-ketone, adding 4L of anhydrous methanol and 150g of concentrated hydrochloric acid, stirring uniformly, adding 5g of 5% Pt/C, and fully stirring and mixing to form a material I;
2) respectively conveying the material I preheated in the step 1) and hydrogen to a reaction module group of a microchannel reactor for reaction, wherein: the flow rate of the stock pump is adjusted so that the flow rate of the stock I is 35.0 g-min, adjusting H2The flow rate of the gas flow meter is 600ml/min, the reaction temperature is 60 ℃, the temperature of the cooling module is 20 ℃, the reaction pressure is 1.0Mpa, and the reaction pressure is 3- (2-chloroethyl) -2-methyl-9-hydroxy-4H-pyrido [1,2-A ]]Pyrimidin-4-ones and H2The molar ratio of (1: 3.0) and the total residence time of the reaction in the reaction module group is 22 s; collecting reaction solution flowing out of cooling module, filtering to recover catalyst, distilling under reduced pressure to remove solvent, adding 500ml of water into residue to dissolve completely, and adding saturated NaHCO3Under the condition of a solution, adding 1.2L of ethyl acetate into a crude product, heating to 60 ℃ for dissolution, slowly dropwise adding 1.2L of n-hexane, cooling to 0-10 ℃, keeping the temperature and stirring for 1H, filtering, washing a filter cake with a small amount of n-hexane, and performing vacuum drying at 50 ℃ for 8H to obtain a paliperidone intermediate 3- (2-chloroethyl) -6,7,8, 9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido [1,2-a ]]133.05g of pyrimidin-4-one, yield 90.12% and purity 99.31%.
Example 3
The present embodiment provides a method for synthesizing a paliperidone intermediate using a microchannel reactor, as shown in fig. 1 and fig. 2, the microchannel reactor includes a preheating module, a reaction module group, and a cooling module, wherein: the preheating module is connected with the reaction module group in series, the reaction module group is connected with the cooling module in series, and the reaction module group comprises 1 unit reaction module or is formed by connecting more than two unit reaction modules in series; the method for synthesizing the paliperidone intermediate comprises the following steps:
1) weighing 300g of paliperidone hydrogenation precursor 3- (2-chloroethyl) -2-methyl-9-hydroxy-4H-pyrido [1,2-A ] pyrimidine-4-ketone, adding 6L of absolute ethyl alcohol and 200g of concentrated hydrochloric acid, stirring uniformly, adding 5g of 10% Rh/C, and fully stirring and mixing to form a material I;
2) respectively conveying the material I preheated in the step 1) and hydrogen to a reaction module group of a microchannel reactor for reaction, wherein: adjusting the flow rate of the slurry pump to make the flow rate of the material I be 32.0g/min, and adjusting H2The flow rate of the gas flow meter is 650ml/min, the reaction temperature is 50 ℃, the temperature of the cooling module is 30 ℃, the reaction pressure is 1.5Mpa, and the reaction pressure is 3- (2-chloroethyl) -2-methyl-9-hydroxy-4H-pyrido [ alpha ], [ beta ]1,2-A]Pyrimidin-4-ones and H2Is 1:3.4, and the total residence time of the reaction in the reaction module group is 25 s; collecting reaction solution flowing out of the temperature reduction module, filtering to recover catalyst, distilling under reduced pressure to remove solvent, adding 750ml of water into residue to dissolve completely, and adding saturated NaHCO3Under the condition of a solution, adding 1.8L of ethyl acetate into a crude product, heating to 60 ℃ for dissolution, slowly dropwise adding 1.8L of n-hexane, cooling to 0-10 ℃, keeping the temperature and stirring for 1H, filtering, washing a filter cake with a small amount of n-hexane, and performing vacuum drying at 50 ℃ for 8H to obtain a paliperidone intermediate 3- (2-chloroethyl) -6,7,8, 9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido [1,2-a ]]192.71g of pyrimidin-4-one, 87.02% yield and 98.69% purity.
Example 4
The present embodiment provides a method for synthesizing a paliperidone intermediate using a microchannel reactor, as shown in fig. 1 and fig. 2, the microchannel reactor includes a preheating module, a reaction module group, and a cooling module, wherein: the preheating module is connected with the reaction module group in series, the reaction module group is connected with the cooling module in series, and the reaction module group comprises 1 unit reaction module or is formed by connecting more than two unit reaction modules in series; the method for synthesizing the paliperidone intermediate comprises the following steps:
1) weighing 300g of paliperidone hydrogenation precursor 3- (2-chloroethyl) -2-methyl-9-hydroxy-4H-pyrido [1,2-A ] pyrimidine-4-ketone, adding 6L of anhydrous methanol and 200g of concentrated hydrochloric acid, stirring uniformly, adding 4g of 10% Pd/C, and fully stirring and mixing to form a material I;
2) respectively conveying the material I preheated in the step 1) and hydrogen to a reaction module group of a microchannel reactor for reaction, wherein: adjusting the flow rate of the slurry pump to make the flow rate of the material I38.0 g/min, and adjusting the flow rate of the material H2The flow rate of the gas flowmeter is 700ml/min, the reaction temperature is 60 ℃, the temperature of the cooling module is 20 ℃, the reaction pressure is 1.0Mpa, and the raw materials and H2The molar ratio of (1: 3.4) and the total residence time of the reaction in the reaction module group is 24 s; collecting reaction solution flowing out of cooling module, filtering to recover catalyst, distilling under reduced pressure to remove solvent, adding 750ml of water into residue to dissolve completely, and saturatingNaHCO3The pH value of the solution is 7-8, filtering is carried out, 1.8L of ethyl acetate is added into the crude product, the temperature is raised to 60 ℃ for dissolution, 1.8L of n-hexane is slowly dripped into the crude product, the temperature is reduced to 0-10 ℃, the mixture is kept and stirred for 1H, filtering is carried out, a filter cake is washed by a small amount of n-hexane and is dried for 8H in vacuum at 50 ℃ to obtain the paliperidone intermediate 3- (2-chloroethyl) -6,7,8, 9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido [1,2-a ] after the temperature is lowered to 0-10 ℃ for vacuum drying]199.74g of pyrimidin-4-one, yield 90.20% and purity 99.36%.
Example 5
The present embodiment provides a method for synthesizing a paliperidone intermediate using a microchannel reactor, as shown in fig. 1 and fig. 2, the microchannel reactor includes a preheating module, a reaction module group, and a cooling module, wherein: the preheating module is connected with the reaction module group in series, the reaction module group is connected with the cooling module in series, and the reaction module group comprises 1 unit reaction module or is formed by connecting more than two unit reaction modules in series; the method for synthesizing the paliperidone intermediate comprises the following steps:
1) weighing 200g of 3- (2-chloroethyl) -2-methyl-9-hydroxy-4H-pyrido [1,2-A ] pyrimidin-4-one, adding 4L of absolute ethyl alcohol and 150g of concentrated hydrochloric acid, uniformly stirring, adding 8g of 5% Pt/C, and fully stirring and mixing to form a material I;
2) respectively conveying the material I preheated in the step 1) and hydrogen to a reaction module group of a microchannel reactor for reaction, wherein: adjusting the flow rate of the slurry pump to make the flow rate of the material I35.0 g/min, and adjusting the flow rate of the material H2The flow rate of the gas flow meter is 600ml/min, the reaction temperature is 90 ℃, the temperature of the cooling module is 30 ℃, the reaction pressure is 1.5Mpa, and the raw materials and H2The molar ratio of (1: 3.4) and the total residence time of the reaction in the reaction module group is 24 s; collecting reaction solution flowing out of cooling module, filtering to recover catalyst, distilling under reduced pressure to remove solvent, adding 500ml of water into residue to dissolve completely, and adding saturated NaHCO3The pH value of the solution condition system is 7-8, filtering is carried out, 1.2L of ethyl acetate is added into the crude product, the temperature is raised to 60 ℃ for dissolution, 1.2L of n-hexane is slowly dripped into the crude product, the temperature is reduced to 0-10 ℃ after dripping, heat preservation and stirring are carried out for 1h, filtering is carried out, a filter cake is washed by a small amount of n-hexane, and vacuum drying is carried out for 8 h at 50 ℃ forObtaining the paliperidone intermediate 3- (2-chloroethyl) -6,7,8, 9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido [1,2-a]128.75g of pyrimidin-4-one, 87.21% yield and 99.00% purity.
Example 6
The present embodiment provides a method for synthesizing a paliperidone intermediate using a microchannel reactor, as shown in fig. 1 and fig. 2, the microchannel reactor includes a preheating module, a reaction module group, and a cooling module, wherein: the preheating module is connected with the reaction module group in series, the reaction module group is connected with the cooling module in series, and the reaction module group comprises 1 unit reaction module or is formed by connecting more than two unit reaction modules in series; the method for synthesizing the paliperidone intermediate comprises the following steps:
1) weighing 250g of 3- (2-chloroethyl) -2-methyl-9-hydroxy-4H-pyrido [1,2-A ] pyrimidin-4-one, adding 5L of anhydrous methanol and 250g of concentrated hydrochloric acid, stirring uniformly, adding 5g of 10% Rh/C, and fully stirring and mixing to form a material I;
2) respectively conveying the material I preheated in the step 1) and hydrogen to a reaction module group of a microchannel reactor for reaction, wherein: adjusting the flow rate of the slurry pump to make the flow rate of the material I be 32.0g/min, and adjusting H2The flow rate of the gas flow meter is 650ml/min, the reaction temperature is 40 ℃, the temperature of the cooling module is 20 ℃, the reaction pressure is 1.0Mpa, and the raw materials and H are mixed2The molar ratio of (1: 3.8) and the residence time of the reaction is 22 s; collecting reaction solution flowing out of the cooling module, filtering to recover catalyst, distilling under reduced pressure to remove solvent, adding 600ml of water into residue to dissolve completely, and adding saturated NaHCO3Under the condition of a solution, adding 1.5L of ethyl acetate into a crude product, heating to 60 ℃ for dissolution, slowly dropwise adding 1.5L of n-hexane, cooling to 0-10 ℃, keeping the temperature and stirring for 1H, filtering, washing a filter cake with a small amount of n-hexane, and performing vacuum drying at 50 ℃ for 8H to obtain a paliperidone intermediate 3- (2-chloroethyl) -6,7,8, 9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido [1,2-a ]]162.82g of pyrimidin-4-one, yield 88.23% and purity 98.85%.
The above experimental results show that higher purity and yield can be ensured when the reaction temperature is between 40 ℃ and 90 ℃, the reaction temperature is changed in the range and the influence on the purity and the yield is not large in view of the overall rule, but when the reaction temperature is 60 ℃, the yield and the purity of the reaction product are the highest and the numerical value is changed greatly, the integral rule is not met, and the beneficial effect is unpredictable before the technical scheme and the technical effect of the application are not known.
In order to examine the recycling and reusing efficiency of the catalyst, Pd/C and Pt/C are respectively selected as the catalyst, and the experimental content of recycling and reusing for 7 times is designed together, wherein the catalyst dosage and other key process parameters of each reaction are ensured to be the same, the relationship between the catalyst recycled and reused for many times and the reaction conversion rate is mainly examined, and the results are shown in tables 1 and 2:
TABLE 1 Pd/C cycling experiment
TABLE 2 Pt/C cycling application experiment
The results show that the conversion rates of the Pd/C and Pt/C catalysts which are repeatedly recycled do not obviously decrease in the using process, which indicates that the catalysts which are repeatedly recycled for 7 times still have high activity. When the reaction kettle in the prior art is operated, the catalyst needs to be continuously supplemented to ensure that the catalytic activity is not obviously reduced.
Comparative example (Autoclave)
To a 5L autoclave was added 3- (2-chloroethyl) -2-methyl-9-hydroxy-4H-pyrido [1,2-A]200g of pyrimidine-4-ketone, 4L of anhydrous methanol and 100ml of concentrated hydrochloric acid are added, 20g of 10% Pd/C is added after uniform stirring, and H is introduced into an autoclave2Ensuring the pressure in the reaction kettle to be 2.0-3.0 MpaHeating to 120 deg.C, reacting for 12 hr, cooling to room temperature, filtering, recovering catalyst, distilling under reduced pressure to remove solvent, dissolving the residue in 600ml water, and dissolving with saturated NaHCO3Under the condition of a solution, adding 1.5L of ethyl acetate into a crude product, heating to 60 ℃ for dissolution, slowly dropwise adding 1.5L of n-hexane, cooling to 0-10 ℃, keeping the temperature and stirring for 1H, filtering, washing a filter cake with a small amount of n-hexane, and performing vacuum drying at 50 ℃ for 8H to obtain a paliperidone intermediate 3- (2-chloroethyl) -6,7,8, 9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido [1,2-a ]]144.37g of pyrimidin-4-one, yield 78.23% and purity 97.39%.
By comparing the examples of the present invention with the comparative examples, it can be seen that: the reaction time of the microchannel reactor is only 20s-25s, while the reaction time of the high-pressure kettle is 12 h; in the catalytic hydrogenation reaction process in the paliperidone synthesis process, the hydrogenation operation is very dangerous when the reaction kettle has large liquid holdup (5L), and explosion is very easy to occur, and the danger coefficient is greatly reduced because the liquid holdup of the microchannel reactor is small (less than 50ml), so that the danger is not too high even if a small amount of hydrogen is leaked; the yield is low, the contents of degraded impurities and dechlorination byproducts are high, and the purity is low in the reaction process of the reaction kettle, and the yield is high, the contents of the degraded impurities and the dechlorination byproducts are low, and the purity is high in the reaction process of the microchannel reactor. Therefore, compared with a conventional high-pressure reaction kettle, the microchannel reactor has the advantages of high reaction speed, small liquid holdup, safety, environmental protection and the like, the content of degraded impurities and dechlorination byproducts in the reaction process can be greatly reduced, and the final product has high yield and better quality.
Although the present invention has been described with reference to the preferred embodiments, it should be understood that various changes and modifications can be made therein by those skilled in the art without departing from the spirit and scope of the invention as defined in the appended claims.
Claims (1)
1. A method for synthesizing a paliperidone intermediate by using a microchannel reactor is characterized in that a core part of the microchannel reactor comprises a preheating module, a reaction module group and a cooling module, wherein: the preheating module is connected with the reaction module group in series, the reaction module group is connected with the cooling module in series, and the reaction module group comprises 1 unit reaction module or is formed by connecting more than two unit reaction modules in series; the method for synthesizing the paliperidone intermediate comprises the following steps:
1) reacting 3- (2-chloroethyl) -2-methyl-9-hydroxy-4H-pyrido [1,2-A]Adding the pyrimidine-4-ketone into an organic solvent, adding concentrated hydrochloric acid, adding a noble metal-loaded active carbon catalyst, and taking the mixture as a material
To mix the materials
Conveying the mixture to a preheating module of the microchannel reactor for preheating;
2) preheating the materials in the step 1)
Respectively conveying the hydrogen and the reaction liquid to a reaction module group of a microchannel reactor for mixed reaction, collecting the reaction liquid flowing out of a cooling module, and carrying out post-treatment to obtain the 3- (2-chloroethyl) -6,7,8, 9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido [1,2-a ]]Pyrimidin-4-one; the 3- (2-chloroethyl) -2-methyl-9-hydroxy-4H-pyrido [1, 2-A) in the step 1)]The concentration of the pyrimidine-4-ketone in the organic solvent is 0.1 mol/L-0.4 mol/L; the 3- (2-chloroethyl) -2-methyl-9-hydroxy-4H-pyrido [1, 2-A) in the step 1)]The mass ratio of the pyrimidine-4-ketone to the activated carbon supported noble metal catalyst is 1 (0.01-0.1); the 3- (2-chloroethyl) -2-methyl-9-hydroxy-4H-pyrido [1, 2-A) in the step 1)]The molar ratio of the pyrimidine-4-ketone to the hydrogen is 1 (3.0-4.0); the pressure of the reaction in the step 2) is 0.5 MPa-1.5 MP a; step 2), the total residence time of the material I and the hydrogen in the reaction module group is 10-40 s; the reaction temperature in the step 2) is 30-90 ℃; step 1) the concentrated hydrochloric acid is mixed with 3- (2-chloroethyl) -2-methyl-9-hydroxy-4H-pyrido [1,2-A]The mass ratio of the pyrimidine-4-ketone is 1: (1.0～1.5）；
The organic solvent in the step 1) is any one or a mixture of more of methanol, ethanol and isopropanol;
the catalyst of the activated carbon supported noble metal in the step 1) is Pd/C or Pt/C; wherein the mass ratio of the noble metal accounts for 1 to 10 percent of the total mass of the catalyst.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711324153.1A CN108003154B (en) | 2017-12-13 | 2017-12-13 | Method for synthesizing paliperidone intermediate by using microchannel reactor |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711324153.1A CN108003154B (en) | 2017-12-13 | 2017-12-13 | Method for synthesizing paliperidone intermediate by using microchannel reactor |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN108003154A CN108003154A (en) | 2018-05-08 |
| CN108003154B true CN108003154B (en) | 2021-03-30 |
Family
ID=62058412
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201711324153.1A Active CN108003154B (en) | 2017-12-13 | 2017-12-13 | Method for synthesizing paliperidone intermediate by using microchannel reactor |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108003154B (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109134269A (en) * | 2018-08-01 | 2019-01-04 | 黑龙江鑫创生物科技开发有限公司 | A kind of synthesis of micro passage reaction according to promise Gray's intermediate method |
| CN109988168A (en) * | 2019-05-07 | 2019-07-09 | 重庆天地药业有限责任公司 | A method of southern crude product is trained using micro passage reaction synthesizing imine |
| CN110003239A (en) * | 2019-05-07 | 2019-07-12 | 重庆天地药业有限责任公司 | A method of Cefamandole Nafate intermediate is synthesized using micro passage reaction |
| CN112442017A (en) * | 2019-08-29 | 2021-03-05 | 珠海润都制药股份有限公司 | Method for preparing voriconazole racemate by adopting microchannel reactor |
| CN117720487B (en) * | 2023-12-16 | 2024-08-06 | 深圳智微通科技有限公司 | Method for continuously synthesizing alpha-acetyl-gamma-butyrolactone |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009116071A2 (en) * | 2008-02-05 | 2009-09-24 | Watson Pharma Private Limited | An improved process for preparation of paliperidone |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TWI385157B (en) * | 2008-01-16 | 2013-02-11 | Scinopharm Taiwan Ltd | A novel intermediate for the preparation of paliperidone |
-
2017
- 2017-12-13 CN CN201711324153.1A patent/CN108003154B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009116071A2 (en) * | 2008-02-05 | 2009-09-24 | Watson Pharma Private Limited | An improved process for preparation of paliperidone |
Non-Patent Citations (2)
| Title |
|---|
| Hydrocarbon hydrogenation and dehydrogenation reactions in microfabricated catalytic reactors;R. S. Besser et al.;《Chemical Engineering Science》;20031231;第58卷;19-26 * |
| 微化工技术;陈光文等;《化工学报》;20030430;第54卷(第4期);427-439 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN108003154A (en) | 2018-05-08 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108003154B (en) | Method for synthesizing paliperidone intermediate by using microchannel reactor | |
| CN108017575B (en) | Method for synthesizing crizotinib intermediate by using microchannel reactor | |
| CN102001951A (en) | Method for preparing high-purity p-phenylenediamine | |
| CN107089969B (en) | Method for synthesizing imatinib intermediate | |
| CN109232578B (en) | Method for continuously preparing tetranitrobenzene pyridine tetraazapentalene (BPTAP) by using micro-reaction technology | |
| CN114315612B (en) | Process for continuously producing isopropanolamine | |
| CN111253218A (en) | Synthesis method and device of 2,3, 5-trimethylhydroquinone | |
| CN107739313A (en) | A kind of method of the multi-temperature zone continuous stream micro passage reaction synthesis chlorophenol of 4 amino 3 | |
| CN104844462A (en) | Synthesis process of dimido dipheny compound | |
| CN108329314A (en) | A kind of method of micro passage reaction synthesis Eliquis intermediate | |
| CN107935872B (en) | Method for synthesizing 2-amino-5-chlorobenzophenone by using microchannel reactor | |
| CN104710402B (en) | Dicyclohexyl crown ether synthesis method | |
| CN102675271A (en) | Continuous preparation method for phthalide and derivatives thereof | |
| CN102718662A (en) | Method for preparing cinacalcet hydrochloride | |
| CN108285421A (en) | A kind of method of micro passage reaction synthesis lapatinib intermediate | |
| CN113121424A (en) | Continuous reaction for preparing piperazine pyridine compound | |
| CN108283940B (en) | Preparation method of palbociclib intermediate | |
| CN114230504B (en) | Synthetic method of pyrrolidone intermediate | |
| CN107674022A (en) | A kind of pa wins the synthetic method of XiLin intermediate | |
| CN108947853A (en) | A kind of method of micro passage reaction synthesis Mirabegron intermediate | |
| CN107674043A (en) | A kind of method that Nintedanib intermediate is synthesized using micro passage reaction | |
| CN108658880A (en) | A kind of preparation method of ultra-violet absorber | |
| CN108047095A (en) | A kind of preparation method of p-aminobenzene sulfonic acid | |
| CN108069882A (en) | The preparation method of orthanilic acid | |
| CN106854200A (en) | The preparation method of Ceritinib and its intermediate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |