CN114524803B - Synthesis method of quinoline compound intermediate - Google Patents

Synthesis method of quinoline compound intermediate Download PDF

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CN114524803B
CN114524803B CN202210217854.XA CN202210217854A CN114524803B CN 114524803 B CN114524803 B CN 114524803B CN 202210217854 A CN202210217854 A CN 202210217854A CN 114524803 B CN114524803 B CN 114524803B
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quinoline compound
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罗枭
陈东
谢鸷生
程婷婷
秦超
马鹏岗
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China Resources Sanjiu Medical and Pharmaceutical Co Ltd
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
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Abstract

The invention relates to the technical field of organic synthesis, and particularly provides a method for synthesizing a quinoline compound intermediate shown as a formula II, which comprises the following steps: (1) Taking a compound shown in a formula IV, a basic catalyst and phenyl chloroformate, and contacting and reacting in an NMP environment to obtain a reaction solution; (2) The method can realize two-step homogeneous reaction, greatly improve the yield of the intermediate of the quinoline compound shown as the formula II, only needs the last purification process, does not need to replace a new solvent after steaming off the original reaction solvent in the middle, is convenient to operate and beneficial to industrial large-scale production, and in addition, adopts NMP as the solvent to realize the homogeneous reaction, greatly reduces the using amount of hydrazine hydrate (the molar equivalent is reduced from 60.0eq to 6.0-8.0eq in the prior art), and is beneficial to environmental protection and production safety.

Description

Synthesis method of quinoline compound intermediate
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a method for synthesizing a quinoline compound intermediate.
Background
Quinoline compounds are often used for treating malignant tumors, for example, chinese patent document CN102977014A describes compounds having formula I and salts thereof in the specification, and describes that they are useful for inhibiting various tumor cells such as lung cancer cells, colon cancer cells, stomach cancer cells, liver cancer cells, breast cancer cells, glioblastoma cells, and the like.
Figure BDA0003535405420000011
Figure BDA0003535405420000021
The compound shown in the formula II is used as an important intermediate of the quinoline compound, and the existing synthesis method of the intermediate mainly adopts the compound shown in the structural formula IV to carry out two-step synthesis, wherein the first step is as follows: firstly reacting with phenyl chloroformate in the environment of acetone, purifying to obtain a compound shown as a formula III, and secondly: the catalyst is prepared by reacting a reactant shown in a formula III with hydrazine hydrate in the environment of 1, 4-dioxane, and purifying. The process not only needs two purification steps, is complex to operate, is not suitable for industrialized production, but also has low yield, and the route is disclosed so far, and people do not pay attention to the improvement of the position.
Disclosure of Invention
Therefore, the technical problem to be solved by the invention is to overcome the defects of low yield, complex operation and unsuitability for industrial production of the synthetic method of the quinoline compound intermediate in the prior art.
Therefore, the invention provides a method for synthesizing a quinoline compound intermediate shown as a formula II, which comprises the following steps: (1) Taking a compound shown in a formula IV, an alkaline catalyst and phenyl chloroformate, and contacting and reacting in an NMP environment to obtain a reaction solution;
(2) Mixing the reaction solution prepared in the step (1) with hydrazine hydrate, and reacting to obtain the hydrazine hydrate;
Figure BDA0003535405420000031
wherein NMP is N-methyl pyrrolidone.
In a preferred embodiment, the step (1) comprises dissolving the compound represented by formula IV in NMP to form a solution, mixing the solution with a basic catalyst and phenyl chloroformate, and reacting to obtain a reaction solution; or dissolving the compound shown in the formula IV and the basic catalyst by using NMP to form a solution, mixing the solution with phenyl chloroformate, and reacting to obtain a reaction solution. The two modes are more favorable for forward reaction, and the reaction yield is improved.
The synthesis method adopted in CN102977014A is to prepare the compound shown in formula III first, and react the reactant shown in formula III with hydrazine hydrate, however, the present inventors found that the yield of the quinoline compound intermediate shown in formula II prepared by the method is low, and at the same time, the quinoline compound intermediate contains more hydrazine hydrate residues. After the research, the reason is that the compound shown in the formula III and hydrazine hydrate are in heterogeneous reaction in 1, 4-dioxane, so that the yield of the intermediate of the quinoline compound shown in the formula II is low, and the solvent is distilled off from the reaction system and then the reaction system is filtered, so that more hydrazine hydrate remains in the intermediate of the quinoline compound. The method adopts one-pot reaction, and the reactant shown in the formula III does not need to be purified, so that the method is simple to operate, can improve the reaction yield, can effectively remove hydrazine hydrate residue of the quinoline compound intermediate shown in the formula II, and improves the purity of the quinoline compound intermediate.
As a preferred embodiment, the basic catalyst is selected from at least one of triethylamine, 4-Dimethylaminopyridine (DMAP), potassium carbonate and pyridine.
As a preferred embodiment, the mass to NMP volume ratio of the compound of formula IV is 1.0kg:4.0-6.0L.
As a preferred embodiment, the molar ratio of the compound of formula IV to hydrazine hydrate is 1:6.0-8.0.
As a preferred embodiment, the reaction temperature of step (1) is 20-30 ℃, more preferably, the time is at least 2h, such as 2-3h.
As a preferred embodiment, the molar ratio of the compound of formula IV to phenyl chloroformate is 1:1.0-1.2.
As a preferred embodiment, the reaction temperature of step (2) is 20-30 ℃, more preferably, the time is at least 2h, such as 2-6h.
As a preferred embodiment, in step (1), the dissolution is carried out under stirring at a temperature of 20 to 30 ℃, more preferably for a time of 0.5 to 1.0h.
As a preferred embodiment, in the step (2), phenyl chloroformate is added dropwise at a temperature of not higher than 30 ℃.
In a preferred embodiment, the method further comprises a step of purifying the reaction solution obtained after the reaction in step (2).
More preferably, in the purification step, an alkaline aqueous solution is used for adjusting the pH of the reaction solution to 10-12, crystallization and solid-liquid separation are carried out, solids are collected and dried, and the pure quinoline compound intermediate product shown in the formula II is prepared.
Wherein the solid-liquid separation is carried out in a conventional manner, for example, by filtration or centrifugation.
As a preferred embodiment, the method further comprises the step of adding water in a dropwise manner before adding the alkaline aqueous solution, wherein the dropwise addition time is 3-5h, and the mass-to-water volume ratio of the compound of formula IV is 1kg:15L.
As a preferred embodiment, the crystallization is carried out under stirring, the temperature of the crystallization process is 0-20 ℃, and the time is 6-10h; and/or the alkaline aqueous solution is selected from 5-15% of sodium hydroxide aqueous solution in percentage by mass.
In the present invention, the compound of formula IV can be purchased or synthesized by conventional methods, for example, by steps a to H using the synthesis method disclosed in example 1 of patent document CN 102977014A.
Figure BDA0003535405420000051
The invention also improves the steps A-H to meet the requirement of industrial mass production, for example, in the step A, the prior art adopts a mode of dropwise adding 1-bromo-3-chloropropane to 3-methoxy-4-hydroxyacetophenone, while the preferred embodiment of the invention adopts a mode of adding 3-methoxy-4-hydroxyacetophenone to 1-bromo-3-chloropropane in divided times (for example, three times on average).
In step B, in the prior art, the reaction solution is poured into ice water, an organic layer is collected, the organic layer is washed to be neutral by saturated sodium bicarbonate aqueous solution, dried by anhydrous sodium sulfate and purified by evaporating the solvent, but the preferred embodiment of the invention adopts the way that the reaction solution is poured into ice water, and then the water phase is purified by CH 2 Cl 2 Extracting twice, combining organic phases, washing the organic phases with water until the water phase is nearly neutral, and evaporating the solvent under reduced pressure.
In step F, the reaction is quenched by adding the reaction solution to ice water in the prior art. While the preferred embodiment of the present invention employs quenching by pouring ice water into the reaction system. Through the comprehensive improvement of the steps, the improved synthesis method is suitable for large-scale production.
The invention also provides a synthesis method of the quinoline compound shown in the formula I, which comprises the synthesis method of any one of claims 1-9, and further comprises the step of carrying out condensation reaction on the intermediate of the quinoline compound shown in the formula II and 2, 4-difluorobenzaldehyde to obtain the quinoline compound shown in the formula I.
The method for synthesizing the quinoline compound shown in the formula I comprises the following steps,
in NMP, under the catalysis of organic acid, 2, 4-difluorobenzaldehyde is contacted with a quinoline compound intermediate shown in a formula II to react, so as to obtain the compound;
Figure BDA0003535405420000061
Figure BDA0003535405420000071
wherein NMP is N-methyl pyrrolidone.
In the process of synthesizing the quinoline compound, the inventor considers a plurality of solvents at the early stage, such as ethanol, isopropanol, THF and other solvents, and can not realize homogeneous reaction, and unexpectedly discovers that NMP is used as a reaction solvent to contact 2, 4-difluorobenzaldehyde with the quinoline compound intermediate shown in the formula II for reaction, so that the homogeneous reaction can be realized, the yield of the quinoline compound is obviously improved, the purity of a crude product is greatly improved, the purification difficulty is reduced, the operation is convenient, the industrial large-scale production is facilitated, the yield of the crude product is up to more than 95 percent, the purity is up to more than 94 percent, and the crude product after purification meets the quality requirements of the raw materials in Chinese pharmacopoeia and ICH related guiding principles.
As a preferred embodiment, the organic acid is at least one selected from the group consisting of acetic acid, p-toluenesulfonic acid and oxalic acid.
As a preferred embodiment, the molar ratio of 2, 4-difluorobenzaldehyde to the quinoline compound intermediate represented by formula II is 2.8 to 3.2:1.0.
as a preferred embodiment, the ratio of the mass of the quinoline compound intermediate represented by formula II to the volume of NMP is 1.0kg:5.0 to 8.0L.
As a preferred embodiment, the synthesis method specifically comprises the following steps:
(1) Mixing 2, 4-difluorobenzaldehyde, NMP and organic acid to obtain a mixed solution;
(2) And (2) mixing the mixed solution obtained in the step (1) with a quinoline compound intermediate shown in a formula II, and reacting to obtain the quinoline compound shown in the formula I.
As a preferable embodiment, in the step (1), the mixture is mixed under stirring at a temperature of 20 to 30 ℃ for 0.5 to 1 hour.
As a preferable embodiment, in the step (2), the reaction is carried out under stirring at a temperature of 35 to 45 ℃ for 6 to 16 hours.
In a preferred embodiment, the method further comprises a step of purifying the reaction solution after the reaction.
In a more preferred embodiment, in the purification step, the pH of the reaction solution is adjusted to 9 to 10 with an aqueous alkaline solution, and the resulting solution is crystallized, filtered, collected as a solid, and dried to obtain the quinoline compound represented by formula I.
As a preferred embodiment, the crystallization is carried out under stirring, wherein the temperature of the crystallization process is 0-30 ℃ and the time is 4-6h.
As a preferred embodiment, the alkaline aqueous solution is selected from an aqueous solution of sodium carbonate with a mass percentage of 5% to 15%.
As a preferred embodiment, after the purification step, the method further comprises the steps of taking a crude quinoline compound shown in the formula I, adding water for mixing, and carrying out solid-liquid separation; taking the solid, adding tetrahydrofuran, and heating to dissolve; and then adding water for mixing, cooling, carrying out solid-liquid separation, taking the solid for drying, and obtaining the pure quinoline compound shown in the formula I.
As a preferred embodiment, the mass ratio of the volume of water added for the first time to the quinoline compound intermediate represented by formula II is 10. The mass ratio of the volume of the first added water to the quinoline compound intermediate represented by formula II is 3.
As a preferred embodiment, the mass ratio of the volume of tetrahydrofuran to the quinoline compound intermediate represented by formula II is 10.
As a preferred embodiment, after the purification step, the method further comprises the steps of taking a crude quinoline compound shown in the formula I, adding water, mixing, and centrifuging; taking the solid, adding tetrahydrofuran, and heating and dissolving at the temperature of 55-65 ℃; then adding water, stirring and mixing for 3h at the temperature of 55-65 ℃, slowly cooling to 20-30 ℃ within 7h, filtering and drying to obtain the pure quinoline compound shown in the formula I.
The technical scheme of the invention has the following advantages:
1. the invention provides a method for synthesizing a quinoline compound intermediate, wherein the same solvent is used in the step (1) and the step (2), the inventor considers a plurality of solvents such as dichloromethane, THF, 1, 4-dioxane, DMSO, ethyl acetate and the like in the earlier stage, and can not realize homogeneous reaction of two steps, and the invention unexpectedly finds that NMP is used as a reaction solvent, the compound shown in the formula IV, a basic catalyst and phenyl chloroformate react under the contact of NMP, and then the reaction is mixed with hydrazine hydrate for reaction, so that the two-step homogeneous reaction can be realized, the yield of the quinoline compound intermediate shown in the formula II can be greatly improved, the purity of a crude product can be greatly improved, the purification difficulty can be reduced, only the last purification process is needed, the new solvent is not needed to be replaced after the original reaction solvent is distilled off in the middle, the operation is convenient, and the industrial scale production can be facilitated, in addition, the NMP is used as the solvent for realizing the homogeneous reaction, and the consumption of hydrazine hydrate can be greatly reduced (from 60.0eq to 6.0-8.0eq, namely, the consumption of hydrazine hydrate in the prior art is only needed, and the invention is beneficial to environmental protection and the production safety.
In addition, the method can adopt NMP to dissolve the compound shown in the formula IV to form a solution, and the solution is taken to be mixed with the alkaline catalyst and the phenyl chloroformate for reaction to obtain a reaction solution; or dissolving the compound shown in the formula IV and the basic catalyst by adopting NMP to form a solution, mixing the solution with phenyl chloroformate, and reacting to obtain a reaction liquid. The above two modes can realize homogeneous reaction of the reaction liquid and hydrazine hydrate.
2. According to the synthesis method of the quinoline compound intermediate, the basic catalyst is selected from at least one of triethylamine, DMAP, potassium carbonate and pyridine, and the basic catalysts are used as an acid-binding agent and a catalyst. Compared with other basic catalysts, the method for preparing the quinoline compound intermediate by preferably using pyridine is safe and reliable, does not influence the safety due to the generation of a large amount of carbon dioxide gas, is more suitable for industrial large-scale production, and has the yield obviously higher than the yield of the quinoline compound intermediate prepared by using other basic catalysts.
3. The invention provides a method for synthesizing a quinoline compound intermediate, which comprises the following steps of controlling the molar ratio of a compound shown in a control formula IV to hydrazine hydrate to be 1.0:6.0 to 8.0 percent, under the reaction condition of 20 to 30 ℃, the compound shown in the formula II can be synthesized with high yield (the total yield from the formula IV to the formula II is more than 94 percent, and the purity is more than 94 percent), and compared with the synthesis of similar compounds in patent CN102977014A, the usage amount of hydrazine hydrate is greatly reduced (from 60.0eq to 6.0-8.0 eq), and the production safety and the environmental protection are improved.
By controlling the molar ratio of the compound represented by formula IV to phenyl chloroformate to be 1.0: 1.0-1.2, and realizing the high-efficiency conversion of the compound of the formula IV into the compound of the formula III (the purity is more than 95 percent) under the reaction condition of 20-30 ℃; because the purity is high (the purity is more than 95 percent), separation and purification are not needed, the compound in the formula IV is completely converted into the compound in the formula III, hydrazine hydrate is added for reaction to obtain the compound in the formula II, the total yield of the two steps is more than 94 percent, the purity is more than 94 percent, the production operation steps are reduced, and the industrial production is facilitated.
4. According to the synthesis method of the quinoline compound intermediate provided by the invention, earlier researches also find that the quinoline compound intermediate prepared by the existing method is further reacted with 2, 4-difluorobenzaldehyde to obtain the quinoline compound with low purity and more byproducts. It is known through research that a large amount of hydrazine hydrate is used in the synthesis of a quinoline compound intermediate, so that part of hydrazine hydrate remains in the quinoline compound intermediate, and side reactions with 2, 4-difluorobenzaldehyde are generated subsequently. The research of the invention finds that the pH value of the reaction liquid prepared in the step (2) is adjusted to 10-12 by adopting an alkaline aqueous solution, then the crystallization and filtration method effectively removes the unreacted hydrazine hydrate and other possible unknown impurities (the hydrazine hydrate and other water-soluble impurities are left in the alkaline aqueous solution), improves the purity of the intermediate of the quinoline compound, further improves the purity of the product of the quinoline compound and reduces the purification difficulty.
5. According to the synthesis method of the quinoline compound intermediate, provided by the invention, the quinoline compound intermediate is crystallized under stirring, the temperature in the crystallization process is 0-20 ℃, the time is 6-10h, impurities can be further removed, and the product purity is improved.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, and it is obvious that the drawings in the following description are some embodiments of the present invention, and other drawings can be obtained by those skilled in the art without creative efforts.
FIG. 1 is a schematic representation of the quinoline compound of formula I of example 4 1 H NMR spectrum.
Detailed Description
The following examples are provided to further understand the present invention, not to limit the scope of the present invention, but to provide the best mode, not to limit the content and the protection scope of the present invention, and any product similar or similar to the present invention, which is obtained by combining the present invention with other prior art features, falls within the protection scope of the present invention.
The examples do not indicate specific experimental procedures or conditions, and can be performed according to the procedures or conditions of the conventional experimental procedures described in the literature in the field. The reagents or instruments used are conventional reagent products which are commercially available, and manufacturers are not indicated.
The purity of the quinoline compound shown in the formula I in each example and comparative example of the invention is detected by a high performance liquid chromatography, 10mg of the quinoline compound shown in the formula I is added with 10ml of methanol to prepare a sample solution, and the sample solution is injected into a liquid phase for detection, wherein the chromatographic conditions are as follows:
Figure BDA0003535405420000111
Figure BDA0003535405420000121
the purity of the quinoline compound intermediate shown in the formula II is detected by a high performance liquid chromatography, 10mg of the quinoline compound shown in the formula II is added with 10ml of methanol to prepare a test solution, the test solution is injected into a liquid phase for detection, and the chromatographic conditions are as follows:
Figure BDA0003535405420000122
Figure BDA0003535405420000131
the purity of the quinoline compound intermediate shown in the formula III is detected by a high performance liquid chromatography, 10mg of the quinoline compound shown in the formula III is added with 10ml of methanol to prepare a test solution, the test solution is injected into a liquid phase for detection, and the chromatographic conditions are as follows:
Figure BDA0003535405420000132
detecting the purity of the intermediate IV by a high performance liquid chromatography, taking 10mg of the intermediate IV and 10ml of methanol to prepare a test solution, and injecting the test solution into a liquid phase for detection, wherein the chromatographic conditions are as follows:
Figure BDA0003535405420000141
the purity of the intermediates V, VI, VII, VIII, IX and XI is detected by a high performance liquid chromatography, 10mg of the intermediate is taken and 10ml of methanol is added to prepare a sample solution, the sample solution is taken and injected into a liquid phase for detection, and the chromatographic conditions are as follows:
Figure BDA0003535405420000142
Figure BDA0003535405420000151
EXAMPLE 1 Synthesis of quinoline Compound intermediates of formula II
The embodiment provides a method for synthesizing a quinoline compound intermediate shown as a formula II, which comprises the following steps:
adding 15.8kg (36mol, 1.0 eq) of compound shown in formula IV and 79L (5V) of NMP into a reaction kettle, controlling the temperature in the reaction kettle to be 20-30 ℃, stirring for 0.75h until reaction liquid is clear, and adding 5.7kg (72mol, 2.0 eq) of pyridine into the reaction kettle. Controlling the temperature in the reaction kettle to be 20-30 ℃, slowly dropwise adding 6.2kg (39.6 mol, 1.1eq) of phenyl chloroformate into the reaction kettle, stirring and reacting for 2.5h at 20-30 ℃, checking the complete reaction (< 0.5%) of the compound in formula IV and the purity (> 95%) of the compound in formula III by HPLC, adding 15.7kg (252mol, 7.0 eq) of 80% (w/w) hydrazine hydrate aqueous solution into the reaction kettle, and stirring and reacting for 3h at 20-30 ℃. Slowly adding purified water 237L (15V) into the reaction kettle (the adding time is 4.0 h), slowly adding 10 percent (w/w) of NaOH aqueous solution at the temperature of 20-30 ℃ to adjust the pH of the reaction solution to 10-11 (measured by adopting a pH colorimetric card). Adjusting the internal temperature of the reaction kettle to be 0-20 ℃, and stirring for crystallization for 8 hours. Filtration and washing of the filter cake with purified water. The filter cake was dried in vacuo at 45 ℃ for 20h to give 11.8kg of the product (intermediate of quinoline compound represented by formula II), yield 95.2%, purity 95.7%.
The compound of formula IV used in this example was prepared as follows:
(1) Step A: synthesis of intermediate XI
91.5kg of 1-bromo-3-chloropropane and 80.3kg of anhydrous potassium carbonate are added into a reaction kettle, 330kg of DMF is added, 23.0kg of 3-methoxy-4-hydroxyacetophenone is added at room temperature, the reaction lasts for 3.5h at room temperature, 23.0kg of 3-methoxy-4-hydroxyacetophenone is added at room temperature, the reaction lasts for 5h at room temperature, 23.0kg of 3-methoxy-4-hydroxyacetophenone is added at room temperature, the reaction lasts for 15.5h at room temperature, the obtained reaction solution is poured into 690kg of ice water, the stirring is carried out for 2.0h, and the solid (intermediate XI) of 92.0kg is obtained through filtering and drying, the yield is 92.0%, and the purity is 99.1%.
(2) And step B and step C: synthesis of intermediate IX
740kg of DCM and 92.0kg of the intermediate obtained in the step A are added into a reaction kettle and cooled to-15-10 ℃, fuming nitric acid (89.6 kg, 3.75eq) is slowly added into the reaction kettle by a peristaltic pump to react for 2.0h at-15-10 ℃, the system is poured into ice water, and then the water phase is treated by CH 2 Cl 2 Extracting twice, combining organic phases, washing the organic phases with water until the water phase is nearly neutral, and evaporating the solvent under reduced pressure. 153kg of N, N-dimethylformamide dimethyl acetal (DMF-DMA) and 397kg of toluene are added to react at the temperature of 95 ℃ for 16h, the solvent is evaporated under reduced pressure, 136kg of methyl tert-butyl ether (MTBE) is added, the temperature is reduced to-15 to-10 ℃, the mixture is stirred for 3h, and the mixture is filtered and dried to obtain 85.0kg of solid (intermediate IX), the yield is 65.0 percent and the purity is 95.3 percent.
(3) Step D: synthesis of intermediate VIII
710kg of acetic acid was pumped into a 2000L reactor, and the intermediates from Steps B and C (85.0 kg,1.0 eq) were added to the reactor and warmed to 70 ℃. Fe (69.2 kg of total mass) is added in batches and the temperature is controlled to be 95-100 ℃. The reaction system reacts for 40min at the temperature of 95-100 ℃. Filtering and collecting filtrate, adding MTBE 1700L (20V) into the filtrate under stirring, stirring for 0.5h at-5-0 ℃, filtering to obtain a filter cake, washing with 680L (8V) of water, and drying the filter cake under reduced pressure at 50 ℃ to obtain 34.8kg of a product (intermediate VIII), wherein the yield is 52.5% and the purity is 97.0%.
(4) And E, step E: synthesis of intermediate VII
Mixing acetonitrile (CH) 3 CN) 174L, pumping into a kettle, adding 34.7kg of the intermediate obtained in the step D and 51.4kg of 4-methylpiperidine into the reaction kettle, and reacting for 4 hours at 75-80 ℃. The solvent was evaporated under reduced pressure, ethyl acetate (EtOAc) 174L was added to the concentrated system, stirred for 3.5h, and filtered to collect a cake. The filter cake was dried at 50 ℃ under reduced pressure to give 35.8kg of product (intermediate VII) in 83.5% yield.
(5) Step F: synthesis of intermediate VI
Will CH 3 CN 107L and phosphorus oxychloride 5.5kg (POCl) 3 6.9 eq) is pumped into a reaction kettle, 35.8kg of the intermediate obtained in the step E is added into the reaction kettle, and the reaction is carried out for 4 hours at the temperature of 75-80 ℃. The solvent was distilled off under reduced pressure at 45 ℃ and the reaction mixture was quenched by pouring ice water 573L. The pH was adjusted to 11-12 with 50% (w/v) aqueous sodium hydroxide. Adding water 573L at 40-45 ℃ to dilute until the salt is dissolved, transferring the feed liquid to a centrifuge for filtration, washing a filter cake for 5 times by using 14.3L of water, and drying the filter cake at 50 ℃ under reduced pressure to obtain 31.5kg of a product (an intermediate VI), wherein the yield is 83.6 percent and the purity is 98.4 percent.
(6) G: synthesis of intermediate V
Pumping 100L of ethanol into a reaction kettle, heating and refluxing for 30min, discharging, pumping 100L of chlorobenzene into the reaction kettle, washing for 30min, and discharging. And (4) pumping 157L (5V) of chlorobenzene into a reaction kettle, adding 31.4kg of the intermediate obtained in the step F and 21kg of 2-fluoro-4 nitrophenol into the reaction kettle, and reacting for 12 hours at the temperature of 135-140 ℃. Cooling the reaction system to-10-5 ℃ for crystallization for 2h. Filtration gave a filter cake which was dissolved with DCM 628L (20V) and taken up with 10% (w/w) K 2 CO 3 Solution 502L (16V) washes the organic phase 5 times until the aqueous layer is nearly colorless. Washing the organic phase twice with 5% (w/w) salt solution (16V), concentrating the organic phase at 35-40 deg.C, adding isopropyl ether 251L (8V), crystallizing at 20-30 deg.C for 4h, and vacuum filtering to obtain filter cake. Dissolving the filter cake with EtOH 314L (10V), heating to 80 ℃, stirring for 0.5h, cooling to 20-30 ℃, crystallizing for 5h, filtering to obtain the filter cake, washing the filter cake with a small amount of EtOH 9.4L (0.3V), and drying to obtain 21.0kg of product (intermediate V), wherein the yield is 50.0% and the purity is 97.7%.
(7) Step H: synthesis of intermediate IV
Pumping 100L of ethanol into the reaction kettle, heating and refluxing for 30min, and discharging (repeating for 2 times). Ethanol 252L (12V) was pumped into the reaction kettle. Adding concentrated HCl into a reaction kettle, heating to 60-65 ℃, adding 15kg (6 eq.) of Fe powder into the reaction kettle, and stirring for 10min. And G, adding 21.0kg of the intermediate obtained in the step G in batches, heating to 75-80 ℃ and reacting for 2h. Cooling to 50-55 ℃, adding an EtOH42L (2V) solution of activated carbon, heating to 75-80 ℃, reacting for 0.5h, adding 42L (2V) of water, refluxing for 10min at 75-80 ℃, and filtering to obtain a filtrate. Cooling to 10-15 ℃ and applying 5% (w/w) K 2 CO 3 Adjusting the pH value to 10-11. Adding 1260L (60V) of water for dilution and crystallizing for 2h at the temperature of 15-20 ℃. Filtering to obtain filter cake, washing with water until pH of the filtrate is about 7, and drying the filter cake at 45 deg.C under reduced pressure to obtain 15.8Kg of product (i.e. compound of formula IV), with yield of 80.0% and purity of 99.0%.
EXAMPLE 2 Synthesis of quinoline Compound intermediates of formula II
The embodiment provides a method for synthesizing a quinoline compound intermediate shown as a formula II, which comprises the following steps:
adding 15.8kg (36mol, 1.0 eq) of compound shown in formula IV and 79L (5V) of NMP into a reaction kettle, controlling the temperature in the reaction kettle to be 20-30 ℃, stirring for 1h until a reaction solution is clear, and adding 5.7kg (72mol, 2.0 eq) of pyridine into the reaction kettle. Controlling the temperature in the reaction kettle to be 20-30 ℃, slowly dropwise adding 6.2kg (39.6 mol, 1.1eq) of phenyl chloroformate into the reaction kettle, stirring and reacting for 2h at 20-30 ℃, checking the complete reaction (< 0.5%) of the compound in formula IV and the purity (> 95%) of the compound in formula III by HPLC, adding 15.7kg (252mol, 7.0 eq) of 80% (w/w) hydrazine hydrate aqueous solution into the reaction kettle, and stirring and reacting for 2h at 20-30 ℃. Slowly adding purified water 237L (15V) into the reaction kettle (the adding time is 4.0 h), controlling the temperature to be 20-30 ℃, and slowly adding 10% (w/w) NaOH aqueous solution to adjust the pH of the reaction solution to be 10-11. Adjusting the internal temperature of the reaction kettle to be 0-20 ℃, stirring and crystallizing for 6 hours. Filtration and washing of the filter cake with purified water. The filter cake is dried in vacuum for 20h at 45 ℃ to obtain 12.0kg of the product (the intermediate of the quinoline compound shown in the formula II), the yield is 97.0 percent, and the purity is 95.1 percent.
EXAMPLE 3 Synthesis of quinoline Compound intermediates of formula II
The embodiment provides a method for synthesizing a quinoline compound intermediate shown as a formula II, which comprises the following steps:
15.8kg (36mol, 1.0 eq) of the compound of formula IV and NMP 79L (5V) are added into a reaction kettle, the temperature in the reaction kettle is controlled to be 20-30 ℃, the mixture is stirred for 1h until the reaction solution is clear, and 5.7kg (72mol, 2.0 eq) of pyridine is added into the reaction kettle. Controlling the temperature in the reaction kettle to be 20-30 ℃, slowly dropwise adding 6.2kg (39.6 mol, 1.1eq) of phenyl chloroformate into the reaction kettle, stirring and reacting for 6h at 20-30 ℃, checking the complete reaction (< 0.5%) of the compound in formula IV and the purity (> 95%) of the compound in formula III by HPLC, adding 15.7kg (252mol, 7.0 eq) of 80% (w/w) hydrazine hydrate aqueous solution into the reaction kettle, and stirring and reacting for 6h at 20-30 ℃. Slowly adding purified water 237L (15V) into the reaction kettle (the adding time is 4.0 h), controlling the temperature to be 20-30 ℃, and slowly adding 10% (w/w) NaOH aqueous solution to adjust the pH of the reaction solution to be 10-11. Adjusting the internal temperature of the reaction kettle to be 0-20 ℃, stirring and crystallizing for 10 hours. Filtration and washing of the filter cake with purified water. The filter cake was dried in vacuo at 45 ℃ for 20h to give 11.78kg of the product (intermediate of quinoline compound represented by formula II), yield 95.2%, purity 95.6%.
EXAMPLE 4 Synthesis of quinoline Compounds of formula I
This example provides a method for synthesizing a quinoline compound of formula I, comprising the steps of:
9.9kg (3.0 eq) of 2,4-difluorobenzaldehyde, 58.5L (5V) of NMP and 0.4kg (0.3 eq) of AcOH were added to the reaction vessel, stirred at 20-30 ℃ for 0.5 hour, and 11.7kg (1.0 eq) of the intermediate of formula II obtained in example 1 above was added to the reaction vessel. The temperature is adjusted to 35-45 ℃, and the mixture is stirred and reacted for 8 hours. Regulating the temperature to 20-30 ℃, and slowly dripping 10% (w/w) Na 2 CO 3 The solution adjusts the pH value of the reaction solution to about 9-10, and the solution is stirred and crystallized for 5 hours at the temperature of 20-30 ℃. Filtering, rinsing the filter cake with purified water, and drying to obtain 14.0kg of crude product, wherein the yield is 95.6 percent and the purity is 94.8 percent.
Returning the filter cake to the kettle, adding 117L (10V) of purified water, pulping for 6h at 20-30 ℃, centrifuging, and rinsing the filter cake by using 23.4L (2V) of purified water. Returning the obtained filter cake to a kettle, adding 117L (10V) of tetrahydrofuran into the reaction kettle, heating to 55-65 ℃, keeping the temperature, stirring, dissolving, slowly dropwise adding 35.1L (3V) of purified water, stirring at 55-65 ℃ for 3h, controlling the temperature to be slowly reduced to 20-30 ℃ for 7h, filtering, rinsing the filter cake with 23.4L (2V) of purified water, and drying the filter cake at 45-55 ℃ under reduced pressure for 20h to obtain 10.1kg of a quinoline compound pure product shown in the formula I, wherein the yield is 69.1%, and the purity is 99.3%.
Through detection:
ESI-MS[M+H] + 622.2
1 H-NMR (Nuclear magnetic solvent: DMSO-d) 6 )
Figure BDA0003535405420000201
TABLE 1 Compounds of formula I 1 H-NMR data and attribution
Figure BDA0003535405420000211
Comparative example 1
This comparative example provides a synthesis of a quinoline compound intermediate of formula II, essentially using the synthesis of example 1, differing from example 1 only in that the scale of synthesis is reduced in equal proportion, using the corresponding volume of dichloromethane instead of NMP.
The method comprises the following specific steps: adding 15.8g (36mmol, 1.0 eq) of the compound shown in the formula IV and 79mL (5V) of dichloromethane into a reaction kettle, controlling the temperature in the reaction kettle to be 20-30 ℃, stirring for 0.75h till reaction liquid is clear, and adding 5.7g (72mmol, 2.0 eq) of pyridine into the reaction kettle. Controlling the temperature in the reaction kettle to be 20-30 ℃, slowly dropwise adding 6.2g (39.6 mmol, 1.1eq) of phenyl chloroformate into the reaction kettle, stirring and reacting for 2.5h at 20-30 ℃, checking the incomplete reaction (more than 30%) of the compound of formula IV and the purity (less than 60%) of the compound of formula III by HPLC (high performance liquid chromatography), and prompting that a large amount of the compound of formula IV in the current reaction liquid is remained by HPLC detection results, so that the subsequent reaction is not suitable for being carried out, and the subsequent reaction is not carried out.
Comparative example 2
This comparative example provides a synthesis of a quinoline compound intermediate of formula II, essentially using the synthesis of example 1, differing from example 1 only in that the scale of synthesis is reduced by an equal ratio, using the corresponding volume of THF instead of NMP.
The method comprises the following specific steps: adding 15.8g (36mmol, 1.0 eq) of the compound shown in the formula IV and 79mL (5V) of THF into a reaction kettle, controlling the temperature in the reaction kettle to be 20-30 ℃, stirring for 0.75h till reaction liquid is clear, and adding 5.7g (72mmol, 2.0 eq) of pyridine into the reaction kettle. Controlling the temperature in the reaction kettle to be 20-30 ℃, slowly dropwise adding 6.2g (39.6 mmol, 1.1eq) of phenyl chloroformate into the reaction kettle, stirring and reacting for 2.5h at 20-30 ℃, checking the incomplete reaction (more than 30%) of the compound of formula IV and the purity (less than 60%) of the compound of formula III by HPLC (high performance liquid chromatography), wherein the HPLC detection result indicates that a large amount of the compound of formula IV remains in the current reaction liquid, and the compound is not suitable for subsequent reaction, so that the subsequent reaction is not carried out.
Comparative example 3
This comparative example provides a synthesis of a quinoline compound intermediate of formula II, essentially using the synthesis of example 1, differing from example 1 only in that the scale of synthesis is reduced in an equal ratio, using a corresponding volume of 1, 4-dioxane instead of NMP.
The method comprises the following specific steps: adding 15.8g (36mmol, 1.0 eq) of the compound shown in the formula IV and 79mL (5V) of 1, 4-dioxane into a reaction kettle, controlling the temperature in the reaction kettle to be 20-30 ℃, stirring for 0.75h till reaction liquid is clear, and adding 5.7g (72mmol, 2.0 eq) of pyridine into the reaction kettle. Controlling the temperature in the reaction kettle to be 20-30 ℃, slowly dropwise adding 6.2g (39.6 mmol, 1.1eq) of phenyl chloroformate into the reaction kettle, stirring and reacting for 2.5h at 20-30 ℃, checking the incomplete reaction (more than 30%) of the compound of formula IV and the purity (less than 60%) of the compound of formula III by HPLC (high performance liquid chromatography), and prompting that a large amount of the compound of formula IV in the current reaction liquid is remained by HPLC detection results, so that the subsequent reaction is not suitable for being carried out, and the subsequent reaction is not carried out.
Comparative example 4
This comparative example provides a synthesis of a quinoline compound intermediate of formula II, essentially using the synthesis of example 1, differing from example 1 only in that the scale of synthesis is reduced in equal proportion, using the corresponding volume of DMSO instead of NMP.
The method comprises the following specific steps: adding 15.8g (36mmol, 1.0 eq) of the compound shown in the formula IV and 79mL (5V) of DMSO into a reaction kettle, controlling the temperature in the reaction kettle to be 20-30 ℃, stirring for 0.75h till the reaction solution is clear, and adding 5.7g (72mmol, 2.0 eq) of pyridine into the reaction kettle. Controlling the temperature in the reaction kettle to be 20-30 ℃, slowly dropwise adding 6.2g (39.6 mmol, 1.1eq) of phenyl chloroformate into the reaction kettle, stirring and reacting for 2.5h at 20-30 ℃, checking the incomplete reaction (more than 25%) of the compound of formula IV and the purity (less than 65%) of the compound of formula III by HPLC (high performance liquid chromatography), and prompting that a large amount of the compound of formula IV in the current reaction liquid is remained by HPLC detection results, so that the subsequent reaction is not suitable for being carried out, and the subsequent reaction is not carried out.
Comparative example 5
This comparative example provides a synthesis of a quinoline compound intermediate of formula II, essentially using the synthesis of example 1, differing from example 1 only in that the scale of synthesis is reduced in an equal ratio, using the corresponding volume of ethyl acetate instead of NMP.
The method comprises the following specific steps: adding 15.8g (36mmol, 1.0 eq) of the compound shown in the formula IV and 79mL (5V) of ethyl acetate into a reaction kettle, controlling the temperature in the reaction kettle to be 20-30 ℃, stirring for 0.75h until reaction liquid is clear, and adding 5.7g (7.2mmol, 2.0 eq) of pyridine into the reaction kettle. Controlling the temperature in the reaction kettle to be 20-30 ℃, slowly dropwise adding 6.2g (39.6 mmol, 1.1eq) of phenyl chloroformate into the reaction kettle, stirring and reacting for 2.5h at 20-30 ℃, checking the incomplete reaction (more than 30%) of the compound of formula IV and the purity (less than 60%) of the compound of formula III by HPLC (high performance liquid chromatography), and prompting that a large amount of the compound of formula IV in the current reaction liquid is remained by HPLC detection results, so that the subsequent reaction is not suitable for being carried out, and the subsequent reaction is not carried out.
It should be understood that the above examples are only for clarity of illustration and are not intended to limit the embodiments. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. And are neither required nor exhaustive of all embodiments. And obvious variations or modifications therefrom are within the scope of the invention.

Claims (10)

1. A method for synthesizing a quinoline compound intermediate shown as a formula II is characterized by comprising the following steps:
(1) Taking a compound shown in a formula IV, a basic catalyst and phenyl chloroformate, and contacting and reacting in an NMP environment to obtain a reaction solution;
(2) Mixing the reaction solution prepared in the step (1) with hydrazine hydrate, and reacting to obtain the hydrazine hydrate;
Figure 719189DEST_PATH_IMAGE001
formula II
Figure 533561DEST_PATH_IMAGE002
Formula IV.
2. The synthesis method according to claim 1, wherein the step (1) comprises dissolving the compound represented by the formula IV with NMP to form a solution, mixing the solution with a basic catalyst and phenyl chloroformate, and reacting to obtain a reaction solution; or, the step (1) includes dissolving the compound represented by the formula IV and the basic catalyst with NMP to form a solution, mixing the solution with phenyl chloroformate, and reacting to obtain a reaction solution.
3. The synthesis method according to claim 2, wherein in the step (1), the solution is performed under stirring at a temperature of 20 to 30 ℃; and/or the ratio of the mass of the compound represented by formula IV to the volume of NMP is 1.0kg:4.0-6.0L.
4. A synthesis process according to any one of claims 1 to 3, characterised in that the basic catalyst is selected from at least one of triethylamine, DMAP, potassium carbonate and pyridine.
5. The synthesis method according to any one of claims 1 to 3, wherein the reaction temperature in step (1) is 20 to 30 ℃; and/or, the molar ratio of the compound shown in the formula IV to the phenyl chloroformate is 1:1.0-1.2.
6. The synthesis method according to any one of claims 1 to 3, wherein the reaction temperature in step (2) is 20 to 30 ℃; and/or, the molar ratio of the compound shown in the formula IV to the hydrazine hydrate is 1:6.0-8.0.
7. The method according to any one of claims 1 to 3, wherein in the step (1), the phenyl chloroformate is added dropwise at a temperature of not higher than 30 ℃.
8. The synthesis method according to any one of claims 1 to 3, further comprising a step of purifying the reaction solution obtained after the reaction in step (2);
in the purification step, adjusting the pH of the mixed solution to 10-12 by adopting an alkaline aqueous solution, crystallizing, carrying out solid-liquid separation, collecting solids, and drying to obtain the pure quinoline compound intermediate product shown in the formula II.
9. The method of claim 8, further comprising the step of adding water dropwise prior to the addition of the aqueous alkaline solution, wherein the dropwise addition is performed for a period of 3-5 hours, and the ratio of the mass of the compound of formula IV to the volume of water added is 1kg:15L; and/or, crystallizing under stirring, wherein the temperature of the crystallization process is 0-20 ℃, and the time is 6-10h; and/or the alkaline aqueous solution is selected from 5-15% of sodium hydroxide aqueous solution in percentage by mass.
10. A method for synthesizing a quinoline compound shown as a formula I is characterized by comprising the synthesis method of any one of claims 1 to 9, and further comprising the step of carrying out condensation reaction on a quinoline compound intermediate shown as a formula II and 2, 4-difluorobenzaldehyde to obtain the quinoline compound shown as the formula I;
Figure 356024DEST_PATH_IMAGE003
formula I.
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