CN112409354B - Synthesis process of 7-fluoroimidazo [1,2-A ] pyridine and intermediate thereof - Google Patents
Synthesis process of 7-fluoroimidazo [1,2-A ] pyridine and intermediate thereof Download PDFInfo
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Abstract
The invention relates to a synthesis process of 7-fluoroimidazo [1,2-A ] pyridine and an intermediate thereof, which comprises the steps of using 4-chloro-2-aminopyridine as an initial material, cyclizing with 2-chloroacetaldehyde to obtain 7-chloroimidazo [1,2-A ] pyridine, reacting the 7-chloroimidazo [1,2-A ] pyridine with halide to obtain 7-chloroimidazo [1,2-A ] pyridine quaternary ammonium salt, fluorinating to obtain 7-fluoroimidazo [1,2-A ] pyridine quaternary ammonium salt, and finally removing a protecting group under the action of an acidic substance to obtain the 7-fluoroimidazo [1,2-A ] pyridine. The 7-fluoroimidazo [1,2-A ] pyridine is prepared by the intermediate quaternary ammonium salt, has the advantages of cheap and easily-obtained raw materials, high reactant activity, mild reaction conditions, high yield and low production cost, and is suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a synthesis process of 7-fluoroimidazo [1,2-A ] pyridine and an intermediate thereof.
Background
7-fluoroimidazo [1,2-A ] pyridines are important intermediates for a number of antiviral drugs. Currently, 7-fluoroimidazo [1,2-a ] pyridine is generally obtained by reacting 2-amino-4-fluoropyridine with 2-chloroacetaldehyde in the prior art, and the synthesis method of the raw material 2-amino-4-fluoropyridine mainly comprises the following two methods:
the method comprises the following steps: patent application No. WO201100790761 reports the preparation of 2-amino-4-fluoropyridine using 2-chloro-4-fluoropyridine as a starting material according to the following reaction scheme.
The second method comprises the following steps: patent application No. CN108440402 reports the preparation of 2-amino-4-fluoropyridine using the following reaction formula, using 4-chloro-2-pyridinecarboxylic acid as starting material.
However, the first method uses a palladium catalyst, has high cost and is not suitable for large-scale production; when the second method uses sodium fluoride for fluorination, the reaction conditions are harsh, and the temperature is 180 DEGoC) Higher, not suitable for scale-up production.
Disclosure of Invention
The invention aims to provide a synthesis process of 7-fluoroimidazo [1,2-A ] pyridine and an intermediate thereof, which has the advantages of short process route, simple and convenient operation, low production cost, no need of silica gel chromatographic purification, avoidance of high-temperature reaction, mild reaction conditions and suitability for industrial production.
The technical scheme adopted by the invention for solving the problems is as follows: a7-fluoroimidazo [1,2-A ] pyridine intermediate having the structure:
wherein R is benzyl or p-methoxybenzyl, X is Cl or F, X1Is Cl or Br.
The invention further aims to provide a synthesis process of a 7-fluoroimidazo [1,2-A ] pyridine intermediate, which has the following reaction formula:
the method comprises the following steps:
(1) under the action of alkaline substances, 2-amino-4-chloropyridine is used as a starting material to form a ring with 2-chloroacetaldehyde to obtain the 7-chloroimidazo [1,2-A ] pyridine.
(2) The 7-chloroimidazo [1,2-A ] pyridine reacts with halide to obtain the 7-chloroimidazo [1,2-A ] pyridine quaternary ammonium salt.
(3) The 7-chloroimidazo [1,2-A ] pyridine quaternary ammonium salt reacts with a fluorinating reagent to obtain the 7-fluoroimidazo [1,2-A ] pyridine quaternary ammonium salt.
Wherein, the 7-chloroimidazo [1,2-A ] pyridine quaternary ammonium salt and the 7-fluoroimidazo [1,2-A ] pyridine quaternary ammonium salt are both 7-fluoroimidazo [1,2-A ] pyridine intermediates.
Preferably, the molar ratio of the 2-amino-4-chloropyridine to the 2-chloroacetaldehyde in step (1) is 0.5 to 1: 1, the molar ratio of the basic substance to the 2-amino-4-chloro-pyridine is 1-4: 1.
preferably, in the step (1), the basic substance is one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, potassium methoxide, triethylamine and diisopropylethylamine.
Preferably, in the step (2), the halide is at least one of benzyl bromide, benzyl chloride, p-methoxy benzyl bromide and p-methoxy benzyl chloride, and the molar ratio of the halide to the 7-chloroimidazo [1,2-A ] pyridine is 1-2: 1.
preferably, the fluorinating agent in the step (3) is at least one of sodium fluoride, potassium fluoride, cesium fluoride and tetramethylammonium fluoride, and the molar ratio of the fluorinating agent to the 7-chloroimidazo [1,2-A ] pyridine quaternary ammonium salt is 1-5: 1.
preferably, the step (1), the step (2) and the step (3) are all performed in a solvent system, the solvent in the step (1) is at least one of an organic alcohol solvent, an organic amide solvent, an organic ether solvent and acetonitrile, and the solvents in the step (2) and the step (3) are all organic amide solvents.
Preferably, the reaction temperature in the step (1) is 75-80 ℃, the reaction temperature in the step (2) is 80-90 ℃, and the reaction temperature in the step (3) is 90-100 ℃.
Another purpose of the invention is to provide a synthesis process of 7-fluoroimidazo [1,2-A ] pyridine, wherein the reaction formula is as follows:
the method comprises the following synthetic steps:
and (3) removing a protecting group from the 7-fluoroimidazo [1,2-A ] pyridine quaternary ammonium salt at the temperature of 60-80 ℃ under the action of an acidic substance to obtain the 7-fluoroimidazo [1,2-A ] pyridine.
Preferably, the acidic substance is at least one of hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid and trifluoromethanesulfonic acid, and the molar ratio of the acidic substance to the 7-fluoroimidazo [1,2-A ] pyridine quaternary ammonium salt is 5-20: 1.
Preferably, the synthesis step is performed in a solvent system, and the solvent is at least one of an organic alcohol solvent, an organic amide solvent, an organic ether solvent and acetonitrile.
More preferably, the organic amide solvent is at least one of N, N-dimethylacetamide, N-dimethylformamide and N-methylpyrrolidone.
Compared with the prior art, the invention has the advantages that:
(1) compared with the prior art, the invention has the advantages that the starting materials are cheap and easy to obtain, expensive heavy metal is not required to be used as a catalyst, and the production cost is low.
(2) The 7-fluoroimidazo [1,2-A ] pyridine intermediate 7-chloroimidazo [1,2-A ] pyridine quaternary ammonium salt synthesized by the method can be directly put into the next reaction without separation and purification, the production period is obviously shortened, and the yield is high; meanwhile, 7-chloroimidazo [1,2-A ] pyridine quaternary ammonium salt is used as a raw material to carry out the subsequent synthesis of 7-fluoroimidazo [1,2-A ] pyridine, so that the activity of reactants is increased, and the reaction yield is improved.
(3) The method has the advantages of short process route, simple and convenient operation, no need of silica gel chromatographic purification, avoidance of high-temperature reaction, mild reaction conditions and suitability for industrial production.
Drawings
FIG. 1 is a 1HNMR map of 7-fluoroimidazo [1,2-A ] pyridine in example 1 of the present invention.
Detailed Description
The invention is described in further detail below with reference to the accompanying examples.
As shown in FIG. 1, a 1HNMR map of 7-fluoroimidazo [1,2-A ] pyridine in example 1.
Example 1
(1) Preparation of 7-chloroimidazo [1,2-A ] pyridine
Adding 128g (1.0 mol) of 2-amino-4-chloropyridine, 1.28L of ethanol, 336g (4.0 mol) of sodium bicarbonate and 235g of 50% chloroacetaldehyde aqueous solution into a 3L three-necked bottle with a magnetic stirring device at room temperature, heating to 80 ℃ after the addition is finished, refluxing, and reacting for 2 hours; cooling the reaction to 20-30%oAnd C, concentrating, removing ethanol, sequentially adding water and ethyl acetate, separating liquid, and concentrating an organic phase to obtain 136g of brownish red oily liquid with the yield of 90%.
(2) Preparation of 7-chloroimidazo [1,2-A ] pyridine quaternary ammonium salt
To a 1L three-necked flask equipped with a magnetic stirrer was added 100g (655 mmol) of 7-chloroimidazo [1,2-A ]]Pyridine, 107g (688 mmol) of p-methoxybenzyl chloride and 500mL of N, N-dimethylformamide are replaced by nitrogen, and the temperature is raised to 90 DEGoC, stirring for 2 hours; and after the reaction is finished, cooling to 20-30 ℃, and directly feeding the reaction solution into the next reaction.
Taking a small amount of separation and purification for characterization, and identifying the nuclear magnetic structure as follows:
1HNMR(DMSO-d6，400MHz) δ ppm 8.56（d,1H），7.90（d,1H），7.72（d,1H），7.42（m,2H），7.16（d,2H），6.82(d,2H），5.96（s,2H），3.80（s，3H）。
(3) preparation of 7-fluoroimidazo [1,2-A ] pyridine quaternary ammonium salt
196g (1.3 mol) of cesium fluoride was added to the reaction solution of the step (2), nitrogen gas was replaced, and the temperature was raised to 100oC, stirring for 1 hour, and cooling to 20-30 ℃ after the reaction is finishedoAnd C, adding water and n-butanol, stirring, separating liquid, and concentrating an organic phase to obtain 280 g of a brown yellow solid with the yield of two steps being 91%.
The nuclear magnetic structure identification results are as follows:
1HNMR(DMSO-d6，400MHz) δ ppm 8.55（d,1H），7.90（d,1H），7.72（d,1H），7.16（d,2H），7.09（m,2H），6.82(d,2H），5.96（s,2H），3.80（s，3H）。
(4) preparation of 7-fluoroimidazo [1,2-A ] pyridines
To a 1L three-necked flask equipped with a magnetic stirrer was added 100g (324 mmol) of 7-fluoroimidazo [1,2-A]Quaternary pyridinium salt and 300mL (4620mmol) methanesulfonic acid, substitutionNitrogen, heating to 80 deg.CoC, stirring for 2 hours, cooling to 20-30 ℃ after the reaction is finishedoC, adding water and ethyl acetate, adjusting the pH of the water phase to 9-10 by using 50% sodium hydroxide, separating the liquid, concentrating the organic phase, and recrystallizing by using ethyl acetate-n-heptane to obtain 35.2g of light yellow solid with the yield of 80%.
The nuclear magnetic identification results are as follows:
1HNMR(DMSO-d6，400MHz) δ ppm 8.00（t,1H），7.52（d，2H），7.19（d，1H），6.61（t，1H）。
example 2
The procedures (1), (2) and (3) are the same as those in example 1.
Step (4) preparation of 7-fluoroimidazo [1,2-A ] pyridine
To a 1L three-necked flask equipped with a magnetic stirrer was added 100g (324 mmol) of 7-fluoroimidazo [1,2-A]Quaternary pyridinium salt and 300mL (3398mmol) of trifluoromethanesulfonic acid, displacing nitrogen, and heating to 80 deg.CoC, stirring for 1 hour, and cooling to 20-30 ℃ after the reaction is finishedoC, adding water and ethyl acetate, adjusting the pH of the water phase to 9-10 by using 50% sodium hydroxide, separating, concentrating the organic phase, and recrystallizing by using ethyl acetate-n-heptane to obtain 36.1g of light yellow solid with the yield of 81%.
Example 3
The procedures (1), (2) and (3) are the same as those in example 1.
Step (4) preparation of 7-fluoroimidazo [1,2-A ] pyridine
To a 1L three-necked flask equipped with a magnetic stirrer was added 100g (324 mmol) of 7-fluoroimidazo [1,2-A]Quaternary pyridinium salt and 400m (5367mmol) trifluoroacetic acid, displacing nitrogen, heating to 70 deg.CoC, stirring for 3 hours, cooling to 20-30 ℃ after the reaction is finishedoC, adding water and ethyl acetate, adjusting the pH of the water phase to 9-10 by using 50% sodium hydroxide, separating the liquid, concentrating the organic phase, and recrystallizing by using ethyl acetate-n-heptane to obtain 34.2g of light yellow solid with the yield of 77%.
In addition to the above embodiments, the present invention also includes other embodiments, and any technical solutions formed by equivalent transformation or equivalent replacement should fall within the scope of the claims of the present invention.
Claims (9)
1. A synthesis process of a 7-fluoroimidazo [1,2-A ] pyridine intermediate is characterized by comprising the following steps: the reaction formula is as follows:
wherein R is benzyl or p-methoxybenzyl, X1Is Cl or Br;
the method comprises the following steps:
(1) under the action of alkaline substances, 2-amino-4-chloropyridine is used as a starting material to form a ring with 2-chloroacetaldehyde to obtain 7-chloroimidazo [1,2-A ] pyridine;
(2) reacting 7-chloroimidazo [1,2-A ] pyridine with halide to obtain 7-chloroimidazo [1,2-A ] pyridine quaternary ammonium salt;
(3) reacting 7-chloroimidazo [1,2-A ] pyridine quaternary ammonium salt with a fluorinating reagent to obtain 7-fluoroimidazo [1,2-A ] pyridine quaternary ammonium salt;
wherein, the 7-chloroimidazo [1,2-A ] pyridine quaternary ammonium salt and the 7-fluoroimidazo [1,2-A ] pyridine quaternary ammonium salt are both 7-fluoroimidazo [1,2-A ] pyridine intermediates.
2. The process of synthesis of a 7-fluoroimidazo [1,2-a ] pyridine intermediate according to claim 1, characterized in that: the molar ratio of the 2-amino-4-chloropyridine to the 2-chloroacetaldehyde in the step (1) is 0.5-1: 1, the molar ratio of the basic substance to the 2-amino-4-chloro-pyridine is 1-4: 1.
3. the process of synthesis of a 7-fluoroimidazo [1,2-a ] pyridine intermediate according to claim 1, characterized in that: in the step (1), the alkaline substance is one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, potassium methoxide, triethylamine and diisopropylethylamine.
4. The process of synthesis of a 7-fluoroimidazo [1,2-a ] pyridine intermediate according to claim 1, characterized in that: in the step (2), the halide is at least one of benzyl bromide, benzyl chloride, p-methoxy benzyl bromide and p-methoxy benzyl chloride, and the molar ratio of the halide to the 7-chloroimidazo [1,2-A ] pyridine is 1-2: 1.
5. the process of synthesis of a 7-fluoroimidazo [1,2-a ] pyridine intermediate according to claim 1, characterized in that: in the step (3), the fluorinating reagent is at least one of sodium fluoride, potassium fluoride, cesium fluoride and tetramethylammonium fluoride, and the molar ratio of the fluorinating reagent to the 7-chloroimidazo [1,2-A ] pyridine quaternary ammonium salt is 1-5: 1.
6. the process of synthesis of a 7-fluoroimidazo [1,2-a ] pyridine intermediate according to claim 1, characterized in that: the step (1), the step (2) and the step (3) are all carried out in a solvent system, the solvent in the step (1) is at least one of an organic alcohol solvent, an organic amide solvent, an organic ether solvent and acetonitrile, and the solvents in the step (2) and the step (3) are all organic amide solvents.
7. A synthesis process of 7-fluoroimidazo [1,2-A ] pyridine is characterized by comprising the following steps: the reaction formula is as follows:
wherein R is benzyl or p-methoxybenzyl, X1Is Cl or Br;
the method comprises the following synthetic steps:
removing a protecting group from the 7-fluoroimidazo [1,2-A ] pyridine quaternary ammonium salt under the action of an acidic substance to obtain 7-fluoroimidazo [1,2-A ] pyridine;
wherein the 7-fluoroimidazo [1,2-A ] pyridine quaternary ammonium salt is prepared by the following steps:
wherein R is benzyl or p-methoxybenzyl, X1Is Cl or Br;
(1) under the action of alkaline substances, 2-amino-4-chloropyridine is used as a starting material to form a ring with 2-chloroacetaldehyde to obtain 7-chloroimidazo [1,2-A ] pyridine;
(2) reacting 7-chloroimidazo [1,2-A ] pyridine with halide to obtain 7-chloroimidazo [1,2-A ] pyridine quaternary ammonium salt;
(3) the 7-chloroimidazo [1,2-A ] pyridine quaternary ammonium salt reacts with a fluorinating reagent to obtain the 7-fluoroimidazo [1,2-A ] pyridine quaternary ammonium salt.
8. The process of synthesizing 7-fluoroimidazo [1,2-a ] pyridine according to claim 7, characterized in that: the acidic substance is at least one of hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid and trifluoromethanesulfonic acid, and the molar ratio of the acidic substance to the 7-fluoroimidazo [1,2-A ] pyridine quaternary ammonium salt is 5-20: 1.
9. The process of synthesizing 7-fluoroimidazo [1,2-a ] pyridine according to claim 7, characterized in that: the synthesis step of removing the protecting group of the 7-fluoroimidazo [1,2-A ] pyridine quaternary ammonium salt under the action of an acidic substance to obtain the 7-fluoroimidazo [1,2-A ] pyridine is carried out in a solvent system, and the solvent is at least one of an organic alcohol solvent, an organic amide solvent, an organic ether solvent and acetonitrile.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110759827A (en) * | 2019-11-07 | 2020-02-07 | 江苏索普化工股份有限公司 | A kind of method for preparing ethyl acetate by catalytic esterification |
| CN111635401A (en) * | 2020-06-18 | 2020-09-08 | 镇江卡博医药科技有限公司 | Copper complex promoted 7-fluoroimidazo [1,2-a ] pyridine synthesis method |
| CN112047942A (en) * | 2020-10-26 | 2020-12-08 | 都创(上海)医药科技有限公司 | Synthesis method of 7-fluoroimidazo [1,2-A ] pyridine |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110759827A (en) * | 2019-11-07 | 2020-02-07 | 江苏索普化工股份有限公司 | A kind of method for preparing ethyl acetate by catalytic esterification |
| CN111635401A (en) * | 2020-06-18 | 2020-09-08 | 镇江卡博医药科技有限公司 | Copper complex promoted 7-fluoroimidazo [1,2-a ] pyridine synthesis method |
| CN112047942A (en) * | 2020-10-26 | 2020-12-08 | 都创(上海)医药科技有限公司 | Synthesis method of 7-fluoroimidazo [1,2-A ] pyridine |
Non-Patent Citations (1)
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| DEALKYLATION OF QUATERNARY 1-ALKYLAZOLO[a]PYRIDINIUM SALTS;L. M. Potikha 等;《Chemistry of Heterocyclic Compounds》;20120531;第48卷(第2期);第351页结构式部分、第353页第3段 * |
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