CN111978245A - Preparation method of 3-fluoro-2-isobutyl pyridine - Google Patents
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- CN111978245A CN111978245A CN202010966009.3A CN202010966009A CN111978245A CN 111978245 A CN111978245 A CN 111978245A CN 202010966009 A CN202010966009 A CN 202010966009A CN 111978245 A CN111978245 A CN 111978245A
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Abstract
The invention provides a preparation method of 3-fluoro-2-isobutyl pyridine, relating to the technical field of chemical intermediate synthesis and providing a new synthetic route of 3-fluoro-2-isobutyl pyridine, the method comprises the steps of taking 2-bromo-3-fluoropyridine as a raw material, preparing (3-fluoropyridin-2-yl) magnesium chloride by a Grignard reagent exchange method, adding (3-fluoropyridin-2-yl) magnesium chloride and isobutyraldehyde to obtain 1- (3-fluoropyridin-2-yl) -2-methylpropane-1-ol, and reacting 1- (3-fluoropyridin-2-yl) -2-methylpropane-1-ol with triethylsilane to remove hydroxyl groups to obtain a final product, namely 3-fluoro-2-isobutylpyridine; the method uses commercially available reagents to synthesize the 3-fluoro-2-isobutylpyridine by a simple process, and has the advantages of simple post-treatment, high product yield and low cost.
Description
Technical Field
The invention relates to the technical field of chemical intermediate synthesis, in particular to a preparation method of 3-fluoro-2-isobutyl pyridine.
Background
The pyridine compounds are important pharmacophores in therapeutic drugs, but the definite functions of the pyridine compounds are the combined action of nitrogen-containing fused heterocycles and modified substituents of the nitrogen-containing fused heterocycles. Alkylated pyridines are particularly common pyridines, such as: esomeprazole is used as a proton pump inhibitor, and a replacement therapy for gastroesophageal reflux disease; nevirapine is a non-nucleoside reverse transcriptase inhibitor of HIV-1, and is used in combination with other antiretroviral drugs for the treatment of HIV-1 infection; pioglitazone belongs to insulin sensitizer and is an antidiabetic drug. Alkyl groups play a variety of roles in drug development, for example as hydrophobic chains, altering the binding properties of Lewis basic nitrogen atoms, preventing oxidative metabolism and linking other parts of the molecule, and the effect of alkyl groups on pyridine is also applicable to other applications such as redox-active molecules in ligands, materials and batteries. 3-fluoro-2-isobutylpyridine is one of alkylated pyridines and is also an important pharmaceutical intermediate.
Literature study on the activity of pyridine alkylation studies on the activity of pyridine alkylation, and methods for direct alkylation of pyridine include lithium alkyls, Grignard reagents, and fatty acid radical methods. Wherein, the yield of the alkyl lithium is high, but the alkyl lithium can react with oxygen and spontaneously combust in the air, which releases heat in a large amount, is dangerous and is not suitable for being used in a large amount; the fatty acid free radical method has expensive reagents, more byproducts and difficult separation and purification; the Grignard reagent has a low yield because magnesium atoms have a large volume, are added to nitrogen, increase steric hindrance, and have a poor nucleophilicity as compared with alkyllithium.
The method for indirectly introducing alkyl into pyridine includes aldehyde-ammonia method, ketone-ammonia method unsaturated alkylation method, etc., wherein, nitrogen atom is introduced by aldehyde-ammonia method or ketone-ammonia method, which is not suitable for nitrogen-free substrate; unsaturated alkylation methods such as palladium-catalyzed coupling of halogenated pyridine with olefin, alkene boronic acid, alkene borate and alkyne, ylide reaction of pyridine aldehyde ketone and the like, the palladium catalyst has good effect, but is expensive and is not suitable for large-scale amplification; the ylide reagents of the pyridine aldehyde ketone and the corresponding alkane are not commercially available, and need to be prepared in a plurality of steps.
In the prior art, no document reports about the synthesis of 3-fluoro-2-isobutyl pyridine. Compounds structurally related to 3-fluoro-2-isobutylpyridine are disclosed in the prior art, for example, three synthetic routes to 2- (2-alkyl) vinyl 3-fluoropyridine:
in the route (1), 2-bromo-3-fluoropyridine is used as a raw material and reacts with vinyl potassium fluoroborate or alkenyl boric acid under the condition of a palladium catalyst to generate 2- (2-alkyl) vinyl 3-fluoropyridine, and then the 2- (2-alkyl) vinyl 3-fluoropyridine is generated by heating reflux of an ammonium formate methanol solution or reduction of an iron powder ammonium chloride alcoholic solution or palladium carbon and the like; the method needs expensive palladium catalyst, has the problem of incomplete reaction in actual operation, and has the defects that raw materials, products, byproducts and the palladium catalyst are difficult to separate during post-treatment, so that the purification is influenced, and the route is suitable for large-scale production of the process due to cost; the method of the route (2) is similar to that of the route (3), aldehyde is prepared firstly, then the aldehyde reacts with the ylide reagent to generate olefin, and the olefin is reduced to obtain a product; the two routes have more steps, are relatively complicated and consume time.
For the route (2), the cost of the adopted starting raw materials is high, the cost price of the reducing reagents of lithium aluminum hydride and borane selected in the process is also high, and the reaction conditions in the reaction process are also high. In the route (3), an expensive palladium catalyst is required to be used in the route (1), and meanwhile, ozone is an unstable and easily-decomposed strong oxidant, is generally manufactured by an ozone generator on site, and needs a specially-assigned person for operation and maintenance of the ozone generator, so that the consumption cost is further increased. In addition, borane as a reducing agent is highly toxic, and when mixed with air, can form an explosive mixture, which has a potential safety hazard.
The 3-fluoro-2-isobutyl pyridine prepared by the method is not economical and feasible, is safe and reliable, and is not suitable for large-scale use.
Disclosure of Invention
The invention aims to provide a preparation method of 3-fluoro-2-isobutyl pyridine, which adopts Grignard reagent exchange and addition to realize pyridine alkylation, avoids using heavy metal palladium catalyst and strong reduction reagents of borane and lithium aluminum hydride, and has the advantages of cheap and easily-obtained raw materials, short synthetic route and controllable production cost.
In order to achieve the above purpose, the invention provides the following technical scheme: a preparation method of 3-fluoro-2-isobutyl pyridine comprises the following synthetic route:
the preparation method comprises the following specific processes: under the protection of inert gas at room temperature, fully stirring and reacting the compound 1 and isopropyl magnesium chloride in a first organic solvent until the reaction is complete to obtain a reaction solution containing a compound 2; under the protection of inert gas at 0 ℃, uniformly mixing the compound 2 and isobutyraldehyde in a second organic solvent, and stirring at room temperature for reaction for 2-12 h; after the reaction is finished, quenching the reaction solution by saturated ammonium chloride aqueous solution in ice bath, extracting and separating an organic phase, washing the organic phase by saturated saline, drying the organic phase and spin-drying to obtain a compound 3; mixing the compound 3 and triethylsilane in a dichloromethane solvent, adding trifluoroacetic acid into the mixed solution under the condition of controlling the temperature to be-40-0 ℃, and stirring the mixed reaction solution for reaction for 1-3 h under the protection of inert gas; after the reaction is finished, quenching the mixed reaction solution by saturated sodium bicarbonate aqueous solution, extracting and separating an organic phase, washing the organic phase by saturated saline, drying and purifying the organic phase to obtain a compound 4.
Wherein the equivalent ratio of the compound 1 to isopropyl magnesium chloride as reactants is 1: 1-1: 2, and the first organic solvent is anhydrous tetrahydrofuran or diethyl ether; the equivalent ratio of the compound 2 to isobutyraldehyde as reactants is 1: 1-1: 2, and the second organic solvent is anhydrous tetrahydrofuran or diethyl ether; the equivalent ratio of the compound 3, triethylsilane and trifluoroacetic acid as reactants is 1:2: 2-1: 5: 5.
Further, under the protection of inert gas and at 0 ℃, the compound 2 is slowly added into the vigorously stirred isobutyraldehyde anhydrous tetrahydrofuran or ether solution to realize uniform mixing.
Further, the temperature control condition of the trifluoroacetic acid added into the mixed solution is-40 ℃ to-25 ℃.
According to the technical scheme, the preparation method of the 3-fluoro-2-isobutyl pyridine provided by the technical scheme of the invention has the following beneficial effects:
the invention discloses a preparation method of 3-fluoro-2-isobutyl pyridine, and provides a new synthetic route of 3-fluoro-2-isobutyl pyridine, the method comprises the steps of taking 2-bromo-3-fluoropyridine as a raw material, preparing (3-fluoropyridin-2-yl) magnesium chloride by a Grignard reagent exchange method, adding (3-fluoropyridin-2-yl) magnesium chloride and isobutyraldehyde to obtain 1- (3-fluoropyridin-2-yl) -2-methylpropane-1-ol, and reacting 1- (3-fluoropyridin-2-yl) -2-methylpropane-1-ol with triethylsilane to remove hydroxyl groups to obtain a final product, namely 3-fluoro-2-isobutylpyridine; the synthesis route uses commercially available reagents to synthesize the 3-fluoro-2-isobutyl pyridine by a simple process, and has the advantages of short synthesis route, simple post-treatment and high product yield; and in the whole synthesis process, heavy metal palladium catalyst, strong reduction reagent borane and lithium aluminum hydride are completely avoided, so that the synthesis route of the invention has low cost and controllable production cost, and can be used for industrial mass production.
In addition, the invention discovers that in the process of preparing the 3-fluoro-2-isobutyl pyridine by the dehydroxylation reaction of the 1- (3-fluoropyridin-2-yl) -2-methylpropane-1-ol, the reaction temperature is controlled between minus 40 ℃ and minus 25 ℃, the generation of reaction byproducts can be effectively eliminated, and the yield of final products is obviously improved.
It should be understood that all combinations of the foregoing concepts and additional concepts described in greater detail below can be considered as part of the inventive subject matter of this disclosure unless such concepts are mutually inconsistent.
The foregoing and other aspects, embodiments and features of the present teachings can be more fully understood from the following description taken in conjunction with the accompanying drawings. Additional aspects of the present invention, such as features and/or advantages of exemplary embodiments, will be apparent from the description which follows, or may be learned by practice of specific embodiments in accordance with the teachings of the present invention.
Drawings
The drawings are not intended to be drawn to scale. In the drawings, each identical or nearly identical component that is illustrated in various figures may be represented by a like numeral. For purposes of clarity, not every component may be labeled in every drawing. Embodiments of various aspects of the present invention will now be described, by way of example, with reference to the accompanying drawings, in which:
FIG. 1 is a nuclear magnetic hydrogen spectrum diagram of the final product 3-fluoro-2-isobutyl pyridine.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the drawings of the embodiments of the present invention. It is to be understood that the embodiments described are only a few embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the described embodiments of the invention without any inventive step, are within the scope of protection of the invention. Unless defined otherwise, technical or scientific terms used herein shall have the ordinary meaning as understood by one of ordinary skill in the art to which this invention belongs.
The use of "first," "second," and similar terms in the description and claims of the present application do not denote any order, quantity, or importance, but rather the terms are used to distinguish one element from another. Similarly, the singular forms "a," "an," or "the" do not denote a limitation of quantity, but rather denote the presence of at least one, unless the context clearly dictates otherwise. The terms "comprises," "comprising," or the like, mean that the elements or items listed before "comprises" or "comprising" encompass the features, integers, steps, operations, elements, and/or components listed after "comprising" or "comprising," and do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof.
Based on the fact that a literature report of synthesizing a compound 3-fluoro-2-isobutylpyridine is lacked in the prior art, a synthetic route of a compound similar to the 3-fluoro-2-isobutylpyridine needs to use a palladium catalyst, lithium aluminum hydride, borane and other reduction reagents, so that the technical problems of high cost, potential safety hazard and unsuitability for large-scale use exist, and even if the synthetic route is applied to synthesizing the 3-fluoro-2-isobutylpyridine, the synthetic route cannot be economically feasible. Therefore, the invention aims to provide the preparation method of the 3-fluoro-2-isobutylpyridine with controllable production cost, which has the advantages of short synthetic route, convenient post-treatment, high yield and easy batch production.
The specific synthetic route is as follows:
taking 2-bromo-3-fluoropyridine (compound 1) as a raw material, obtaining (3-fluoropyridin-2-yl) magnesium chloride (compound 2) by adopting a Grignard reagent exchange method, adding (3-fluoropyridin-2-yl) magnesium chloride and isobutyraldehyde to obtain 1- (3-fluoropyridin-2-yl) -2-methylpropane-1-ol (compound 3), and reacting the 1- (3-fluoropyridin-2-yl) -2-methylpropane-1-ol with triethylsilane for dehydroxylation to obtain a final product, namely 3-fluoro-2-isobutylpyridine (compound 4).
The preparation of 3-fluoro-2-isobutylpyridine disclosed in the present invention is further described in detail with reference to the following examples. The reagents used in the synthetic route disclosed by the invention are all commercially available and the room temperature is 10-30 ℃; in another example, isopropyl magnesium chloride is provided as a solution of isopropyl magnesium chloride lithium chloride in tetrahydrofuran.
Example 1
1) Under the protection of argon at room temperature, adding isopropyl magnesium chloride-lithium chloride tetrahydrofuran solution (1.3mol/L, 87.4mL, 113.6mmol, 2.0eq) into light yellow anhydrous tetrahydrofuran solution (100mL) of 2-bromo-3-fluoropyridine (10g, 56.8mmol), stirring the mixed solution until complete reaction, wherein the reaction is carried out for 2 hours generally, and the color of the reaction solution becomes dark from bright; a small sample was quenched with acetone and showed disappearance of starting material by platelet TLC (polarity of developing solvent: petroleum ether/ethyl acetate 3: 1) and a new spot with large polarity was generated, yielding a reaction solution containing (3-fluoropyridin-2-yl) magnesium chloride which was immediately used for the next step to synthesize compound 3 because the Grignard reagent was unstable.
2) Under the protection of inert gas at 0 ℃, dropwise adding reaction liquid (56.8mmol) containing (3-fluoropyridin-2-yl) magnesium chloride into vigorously stirred isobutyraldehyde (8.2g, 113.6mmol, 2.0eq) anhydrous tetrahydrofuran solution (200mL), uniformly mixing, stirring at room temperature for 2h, then quenching the reaction liquid with saturated ammonium chloride aqueous solution (25mL) under ice bath, extracting and separating organic phase and aqueous phase, wherein the aqueous phase is extracted with ethyl acetate, combining the organic phases extracted twice, washing with saturated brine, drying with anhydrous magnesium sulfate, spin-drying the solvent, and purifying by silica gel column chromatography to obtain colorless oily 1- (3-fluoropyridin-2-yl) -2-methylpropan-1-ol (8.16g, 48.2mmol), wherein the yield of the product is 84.88%.
3) Triethylsilane (11.22g, 96.5mmol) was added to a solution of 1- (3-fluoropyridin-2-yl) -2-methylpropan-1-ol (8.16g, 48.2mmol) in dichloromethane (100mL), trifluoroacetic acid (11.00g, 96.5mmol) was added to the reaction mixture at-40 ℃ and the reaction mixture was stirred under nitrogen for 3 h; after the reaction, the reaction solution was quenched with saturated aqueous sodium bicarbonate, extracted with dichloromethane, the organic phase and the aqueous phase were separated, the aqueous phase was extracted with ethyl acetate, the zero-time extracted organic phase was combined and washed with saturated brine, the separated organic phase was dried over anhydrous magnesium sulfate, filtered, the solvent was dried by spinning, and purified by silica gel column chromatography to obtain 3-fluoro-2-isobutylpyridine (6.4g, 41.78mmol), the yield of 3-fluoro-2-isobutylpyridine was 86.62%.
Example 2
The difference from example 1 is that when compound 2 was synthesized from compound 1, a solution of isopropyl magnesium chloride lithium chloride in tetrahydrofuran (1.3mol/L, 43.7mL, 56.8mmol) was added to a solution of 2-bromo-3-fluoropyridine (10g, 56.8mmol) in anhydrous tetrahydrofuran (100mL), and the equivalent ratio of reactants was 1: 1; the reaction conditions are unchanged in the preparation process of synthesizing the compound 3 and the compound 4; the yield of the final product, 3-fluoro-2-isobutylpyridine, was 73.35%.
Example 3
The difference from example 1 is that when compound 3 was synthesized from compound 2, a reaction solution containing (3-fluoropyridin-2-yl) magnesium chloride (56.8mmol) was added dropwise to a vigorously stirred solution of isobutyraldehyde (4.1g, 56.8mmol) in anhydrous tetrahydrofuran (200mL) in a reactant equivalent ratio of 1: 1; other reaction conditions are unchanged in the preparation process of the compound 4; the yield of the final product, 3-fluoro-2-isobutylpyridine, was 60.59%.
Example 4
The difference from example 1 is that when compound 3 was synthesized from compound 2, (3-fluoropyridin-2-yl) magnesium chloride-containing reaction solution (56.8mmol) was added dropwise to a vigorously stirred solution of isobutyraldehyde (8.2g, 113.6mmol, 2.0eq) in anhydrous tetrahydrofuran (200mL), mixed well and stirred at room temperature for 12 hours; other reaction conditions are unchanged in the preparation process of the compound 4; the yield of the final product, 3-fluoro-2-isobutylpyridine, was 51.44%.
Example 5
The difference from example 1 is that when compound 3 was synthesized from compound 2, (3-fluoropyridin-2-yl) magnesium chloride-containing reaction solution (56.8mmol) was added dropwise to a vigorously stirred solution of isobutyraldehyde (8.2g, 113.6mmol, 2.0eq) in anhydrous tetrahydrofuran (200mL), mixed well and stirred at room temperature for 8 h; other reaction conditions are unchanged in the preparation process of the compound 4; the yield of the final product, 3-fluoro-2-isobutylpyridine, was 53.79%.
Example 2 differs from example 1 in that compound 2 was synthesized from compound 1 in a 1:2 equivalent ratio of compound 1 to isopropylmagnesium chloride lithium chloride tetrahydrofuran solution, and compound 3 was prepared from compound 2 in a higher yield; example 3 differs from example 1 in that compound 2 and isobutyraldehyde are different in equivalent ratio, 1:2, when compound 3 is synthesized from compound 2, and the yield of compound 3 is higher; examples 4 and 5 are different from example 1 in that the reaction stirring time is different when the compound 3 is synthesized from the compound 2, and the yield of the compound 3 is higher after the reaction time is 3 h;
examples 6 to 12 are different from example 1 in that the equivalent ratio of reactants for synthesizing compound 4 of compound 3, the temperature control of trifluoroacetic acid addition and the stirring reaction time are controlled, the reaction conditions of the preamble are not changed, and the specific reaction conditions are shown in table 1 below.
TABLE 1 reaction conditions and product yields for the preparation of Compound 4 from Compound 3
As shown in the above table, examples 6 and 7 are different from example 1 in that the yield of compound 4 is different due to the different reaction equivalent ratio when compound 4 is synthesized from compound 3, and the highest yield of compound 4 is 1:3:3 with trifluoroacetic acid and triethylsilane. Examples 8 and 9 differ from example 6 in that the reaction temperature is different when synthesizing compound 4 from compound 3, resulting in different yields of compound 4, with the highest yield of compound 4 at-40 ℃; the higher the highest temperature, the lower the yield, and when it was raised to 0 ℃, the total conversion was to 2-methyl-1-phenylpropylene as a hydroxyl elimination by-product. Therefore, the key to the reaction is temperature control.
Example 10, example 11, example 12 and example 6 differ in that the reaction time for synthesizing compound 4 from compound 3 is different, resulting in different yields of compound 4, with the highest yield of compound 4 being obtained for 3 h. Reacting for 1h, wherein the rest raw materials are not reacted completely; when the reaction time is prolonged to 5 hours or 12 hours, by-products may be increased, resulting in a decrease in yield.
Although the present invention has been described with reference to the preferred embodiments, it is not intended to be limited thereto. Those skilled in the art can make various changes and modifications without departing from the spirit and scope of the invention. Therefore, the protection scope of the present invention should be determined by the appended claims.
Claims (10)
1. A preparation method of 3-fluoro-2-isobutyl pyridine is characterized in that the synthetic route of the preparation method is as follows:
the preparation method comprises the steps of taking a compound 1 as a raw material, preparing a compound 2 by adopting a Grignard reagent exchange method, adding the compound 2 and isobutyraldehyde to obtain a compound 3, and reacting the compound 3 with triethylsilane to remove hydroxyl to obtain a final product compound 4.
2. The preparation method of 3-fluoro-2-isobutylpyridine as claimed in claim 1, wherein the step of reacting compound 1 with isopropylmagnesium chloride to obtain compound 2 comprises the steps of reacting compound 1 with isopropylmagnesium chloride in a first organic solvent at room temperature under the protection of inert gas while stirring until the reaction is completed to obtain a reaction solution containing compound 2; wherein, the first organic solvent is anhydrous tetrahydrofuran or diethyl ether.
3. The method for preparing 3-fluoro-2-isobutylpyridine as claimed in claim 1, wherein the step of reacting 2 with isobutyraldehyde to obtain 3 comprises mixing 2 with isobutyraldehyde in a second organic solvent at 0 ℃ under protection of inert gas, and reacting at room temperature for 2-12 h under stirring; after the reaction is finished, quenching the reaction solution by saturated ammonium chloride aqueous solution in ice bath, extracting and separating an organic phase, washing the organic phase by saturated saline, drying the organic phase and spin-drying to obtain a compound 3; wherein the second organic solvent is anhydrous tetrahydrofuran or diethyl ether.
4. The method of claim 3, wherein the compound 2 is slowly added to a vigorously stirred solution of isobutyraldehyde in anhydrous tetrahydrofuran or diethyl ether at 0 ℃ under inert gas to achieve uniform mixing.
5. The preparation method of 3-fluoro-2-isobutylpyridine as claimed in claim 1, wherein the specific process of reacting the compound 3 with triethylsilane to obtain the compound 4 comprises the steps of mixing the compound 3 with triethylsilane in a dichloromethane solvent, adding trifluoroacetic acid into the mixed solution under a temperature-controlled condition, and stirring the mixed reaction solution under the protection of inert gas for 1-3 h; after the reaction is finished, quenching the mixed reaction solution by saturated sodium bicarbonate aqueous solution, extracting and separating an organic phase, washing the organic phase by saturated saline, drying and purifying the organic phase to obtain a compound 4.
6. The method for preparing 3-fluoro-2-isobutylpyridine as claimed in claim 5, wherein the equivalent ratio of the compound 3, triethylsilane and trifluoroacetic acid as reactants is 1:2: 2-1: 5: 5.
7. The method for preparing 3-fluoro-2-isobutylpyridine according to claim 5, wherein the temperature control condition for adding the trifluoroacetic acid into the mixed solution is-40 ℃ to 0 ℃.
8. The process for preparing 3-fluoro-2-isobutylpyridine according to claim 5, wherein the temperature control condition for adding trifluoroacetic acid to the mixed solution is-40 ℃ to-25 ℃.
9. The method for preparing 3-fluoro-2-isobutylpyridine as claimed in claim 2, wherein the compound 1 and isopropylmagnesium chloride are stirred and reacted in the first organic solvent for 2 hours, and the equivalent ratio of the compound 1 to the isopropylmagnesium chloride as reactants is 1: 1-1: 2.
10. The method of claim 3, wherein the equivalent ratio of compound 2 to isobutyraldehyde as reactants is 1:1 to 1: 2.
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