CN118084776A - Synthesis method of substituted pyridine compound - Google Patents

Synthesis method of substituted pyridine compound Download PDF

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CN118084776A
CN118084776A CN202410209242.5A CN202410209242A CN118084776A CN 118084776 A CN118084776 A CN 118084776A CN 202410209242 A CN202410209242 A CN 202410209242A CN 118084776 A CN118084776 A CN 118084776A
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compound
substituted pyridine
reaction
cyano
methoxy
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楼志腾
郝胜先
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Shandong Laifu Technology Development Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/84—Nitriles
    • C07D213/85—Nitriles in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/69—Two or more oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/803—Processes of preparation

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyridine Compounds (AREA)

Abstract

The invention relates to the technical field of synthesis of substituted pyridine compounds, and discloses a synthesis method of a substituted pyridine compound, which comprises the following steps of S1, preparing an intermediate compound 3-cyano-4-methoxy-5-methylpyrrolidone; s2, synthesizing a substituted pyridine compound by taking an intermediate compound as an intermediate; compared with the prior art, (1) the invention synthesizes the substituted pyridine compound through the intermediate compound 3-cyano-4-methoxy-5 methyl pyridone, the raw materials used for preparing the intermediate compound of the invention are cheap and easy to obtain, the temperature involved in the reaction process is lower, the reaction is safer, the high-pressure reaction condition is avoided, and the operation is easy; (2) When the intermediate compound prepared by the invention is used for producing halogenated pyridone, aminopyridone, cyano pyridone, carboxylic pyridone and nitropyridone, the process is shortened, the yield is higher than 85%, and the invention is favorable for industrially preparing important medical and pesticide intermediates.

Description

Synthesis method of substituted pyridine compound
Technical Field
The invention relates to the technical field of synthesis of substituted pyridine compounds, in particular to a synthesis method of substituted pyridine compounds.
Background
Pyridine compounds are very important six-membered ring heterocycles, and are widely applied to the fields of organic ligands, photoelectric materials, medicines, surfactants, polymers and the like, and a plurality of natural products contain the structure. In recent years, the research and development of pyridine compounds, especially fluorine-containing and chlorine-containing heterocyclic compounds, have attracted great attention at home and abroad. Among them, 3-cyano-4-methoxy-5-methylpyrrolidone (also known as 2-hydroxy-3-cyano-4-methoxy-5-methylpyridine) is an important intermediate, and halogenated pyridone, aminopyridone, cyanopyridone, pyridone carboxylate and nitropyridone can be synthesized.
However, the synthesis of 3-cyano-4 methoxy-5-methylpyrrolidone is difficult due to steric hindrance of the substituents.
Disclosure of Invention
In order to conveniently prepare halogenated pyridone, aminopyridone, cyano pyridone, carboxylic pyridone and nitropyridone, the invention provides a synthetic method of substituted pyridine compounds, which adopts the following technical scheme:
a synthetic method of substituted pyridine compounds comprises the following steps:
s1, preparing an intermediate compound 3-cyano-4-methoxy-5-methylpyrrolidone;
the structure of the intermediate compound is as follows:
s2, synthesizing a substituted pyridine compound by taking an intermediate compound as an intermediate;
The structure of the substituted pyridine compound is as follows:
Wherein R1 comprises H and methyl;
R2 comprises H, OH, NH 2, halogen, methoxy;
R3 comprises H, NO 2、NH2 and carboxyl;
r4 comprises OH and halogen.
Preferably, in the step S1, the preparation of the intermediate compound includes the following steps:
1) Subjecting a compound I (malononitrile) and a compound II (trimethyl orthopropionate) to elimination reaction to obtain a compound III; the reaction mechanism of this step is: in malononitrile, since cyano is an electron withdrawing group, the electron on the α -carbon in malononitrile is attracted to the cyano side, the α -carbon is slightly electropositive, whereas in trimethyl orthopropionate, the α -carbon is linked to three methoxy groups, the oxygen atom in the methoxy group has two pairs of lone pairs of electrons, which makes the α -carbon in trimethyl orthopropionate slightly electronegative, and the α -hydrogen in malononitrile and methoxy in trimethyl orthopropionate are easily removed under specific reaction conditions such as heating with concentrated sulfuric acid, and the reaction yields compound iii and methanol.
2) The compound III and the compound IV (N, N-dimethylformamide dimethyl acetal) undergo elimination reaction to obtain a compound V; the reaction mechanism of this step is: similar to the reaction mechanism of 1), the alpha-carbon in the compound III is slightly electropositive under the electron withdrawing effect of cyano, the alpha-carbon of the compound IV is connected with two methoxy groups and N-methyl to be slightly electronegative, and under specific reaction conditions, such as heating by concentrated sulfuric acid, the alpha-hydrogen in the compound III and the methoxy group in the compound IV are easy to be removed, and the compound V and methanol are generated by the reaction.
3) The compound V is subjected to an oxidative condensation reaction to obtain an intermediate compound; the reaction mechanism of this step is: n-demethylation and oxidation of cyano groups to carboxyl groups followed by dehydration condensation to intermediate compounds.
The path is as follows:
Preferably, the structure of the substituted pyridine compound synthesized by S2 is as follows:
Preferably, the structure of the substituted pyridine compound synthesized by S2 is as follows:
Wherein R1 comprises H and methyl;
r2 comprises OH, NH 2 and halogen;
R3 comprises H, NO 2、NH2;
r4 comprises OH and halogen.
Preferably, the step S2 includes the following steps:
1) The intermediate compound 3-cyano-4-methoxy-5-methylpyrrolidone is used as an intermediate to synthesize 2-hydroxy-4-hydroxy-5-methylpyridine, and the structure is as follows:
2) And reacting the 2-hydroxy-4-hydroxy-5-methylpyridine to obtain a substituted pyridine compound.
In summary, compared with the prior art, the invention has the following beneficial technical effects:
(1) According to the invention, the intermediate compound 3-cyano-4-methoxy-5-methyl pyridone is used for synthesizing the substituted pyridine compound, the raw materials used for preparing the intermediate compound are cheap and easy to obtain, the temperature involved in the reaction process is low, the reaction is safer, high-pressure reaction conditions are avoided, and the operation is easy;
(2) When the intermediate compound prepared by the invention is used for producing halogenated pyridone, aminopyridone, cyano pyridone, carboxylic pyridone and nitropyridone, the process is shortened, the yield is higher than 85%, and the invention is favorable for industrially preparing important medical and pesticide intermediates.
Detailed Description
The present invention will be described in detail with reference to specific examples.
A synthetic method of substituted pyridine compounds comprises the following steps:
s1, preparing an intermediate compound 3-cyano-4-methoxy-5-methylpyrrolidone;
the structure of the intermediate compound is as follows:
s2, synthesizing a substituted pyridine compound by taking an intermediate compound as an intermediate;
The structure of the substituted pyridine compound is as follows:
Wherein R1 comprises H and methyl;
R2 comprises H, OH, NH 2, halogen, methoxy;
R3 comprises H, NO 2、NH2 and carboxyl;
r4 comprises OH and halogen.
Further, in the step S1, the preparation of the intermediate compound includes the following steps:
1) Subjecting a compound I (malononitrile) and a compound II (trimethyl orthopropionate) to elimination reaction to obtain a compound III; the reaction mechanism of this step is: in malononitrile, since cyano is an electron withdrawing group, the electron on the α -carbon in malononitrile is attracted to the cyano side, the α -carbon is slightly electropositive, whereas in trimethyl orthopropionate, the α -carbon is linked to three methoxy groups, the oxygen atom in the methoxy group has two pairs of lone pairs of electrons, which makes the α -carbon in trimethyl orthopropionate slightly electronegative, and the α -hydrogen in malononitrile and methoxy in trimethyl orthopropionate are easily removed under specific reaction conditions such as heating with concentrated sulfuric acid, and the reaction yields compound iii and methanol.
2) The compound III and the compound IV (N, N-dimethylformamide dimethyl acetal) undergo elimination reaction to obtain a compound V; the reaction mechanism of this step is: similar to the reaction mechanism of 1), the alpha-carbon in the compound III is slightly electropositive under the electron withdrawing effect of cyano, the alpha-carbon of the compound IV is connected with two methoxy groups and N-methyl to be slightly electronegative, and under specific reaction conditions, such as heating by concentrated sulfuric acid, the alpha-hydrogen in the compound III and the methoxy group in the compound IV are easy to be removed, and the compound V and methanol are generated by the reaction.
3) The compound V is subjected to an oxidative condensation reaction to obtain an intermediate compound; the reaction mechanism of this step is: n-demethylation and oxidation of cyano groups to carboxyl groups followed by dehydration condensation to intermediate compounds.
The path is as follows:
further, the structure of the substituted pyridine compound synthesized by S2 is as follows:
This step oxidizes cyano groups to carboxyl groups, either directly under acidic conditions or by re-acidification under basic conditions.
Further, the structure of the substituted pyridine compound synthesized by S2 is as follows:
Wherein R1 comprises H and methyl;
r2 comprises OH, NH 2 and halogen;
R3 comprises H, NO 2、NH2;
r4 comprises OH and halogen.
Further, the step S2 includes the following steps:
1) The intermediate compound is used as an intermediate to synthesize 2-hydroxy-4-hydroxy-5-methylpyridine, and the structure is as follows:
2) And reacting the 2-hydroxy-4-hydroxy-5-methylpyridine to obtain a substituted pyridine compound.
Example 1
S1, preparing an intermediate compound 3-cyano-4-methoxy-5-methylpyrrolidone;
1) 35mL of concentrated sulfuric acid is weighed and placed in a 50mL reaction bottle, 0.2mol of compound I and 0.15mol of compound II are weighed and added into the reaction bottle, a stirring magnet is added, the reaction is sealed, the reaction is carried out for 2 hours at 90 ℃, and after the reaction is finished, the compound III (0.142 mol) is obtained through column chromatography separation;
2) Placing the compound III obtained in the step 1) into a 50mL reaction bottle filled with 55mL concentrated sulfuric acid, then adding 0.15mol of compound IV, adding a stirring magnet, sealing, reacting for 2 hours at 100 ℃, and separating by column chromatography after the reaction is finished to obtain a compound V (0.14 mol);
3) The compound V obtained in 2) was placed in a 25mL reaction flask, then 0.1mol of 5-bromo-1, 3-phthalonitrile, 0.02mol of CzIPN catalyst, 0.1mol of nickel chloride hexahydrate, 0.06mol of 4,4 '-di-tert-butyl-2, 2' -bipyridine, 0.14mol of sodium pivalate and 20mL of water were added to the flask, the flask was sealed after adding stirring magnet, and the reaction was carried out under light of 450nm for 15 hours, and the intermediate compound was obtained by column chromatography separation, and the yield was 88.9%.
S2, synthesizing a substituted pyridine compound with the following structure by taking an intermediate compound as an intermediate;
The specific operation is as follows: the intermediate compound obtained in 3) is mixed with 30 equivalents of 60% sulfuric acid, reacted at 110℃for 3.5 hours, cooled to room temperature, and the reaction mixture is poured into methanol, whereby methyl iminoate is formed by hydrogen chloride gas. And separating by column chromatography to obtain the substituted pyridine compound shown in the formula 1-1. The final yield was 87.1%.
Example 2
The same procedure as in most of example 1 was followed, except that the following procedure was added to synthesize substituted pyridines of formula 1-2 after synthesizing formula 1-1.
The specific operations added in this embodiment are:
The material of formula 1-1 obtained in example 1 was dissolved in 50mL of toluene, 25mL of diphenyl azide phosphate (DPPA) was added thereto, and the mixture was stirred at room temperature for one hour, and the mixture was heated under reflux overnight to obtain a substituted pyridine compound of formula 1-2, and the yield was found to be 86.3%.
Example 3
S1, preparing an intermediate compound 3-cyano-4-methoxy-5-methylpyrrolidone;
1) 48mL of concentrated sulfuric acid is weighed and placed in a 100mL reaction bottle, 0.35mol of compound I and 0.2mol of compound II are weighed and added into the reaction bottle, a stirring magnet is added, the reaction is sealed, the reaction is carried out for 3 hours at 75 ℃, and after the reaction is finished, the compound III (0.175 mol) is obtained through column chromatography separation;
2) Placing the compound III obtained in the step 1) into a 100mL reaction bottle filled with 70mL of concentrated sulfuric acid, adding 0.2mol of compound IV, adding a stirring magnet, sealing, reacting for 3 hours at 110 ℃, and separating by column chromatography after the reaction is finished to obtain a compound V (0.168 mol);
3) The compound V obtained in 2) was placed in a 50mL reaction flask, then 0.15mol of 5-bromo-1, 3-phthalonitrile, 0.03mol of CzIPN catalyst, 0.15mol of nickel chloride hexahydrate, 0.1mol of 4,4 '-di-tert-butyl-2, 2' -bipyridine, 0.2mol of sodium pivalate and 35mL of water were added to the flask, the flask was sealed after adding stirring magnet, and the reaction was carried out under light of 450nm for 20 hours, and the intermediate compound was obtained by column chromatography separation, and the yield was measured to be 87.8%.
S2, synthesizing a substituted pyridine compound with a structure shown in a formula 2-1 by taking an intermediate compound as an intermediate;
the specific operation is as follows: the intermediate compound obtained in S1 was dissolved in a solution of anhydrous aluminum chloride (1.0 mol) in methylene chloride (75 mL), mixed and heated to reflux, and then the reaction flask was opened with a mask in a fume hood (hydrochloric acid gas was generated by the reaction). The solution was washed twice with water and then dried over magnesium sulfate. Finally, the methylene chloride is removed by rotary evaporation. In this step, the methoxy oxygen coordinates with aluminum to provide oxygen with a partially positive nucleus, which increases the electrophilicity, or reactivity, of the methyl group. At the same time, the nucleophilicity of chloride ions of aluminum trichloride is increased, the aluminum trichloride is combined with methyl to generate methyl chloride, and acid hydrolysis reaction is carried out after the aluminum trichloride is washed with water, so that methoxy is changed into hydroxy. The anhydrous aluminum chloride is cheaper and is convenient to operate.
Then argon protection is carried out on a round bottom flask, the constant temperature is carried out, the temperature is 0 ℃, a dispersion of sodium in toluene is added, then 12-crown 4 is added, stirring is carried out for 10min, the substance obtained after rotary evaporation and tetrahydrofuran are prepared into a solution, then the solution is added into a reactor, stirring is carried out for 20min, a saturated sodium bicarbonate aqueous solution is added into the reactor, stirring is continued for one hour, quenching reaction is carried out, diethyl ether and a saturated sodium chloride aqueous solution are added for extraction, and after an organic phase is dried and concentrated, column chromatography purification is carried out, thus obtaining the substituted pyridine compound with the structure shown in the target formula 2-1.
The total reaction yield was 88.0%.
Example 4
The same procedure as in most of example 3 was followed, except that this example was followed by additional operations to synthesize substituted pyridines of formula 2-2 after the synthesis of the compounds of formula 2-1.
The specific operation added is as follows:
The compound of formula 2-1 obtained by the procedure of example 3 was added to a potassium permanganate solution (100 mL), a reaction of oxidation of methyl groups at the 2-position to carboxyl groups was performed, then a liquid separation and extraction washing operation was performed, the used extractant was methylene chloride, the methylene chloride was subsequently removed by rotary evaporation, then the obtained organic matter was mixed with nitric acid, heated to 65 ℃ and reacted for 2.5 hours, and the target compound of formula 2-2 was collected by gas chromatography. The reaction yield was 87.5%.
Example 5
The same procedure as in most of example 4 was followed, except that this example was followed by additional operations to synthesize substituted pyridines of formula 2-3.
The specific operation added is as follows:
The compound of formula 2-2 obtained by the procedure of example 4 was mixed with hydrochloric acid to undergo a reaction in which the hydroxyl group was replaced with a chlorine atom, and the target compound of formula 2-3 was collected by gas chromatography, with a reaction yield of 89.1%.
Example 6
The same procedure as in most of example 3 was followed, except that this example was followed by additional operations to synthesize substituted pyridines of formula 2-4 after the synthesis of the compound of formula 2-1.
The specific operation added is as follows:
The compound of formula 2-1 obtained by the procedure of example 3 was mixed with hydrochloric acid to cause a reaction in which the hydroxyl group was replaced with a chlorine atom, and the target compound of formula 2-4 was collected by gas chromatography, whereby the reaction yield was 88.2%.
Example 7
The same procedure as in most of example 3 was followed, except that this example was followed by additional operations to synthesize substituted pyridines of formula 2-5 after the synthesis of the compound of formula 2-1.
The specific operation added is as follows:
the compound of formula 2-1 obtained by the procedure of example 3 was mixed with hydrogen bromide to effect a reaction in which the hydroxyl group was replaced with a bromine atom, and the resultant was collected by gas chromatography to obtain the objective compound of formula 2-5 in a reaction yield of 85.6%.
Example 8
The same procedure as in most of example 7 was followed, except that this example was followed by additional operations to synthesize substituted pyridines of formulas 2-6 after the synthesis of the compounds of formulas 2-5.
The specific operation added is as follows:
The compound of formula 2-5 obtained according to the procedure of example 7 was mixed with a mixture of concentrated nitric acid and concentrated sulfuric acid to effect substitution of the bromine atom with the nitro group, which was only 3-position because of the ortho-para substituent, then reduced with Pd/C, methanol was used as the solvent, 4-fold equivalent of ammonium formate was added, refluxed, finally filtered to dryness, and collected by extraction to give the objective compound of formula 2-5, the reaction yield was 90.3%.
Example 9
The same procedure as in most of example 3 was followed, except that this example was followed by additional operations to synthesize substituted pyridines of formulas 2-7 after the synthesis of the compounds of formula 2-1.
The specific operation added is as follows:
The compound of formula 2-1 obtained by the procedure of example 3 was mixed with p-methylaniline (1 equivalent) solvent trimethylbenzene (100 mL), and reacted at 130℃under reflux for 20 hours, with nitrogen protection. The target compounds of the formulae 2 to 7 were collected by gas chromatography and gave a reaction yield of 87.6%.
Example 10
The same procedure as in most of example 9 was followed, except that this example was followed by additional operations to synthesize substituted pyridines of formulas 2-8.
The specific operation added is as follows:
The compound of formula 2-7 obtained by the procedure of example 9 was mixed with methanol as a solvent and subjected to rapid hydrogenolysis (hydrogenolysis under a hydrogen pressure of 101 kPa) at room temperature using Pd (OH) 2/C as a catalyst for 8 hours, with a reaction yield of 89.4%.
The foregoing is a preferred embodiment of the present invention, and the objects, technical solutions and advantages of the present invention are further described in detail, but not limited to the scope of the present invention, and all equivalent changes according to the structure, shape and principle of the present invention are included in the scope of the present invention.

Claims (5)

1. A synthesis method of substituted pyridine compounds is characterized by comprising the following steps,
S1, preparing an intermediate compound 3-cyano-4-methoxy-5-methylpyrrolidone;
the structure of the intermediate compound is as follows:
s2, synthesizing a substituted pyridine compound by taking an intermediate compound as an intermediate;
The structure of the substituted pyridine compound is as follows:
Wherein R1 comprises H and methyl;
R2 comprises H, OH, NH 2, halogen, methoxy;
R3 comprises H, NO 2、NH2 and carboxyl;
r4 comprises OH and halogen.
2. The method for synthesizing a substituted pyridine compound according to claim 1, wherein,
In the step S1, the preparation of the intermediate compound comprises the following processes:
1) Subjecting a compound I (malononitrile) and a compound II (trimethyl orthopropionate) to elimination reaction to obtain a compound III;
2) The compound III and the compound IV (N, N-dimethylformamide dimethyl acetal) undergo elimination reaction to obtain a compound V;
3) The compound V is subjected to oxidative condensation reaction to obtain an intermediate compound.
The path is as follows:
3. The method for synthesizing a substituted pyridine compound according to claim 1 or 2, wherein the S2 synthesized substituted pyridine compound has the structure:
4. the method for synthesizing a substituted pyridine compound according to claim 1 or 2, wherein the S2 synthesized substituted pyridine compound has the structure:
Wherein R1 comprises H and methyl;
r2 comprises OH, NH 2 and halogen;
R3 comprises H, NO 2、NH2;
r4 comprises OH and halogen.
5. The method for synthesizing a substituted pyridine compound according to claim 4, wherein the step S2 comprises the following steps:
1) The intermediate compound is used as an intermediate to synthesize 2-hydroxy-4-hydroxy-5-methylpyridine, and the structure is as follows:
2) And reacting the 2-hydroxy-4-hydroxy-5-methylpyridine to obtain a substituted pyridine compound.
CN202410209242.5A 2024-02-26 2024-02-26 Synthesis method of substituted pyridine compound Pending CN118084776A (en)

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