CN113754655A - Synthesis method of pyrido-triazine formic acid - Google Patents
Synthesis method of pyrido-triazine formic acid Download PDFInfo
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Abstract
The invention discloses a synthesis method of pyrido-triazine formic acid, which comprises the following specific steps: (1) taking compound II 2-oxo diethyl malonate and compound III 2-hydrazine pyridine as raw materials, taking ethanol as a solvent, and carrying out condensation reaction to generate compound IV; (2) carrying out ring-closure reaction on the compound IV to generate a compound V; (3) and (3) carrying out hydrolysis reaction on the compound V to obtain a compound I. The synthesis method has the advantages of low raw material cost, convenient operation, high yield and suitability for industrial mass production, and high purity intermediates and products can be obtained without purification in each step of reaction.
Description
Technical Field
The invention relates to the field of organic synthesis, in particular to a synthesis method of pyrido-triazine formic acid.
Background
Fused heterocyclic compounds are important organic compounds, refer to compounds in which benzene rings and heterocyclic rings or heterocyclic rings and heterocyclic rings are fused together, and are important components in medicinal chemistry research. The fused heterocyclic compounds have various types and complex structures, and the most common compounds are quinoline, indole, purine and the like. Due to the structural complexity of fused heterocyclic compounds, the synthesis methods are different.
Relatively speaking, common fused heterocyclic compounds such as quinoline and indole have been studied, and various classical synthetic methods such as Skraup quinoline synthesis, Fischer indole synthesis, etc. have been proposed. For such a specific structure of pyridotriazine, a synthesis method is rarely reported.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides a synthesis method of pyrido-triazine formic acid. The synthesis method has the advantages of low raw material cost, convenient operation, high yield and suitability for industrial mass production, and high purity intermediates and products can be obtained without purification in each step of reaction.
The technical scheme adopted by the invention is as follows:
a synthesis method of pyrido triazine formic acid comprises the following steps
Carrying out the following steps:
the method comprises the following specific steps:
(1) taking compound II 2-oxo diethyl malonate and compound III 2-hydrazine pyridine as raw materials, taking ethanol as a solvent, and carrying out condensation reaction to generate compound IV;
(2) carrying out ring-closure reaction on the compound IV to generate a compound V;
(3) and (3) carrying out hydrolysis reaction on the compound V to obtain a compound I.
Preferably, in the step (1), the molar ratio of the diethyl 2-oxomalonate to the 2-hydrazinopyridine is 1: 0.7-1.
Further preferably, in the step (1), the molar ratio of the diethyl 2-oxopropanoate to the 2-hydrazinopyridine is 1: 0.8.
Preferably, in the step (1), the volume amount of the ethanol is 6 to 10 times, preferably 8 times that of the diethyl 2-oxomalonate.
In the step (1), the condensation reaction conditions are as follows: the reaction is carried out for 14 to 18 hours, preferably 16 hours at 78 ℃.
In the step (2), 1,2, 4-trichlorobenzene is adopted as a reaction solvent in the ring closure reaction, and the volume amount of the 1,2, 4-trichlorobenzene is 2-4 times, preferably 2 times that of the compound IV.
In the step (2), the ring-closure reaction conditions are as follows: the reaction is carried out for 24 to 72 hours at the temperature of between 20 and 220 ℃, and the reaction is preferably carried out for 48 hours at the temperature of 210 ℃.
In the step (3), the hydrolysis reaction adopts sodium hydroxide aqueous solution, and the molar concentration is 0.5 mol/L.
In the step (3), the molar ratio of the compound V sodium hydroxide is 1:2-3, preferably in a molar ratio of 1: 2.5.
in the step (3), the hydrolysis reaction conditions are as follows: reacting at 60-80 deg.C for 2-4 hr, preferably at 70 deg.C for 3 hr.
The beneficial technical effects of the invention are as follows:
the invention provides a feasible synthesis method, and on one hand, a carboxyl functional group carried in a molecular structure of a target compound is convenient to connect the fused heterocyclic segment with an active molecular parent nucleus, so that more potential compounds with pharmacological activity are created. The synthesis method has the advantages of low raw material cost, convenient operation, high yield and suitability for industrial mass production, and high purity intermediates and products can be obtained without purification in each step of reaction.
Drawings
FIG. 1 shows the NMR spectrum of Compound I obtained in example 1 of the present invention.
Detailed Description
The present invention will be described in detail with reference to the accompanying drawings and examples.
Example 1:
a synthesis method of pyrido triazine formic acid comprises the following specific steps:
(1): 24L of ethanol is added into a 50L reaction kettle, 3kg (17.2mol) of diethyl 2-oxomalonate and 1.5kg (13.8mol) of 2-hydrazinopyridine are added under stirring, the temperature is raised to 78 ℃, and the reaction is carried out for 16 h; cooling, concentrating the solvent to 1/3 volume, continuously cooling to below 10 deg.C, stirring for 1h, vacuum filtering, and oven drying the filter cake to obtain 3.15kg of compound IV.
(2): adding 4.5L of 1,2, 4-trichlorobenzene into a 10L reaction bottle, adding 2.25kg (8.48mol) of a compound IV under stirring, heating to 210 ℃ for reaction for 48h, cooling to 40 ℃, slowly adding 2.5L of n-heptane, continuing cooling to room temperature under stirring, carrying out suction filtration, and drying a filter cake to obtain 1.32kg of a compound V.
(3): adding 30L (15mol) of sodium hydroxide solution into a 50L reaction kettle, adding 1.315kg (6.0mol) of the product obtained in the previous step under stirring, heating to 70 ℃, stirring for reaction for 3 hours, cooling to room temperature, and acidifying with alkene hydrochloric acid to separate out a solid; and (4) carrying out suction filtration, washing a filter cake with water, methanol and acetone sequentially, and drying to obtain 1.18kg of light yellow solid, namely the compound I.
The nuclear magnetic resonance hydrogen spectrum of the obtained product is shown in figure 1, and as can be seen from figure 1, a single hydrogen peak with a chemical shift of 13.48ppm corresponds to carboxyl hydrogen, and four single hydrogen peaks with chemical shifts of 7.0ppm to 8.4ppm respectively correspond to four connected aromatic hydrogens on a fused heterocycle.
Example 2:
a synthesis method of pyrido triazine formic acid comprises the following specific steps:
(1): adding 3L of ethanol into a 5L reaction bottle, adding 300g (1.72mol) of diethyl 2-oxomalonate and 188g (1.72mol) of 2-hydrazinopyridine into the reaction bottle under stirring, heating to 78 ℃, and reacting for 14 h; cooling, concentrating the solvent to 1/3 volume, continuously cooling to below 10 ℃, keeping the temperature and stirring for 1h, performing suction filtration, and drying the filter cake to obtain 310g of compound IV.
(2): adding 900mL of 1,2, 4-trichlorobenzene into a 2L reaction bottle, adding 225g (0.85mol) of the Intermediate (IV) while stirring, heating to 200 ℃ for reaction for 72h, cooling to 40 ℃, slowly adding 250mL of n-heptane, continuing cooling to room temperature while stirring, carrying out suction filtration, and drying a filter cake to obtain 111g of a compound IV.
(3): adding 3.6L (1.8mol) of sodium hydroxide solution into a 10L reaction bottle, adding 132g (0.6mol) of the product obtained in the previous step under stirring, heating to 60 ℃, stirring for reaction for 4 hours, cooling to room temperature, and acidifying with alkene hydrochloric acid to separate out a solid; and (4) carrying out suction filtration, washing a filter cake with water, methanol and acetone sequentially, and drying to obtain 112g of light yellow solid, namely the compound I.
Example 3:
a synthesis method of pyrido triazine formic acid comprises the following specific steps:
(1): adding 1.8L of ethanol into a 5L reaction bottle, adding 300g (1.72mol) of diethyl 2-oxomalonate and 131g (1.20mol) of 2-hydrazinopyridine into the reaction bottle under stirring, heating to 78 ℃, reacting for 18h, cooling, concentrating the solvent to 1/3 volume, continuously cooling to below 10 ℃, keeping the temperature and stirring for 1 hour, performing suction filtration, and drying a filter cake to obtain 260g of a compound IV.
(2): 450mL of 1,2, 4-trichlorobenzene is added into a 2L reaction bottle, 225g (0.85mol) of compound IV is added under stirring, the temperature is raised to 220 ℃ for reaction for 24h, the temperature is reduced to 40 ℃, 250mL of n-heptane is slowly added, and the temperature is continuously reduced to room temperature under stirring. Suction filtration and drying of the filter cake to obtain 116g of compound V.
(3): adding 2.4L (1.2mol) of sodium hydroxide solution into a 10L reaction bottle, adding 132g (0.6mol) of the product obtained in the previous step under stirring, heating to 80 ℃, stirring for reaction for 2h, cooling to room temperature, and acidifying with alkene hydrochloric acid to separate out a solid; and (4) carrying out suction filtration, washing a filter cake with water, methanol and acetone sequentially, and drying to obtain 115g of light yellow solid, namely the compound I.
Claims (10)
1. The synthesis method of pyrido triazine formic acid is characterized by comprising the following steps
Carrying out the following steps:
the method comprises the following specific steps:
(1) taking compound II 2-oxo diethyl malonate and compound III 2-hydrazine pyridine as raw materials, taking ethanol as a solvent, and carrying out condensation reaction to generate compound IV;
(2) carrying out ring-closure reaction on the compound IV to generate a compound V;
(3) and (3) carrying out hydrolysis reaction on the compound V to obtain a compound I.
2. The synthesis method according to claim 1, wherein in the step (1), the molar ratio of the diethyl 2-oxomalonate to the 2-hydrazinopyridine is 1: 0.7-1.
3. The synthesis method according to claim 2, wherein in step (1), the molar ratio of diethyl 2-oxomalonate to 2-hydrazinopyridine is 1: 0.8.
4. The synthesis method according to claim 1, wherein in the step (1), the volume amount of ethanol is 6-10 times that of diethyl 2-oxomalonate.
5. The synthesis method according to claim 1, wherein in the step (1), the condensation reaction conditions are as follows: reacting for 14-18h at 78 ℃.
6. The synthesis method as claimed in claim 1, wherein in step (2), 1,2, 4-trichlorobenzene is used as the reaction solvent in the ring closure reaction, and the volume amount is 2-4 times of that of compound IV.
7. The synthesis method according to claim 1, wherein in the step (2), the ring-closure reaction conditions are as follows: reacting for 24-72h at 20-220 ℃.
8. The synthesis method of claim 1, wherein in the step (3), the hydrolysis reaction adopts an aqueous solution of sodium hydroxide with a molar concentration of 0.5 mol/L.
9. The synthesis method according to claim 1, wherein in the step (3), the molar ratio of the compound V to the sodium hydroxide is 1: 2-3.
10. The synthesis method according to claim 1, wherein in the step (3), the hydrolysis reaction conditions are as follows: reacting for 2-4h at 60-80 ℃.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| GB1568962A (en) * | 1975-10-31 | 1980-06-11 | Beecham Group Ltd | Reparation and compositions containing them (heterocyclic-carbonylamino)pencillins methods for their p |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| GB1568962A (en) * | 1975-10-31 | 1980-06-11 | Beecham Group Ltd | Reparation and compositions containing them (heterocyclic-carbonylamino)pencillins methods for their p |
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