CN110746367B - Synthesis method of 1,2, 4-triazole-3-methyl carboxylate - Google Patents
Synthesis method of 1,2, 4-triazole-3-methyl carboxylate Download PDFInfo
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- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles 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
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Abstract
The invention provides a synthesis method of 1,2, 4-triazole-3-methyl carboxylate, and particularly relates to the technical field of medicines, 1,2, 4-triazole, potassium carbonate or sodium carbonate, benzyl bromide or benzyl chloride are heated in a DMF solvent for 8-10 h to react, water is added for quenching reaction, MTBE is extracted to obtain an organic phase, 4-benzyl-1, 2, 4-triazole solid obtained by concentrating the organic phase is dissolved in THF, trichloroacetyl chloride is added and cooled for reaction, triethylamine or N, N-diisopropylethylamine is dropwise added, methanol is slowly added into a reaction system, and the organic phase is obtained by reaction; concentrating an organic phase to obtain 4-benzyl-1, 2, 4-triazole-3-methyl carboxylate, carrying out hydrogenation reaction at 0.5Mpa for 8-10 h under the condition of a catalyst Pd/C, filtering, concentrating a solvent, and recrystallizing methanol to obtain the product 1,2, 4-triazole-3-methyl carboxylate. The invention has the advantages of simple preparation method, less waste water generated in the amplification production and the like.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a synthesis method of 1,2, 4-triazole-3-methyl carboxylate.
Background
Methyl 1,2, 4-triazole-3-carboxylate (CAS: 4928-88-5) is an important intermediate of antiviral drug ribavirin (ribavirin). Ribavirin can inhibit ribose synthesis, interfere DNA synthesis and prevent virus replication, is clinically applied to early treatment of viral hepatitis, and can treat simple keratitis, epidemic conjunctivitis and influenza.
Currently, 1,2, 4-triazole-3-methyl carboxylate is industrially prepared by mainly reacting aminoguanidine with oxalic acid in water to obtain 1,2, 4-triazole-5-amino-3-carboxylic acid, and performing denitrification with sodium nitrite and esterification with concentrated sulfuric acid to obtain 1,2, 4-triazole-3-methyl carboxylate. The chemical formula is as follows:
the process can generate a large amount of wastewater which is difficult to treat industrially in each step in industrial production, and under the current environment-friendly situation, the process is eliminated, and a new preparation process of the methyl 1,2, 4-triazole-3-carboxylate needs to be developed.
Disclosure of Invention
Aiming at the defects, the invention aims to provide a synthesis method of 1,2, 4-triazole-3-methyl carboxylate, solves the problems of a large amount of wastewater generated in the reaction of the 1,2, 4-triazole-3-methyl carboxylate and the like, and aims to provide a novel preparation method of the 1,2, 4-triazole-3-methyl carboxylate, and has the advantages of simple preparation method, less wastewater generated in amplification production and the like; the invention is a brand-new preparation method of the 1,2, 4-triazole-3-methyl carboxylate, and provides a new synthesis idea for similar compounds.
The invention provides the following technical scheme:
a method for synthesizing 1,2, 4-triazole-3-methyl carboxylate comprises the following steps:
the specific reaction steps are as follows:
heating and reacting S1, 1,2, 4-triazole, potassium carbonate or sodium carbonate, benzyl bromide or benzyl chloride in a DMF (dimethyl formamide) solvent for 8-10 h, adding water for quenching reaction, extracting MTBE (methyl tert-butyl ether) to obtain an organic phase, and concentrating the organic phase to obtain 4-benzyl-1, 2, 4-triazole solid;
s2, dissolving 4-benzyl-1, 2, 4-triazole in THF, adding trichloroacetyl chloride, cooling to react to 0-5 ℃, dropwise adding triethylamine or N, N-diisopropylethylamine, reacting for 2h at the temperature, slowly adding methanol to the reaction system, reacting for 2h at the temperature of 0-5 ℃, adding water and MTBE, collecting an organic phase,
s3, concentrating an organic phase to obtain 4-benzyl-1, 2, 4-triazole-3-methyl carboxylate, carrying out 0.5Mpa hydrogenation reaction on the 4-benzyl-1, 2, 4-triazole-3-methyl carboxylate under the conditions of a solvent methanol and a catalyst Pd/C for 8-10 h, filtering, concentrating the solvent, and recrystallizing the methanol to obtain the product 1,2, 4-triazole-3-methyl carboxylate.
Preferably, in the step S1, the mass ratio of the solvent to the 1,2, 4-triazole is 8: 1-10: 1; the molar ratio of benzyl bromide or benzyl chloride to 1,2, 4-triazole is 1.1: 1-1.2: 1; the molar ratio of the potassium carbonate or the potassium carbonate to the 1,2, 4-triazole is 2.2: 1-2.5: 1;
preferably, in the step S2, the raw material is trichloroacetyl chloride, and the molar ratio of the trichloroacetyl chloride to the solid 4-benzyl-1, 2, 4-triazole is 1.1:1 to 1.2: 1; the molar ratio of the methanol to the 4-benzyl-1, 2, 4-triazole solid is 2: 1-2.5: 1.
Preferably, in the step S2, the solvent is tetrahydrofuran, and the mass ratio of the tetrahydrofuran to the 4-benzyl-1, 2, 4-triazole solid is 5: 1-6: 1; the molar ratio of triethylamine or N, N-diisopropylethylamine to 4-benzyl-1, 2, 4-triazole solid is 2: 1-2.5: 1.
Preferably, in the step S3, the mass ratio of the methanol to the 4-benzyl-1, 2, 4-triazole-3-carboxylic acid methyl ester is 8: 1-10: 1; the catalyst is 10% Pd/C, and the mass ratio of the 10% Pd/C to methanol to 4-benzyl-1, 2, 4-triazole-3-methyl carboxylate is 0.005: 1-0.01: 1.
The invention has the beneficial effects that:
the invention solves the problems of a large amount of wastewater generated in the reaction of the existing 1,2, 4-triazole-3-methyl carboxylate, and the like, provides a novel preparation method of the 1,2, 4-triazole-3-methyl carboxylate, and has the advantages of simple preparation method, less wastewater generated in large-scale production, and the like; the invention is a brand-new preparation method of the 1,2, 4-triazole-3-methyl carboxylate, and provides a new synthesis idea for similar compounds.
Detailed Description
Example 1
S1, adding 1,2, 4-triazole (0.5Kg, 7.24mol), potassium carbonate (1.0Kg, 16.67mol), DMF3Kg and bromobenzyl (1.4Kg, 8.19mol) into a 10L four-neck flask with a mechanical stirring, a thermometer and a condenser, heating to 80 ℃ for reaction for 10h, cooling to room temperature, pouring the reaction solution into 6Kg of ice water, extracting 3L +2L of MTBE, combining organic phases, decompressing and spin-drying to obtain 0.8Kg of intermediate 4-benzyl-1, 2, 4-triazole, with the yield of 70%. HNMR (solvent CDCl 3; internal standard TMS): δ 5.24(s,2H), δ 7.16-7.18(m,2H), δ 7.24-7.19(m,3H), δ 7.88(s,1H), δ 8.01(s,1H)
S2, adding 4-benzyl-1, 2, 4-triazole (0.8g, 5.03mol), THF4.5Kg, trichloroacetyl chloride (1.05Kg, 5.78mol) into a 5L four-neck flask with mechanical stirring, thermometer and nitrogen protection, cooling the reaction system to 0-5 ℃, slowly dropwise adding triethylamine (1.17Kg, 11.57mol), reacting at 0-5 ℃ for 2h after dropwise adding, dropwise adding methanol (0.5Kg, 15.63mol) at the temperature, reacting at 0-5 ℃ for 2h after dropwise adding, pouring the reaction liquid into 5Kg of ice water, extracting with 3L +2L of MTBE, combining organic phases, and performing rotary drying under reduced pressure to obtain 0.85Kg of intermediate methyl 4-benzyl-1, 2, 4-triazole-3-carboxylate, wherein the yield is 78%. HNMR (solvent CDCl 3; internal standard TMS): δ 4.00(s,3H), δ 5.82(s,2H), δ 7.31-7.36(m,5H), δ 8.02(s, 1H);
s3, adding 4-benzyl-1, 2, 4-triazole-3-methyl carboxylate (0.85Kg, 3.91mol), methanol 8Kg, 10% Pd/C7g into a 15L pressure hydrogenation reaction kettle, replacing the reaction kettle with nitrogen for 3 times, wherein the hydrogenation pressure of a reaction system is 0.5Mpa, the reaction temperature is 35 ℃, the reaction condition is 8 hours, the reaction system has no obvious pressure change, hydrogen in reaction fluorine is removed, the nitrogen is replaced for 3 times, Pd/C is filtered out, the methanol is washed, the obtained filtrate is decompressed, dried in a spinning mode and crystallized by 200mL of methanol to obtain 0.42Kg of 1,2, 4-triazole-3-methyl carboxylate, and the yield is 84%. HNMR (solvent DMSO-d 6; internal standard TMS): δ 3.85(s,3H), δ 8.67(s,1H), δ 13.94(s, 1H); the sample map is consistent with the standard map in comparison;
example 2
S1, adding 1,2, 4-triazole (0.6Kg, 8.69mol), potassium carbonate (1.1Kg, 18.34mol), DMF3Kg and bromobenzyl (1.4Kg, 8.78mol) into a 10L four-neck flask with a mechanical stirring, a thermometer and a condenser, heating to 75 ℃ for reaction for 9 hours, cooling to room temperature, pouring the reaction liquid into 5Kg of ice water, extracting with 3L +2L of MTBE, combining organic phases, and performing rotary drying under reduced pressure to obtain 0.89 Kg of intermediate 4-benzyl-1, 2, 4-triazole with yield of 73%. HNMR (solvent CDCl 3; internal standard TMS): δ 5.24(s,2H), δ 7.16-7.18(m,2H), δ 7.24-7.19(m,3H), δ 7.88(s,1H), δ 8.01(s,1H)
S2, adding 4-benzyl-1, 2, 4-triazole (0.85g, 5.34mol), THF4.55Kg, trichloroacetyl chloride (1.1Kg, 6.06mol) into a 5L four-neck flask with mechanical stirring, thermometer and nitrogen protection, cooling the reaction system to 0-5 ℃, slowly dropwise adding triethylamine (1.2Kg, 11.87mol), reacting at 0-5 ℃ for 2 hours after dropwise adding, dropwise adding methanol (0.55Kg, 17.19mol) at the temperature, reacting at 0-5 ℃ for 2 hours after dropwise adding, pouring the reaction liquid into 5Kg of ice water, extracting with 3L +2L of MTBE, combining organic phases, and performing rotary drying under reduced pressure to obtain an intermediate methyl 4-benzyl-1, 2, 4-triazole-3-carboxylate of 0.88Kg, wherein the yield is 79%. HNMR (solvent CDCl 3; internal standard TMS): δ 4.00(s,3H), δ 5.82(s,2H), δ 7.31-7.36(m,5H), δ 8.02(s, 1H);
s3, adding 4-benzyl-1, 2, 4-triazole-3-methyl carboxylate (0.9Kg, 4.14mol), methanol 8.2Kg, 10% Pd/C7g into a 15L pressure hydrogenation reaction kettle, replacing the reaction kettle with nitrogen for 3 times, wherein the hydrogenation pressure of a reaction system is 0.5Mpa, the reaction temperature is 35 ℃, the reaction condition is 8 hours, the reaction system has no obvious pressure change, hydrogen in reaction fluorine is removed, nitrogen is replaced for 3 times, Pd/C is filtered out, methanol is washed, the obtained filtrate is decompressed, dried and crystallized by 200mL of methanol to obtain 0.46Kg of 1,2, 4-triazole-3-methyl carboxylate, and the yield is 86%. HNMR (solvent DMSO-d 6; internal standard TMS): δ 3.85(s,3H), δ 8.67(s,1H), δ 13.94(s, 1H); the sample map is consistent with the standard map in comparison;
the invention solves the problems of a large amount of wastewater generated in the reaction of the existing 1,2, 4-triazole-3-methyl carboxylate, and the like, provides a novel preparation method of the 1,2, 4-triazole-3-methyl carboxylate, and has the advantages of simple preparation method, less wastewater generated in large-scale production, and the like; the invention is a brand-new preparation method of the 1,2, 4-triazole-3-methyl carboxylate, and provides a new synthesis idea for similar compounds.
Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art will understand that various changes, modifications and substitutions can be made without departing from the spirit and scope of the invention as defined by the appended claims. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (5)
1. A method for synthesizing 1,2, 4-triazole-3-methyl carboxylate is characterized in that,
specifically, the reaction equation is as follows:
the specific reaction steps are as follows:
heating and reacting S1, 1,2, 4-triazole, potassium carbonate or sodium carbonate, benzyl bromide or benzyl chloride in a DMF (dimethyl formamide) solvent for 8-10 h, adding water for quenching reaction, extracting MTBE (methyl tert-butyl ether) to obtain an organic phase, and concentrating the organic phase to obtain 4-benzyl-1, 2, 4-triazole solid;
s2, dissolving 4-benzyl-1, 2, 4-triazole in THF, adding trichloroacetyl chloride, cooling to react to 0-5 ℃, dropwise adding triethylamine or N, N-diisopropylethylamine, reacting for 2h at the temperature, slowly adding methanol to the reaction system, reacting for 2h at the temperature of 0-5 ℃, adding water and MTBE, collecting an organic phase,
s3, concentrating an organic phase to obtain 4-benzyl-1, 2, 4-triazole-3-methyl carboxylate, carrying out 0.5Mpa hydrogenation reaction on the 4-benzyl-1, 2, 4-triazole-3-methyl carboxylate under the conditions of a solvent methanol and a catalyst Pd/C for 8-10 h, filtering, concentrating the solvent, and recrystallizing the methanol to obtain the product 1,2, 4-triazole-3-methyl carboxylate.
2. The method for synthesizing methyl 1,2, 4-triazole-3-carboxylate according to claim 1, which is characterized by comprising the following steps: in the step S1, the mass ratio of the solvent to the 1,2, 4-triazole is 8: 1-10: 1; the molar ratio of benzyl bromide or benzyl chloride to 1,2, 4-triazole is 1.1: 1-1.2: 1; the molar ratio of the potassium carbonate or the sodium carbonate to the 1,2, 4-triazole is 2.2: 1-2.5: 1.
3. The method for synthesizing methyl 1,2, 4-triazole-3-carboxylate according to claim 2, characterized in that: in the step S2, the raw material is trichloroacetyl chloride, and the molar ratio of the trichloroacetyl chloride to the 4-benzyl-1, 2, 4-triazole solid is 1.1: 1-1.2: 1; the molar ratio of the methanol to the 4-benzyl-1, 2, 4-triazole solid is 2: 1-2.5: 1.
4. The method for synthesizing methyl 1,2, 4-triazole-3-carboxylate according to claim 3, characterized in that: in the step S2, the solvent is tetrahydrofuran, and the mass ratio of the tetrahydrofuran to the 4-benzyl-1, 2, 4-triazole solid is 5: 1-6: 1; the molar ratio of triethylamine or N, N-diisopropylethylamine to 4-benzyl-1, 2, 4-triazole solid is 2: 1-2.5: 1.
5. The method for synthesizing methyl 1,2, 4-triazole-3-carboxylate according to claim 4, characterized in that: in the step S3, the mass ratio of methanol to 4-benzyl-1, 2, 4-triazole-3-methyl carboxylate is 8: 1-10: 1; the catalyst is 10% Pd/C, and the mass ratio of the 10% Pd/C to methanol to 4-benzyl-1, 2, 4-triazole-3-methyl carboxylate is 0.005: 1-0.01: 1.
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