CN112759558A - Process for the preparation of triazine rings - Google Patents
Process for the preparation of triazine rings Download PDFInfo
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- CN112759558A CN112759558A CN202011608977.3A CN202011608977A CN112759558A CN 112759558 A CN112759558 A CN 112759558A CN 202011608977 A CN202011608977 A CN 202011608977A CN 112759558 A CN112759558 A CN 112759558A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D253/00—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00
- C07D253/02—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 not condensed with other rings
- C07D253/06—1,2,4-Triazines
- C07D253/065—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members
- C07D253/07—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members 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 belongs to the technical field of organic intermediate preparation, and particularly relates to a preparation method of triazine ring. The method comprises the following steps: adding 2-methyl thiosemicarbazide, diethyl oxalate and mixed alcohol solvent into a reaction bottle, dropwise adding a mixed base catalyst, carrying out cyclization reaction at 45-55 ℃, acidifying with hydrochloric acid, cooling to 0-5 ℃, and carrying out suction filtration to obtain a triazine ring crude product; dissolving the crude triazine ring product in distilled water at 65-70 ℃, cooling to 10-15 ℃ for crystallization to obtain a wet triazine ring product, and drying at 90-100 ℃ for 3-5 hours to obtain a dry triazine ring product. The preparation method does not introduce a new solvent system, has high selectivity, less side reactions, easy recovery and treatment of the solvent system and high product yield; the adopted raw materials are cheap and easy to obtain, the cost is low, and the method is suitable for industrial amplification.
Description
Technical Field
The invention belongs to the technical field of organic intermediate preparation, and particularly relates to a preparation method of triazine ring.
Background
Triazine ring (TTZ) is a key intermediate for synthesizing ceftriaxone sodium, has wide application in polymer materials, dyes, pesticides and pharmaceutical industries, and has very important development value.
The molecular formula is as follows: c4H5N3O2S。
The structural formula is as follows:
at present, the preparation methods of triazine ring mainly comprise the following 2 methods:
(1) 2-methyl thiosemicarbazide and diethyl oxalate are used as raw materials, sodium methoxide is used as a catalyst to carry out cyclization reaction, a large amount of solvent systems are needed for the reaction to be completed, meanwhile, the systems are very viscous, so that local concentration is not uniform, meanwhile, the alkalinity of the sodium methoxide is too strong, and in the presence of local excessive alkali, a large amount of byproducts are generated, so that the cyclization yield is low.
(2) 2-methyl thiosemicarbazide and methyl malonyl chloride are used as raw materials to synthesize 1-oxamyl thiosemicarbazide under the action of a reagent in tetrahydrofuran, and then intramolecular cyclization is carried out under an alkaline reagent to obtain a triazine ring after the triazine ring is subjected to ion exchange resin. The process has complex route, particularly the preparation of the raw material methylmalonyl chloride is complex, the yield is low (about 80 percent), the methylmalonyl chloride is an acyl chloride intermediate with high activity, the operation is inconvenient, meanwhile, the purification must be carried out by using ion exchange resin, the process is complex, the cost is high, the process is not suitable for industrial production, and the process has no practical production significance.
In order to avoid the two disadvantages, patent CN 104177305 a proposes an idea of using a mixed solvent, but the invention introduces one of DMF, DMSO, NMP, HMPA, acetone, acetonitrile, dioxane, and THF, and none of these solvents is the reaction system, and the greatest disadvantage of the above patent is that a new solvent system is introduced, which increases the difficulty of recycling treatment, and introduces a new environmental protection problem.
Disclosure of Invention
The invention aims to provide a preparation method of triazine ring, which does not introduce a new solvent system, has high selectivity, less side reaction, easy recovery and treatment of the solvent system and high product yield; the adopted raw materials are cheap and easy to obtain, the cost is low, and the method is suitable for industrial amplification.
The technical scheme adopted by the invention for solving the technical problems is as follows:
the preparation method of the triazine ring comprises the steps of dropwise adding a mixed base catalyst into 2-methyl thiosemicarbazide, diethyl oxalate and a mixed alcohol solvent, carrying out ring-making reaction at 45-55 ℃, acidifying with hydrochloric acid to obtain a crude triazine ring product, and recrystallizing to obtain the triazine ring.
Specifically, the method comprises the following steps:
adding 2-methyl thiosemicarbazide, diethyl oxalate and mixed alcohol solvent into a reaction bottle, dropwise adding a mixed base catalyst, carrying out cyclization reaction at 45-55 ℃, acidifying with hydrochloric acid, cooling to 0-5 ℃, and carrying out suction filtration to obtain a triazine ring crude product;
dissolving the crude triazine ring product in distilled water at 65-70 ℃, cooling to 10-15 ℃ for crystallization to obtain a wet triazine ring product, and drying at 90-100 ℃ for 3-5 hours to obtain a dry triazine ring product.
The reaction equation for the above reaction is as follows:
wherein:
the molar ratio of the 2-methyl thiosemicarbazide to the diethyl oxalate is 1: 1.05-1: 1.1.
The mass ratio of the mixed alcohol solvent to the 2-methyl thiosemicarbazide is 5: 1-6: 1.
The mixed alcohol solvent is a mixed solution of methanol and ethanol, and the mass ratio of the methanol to the ethanol is 3: 7-5: 5.
The temperature of the dropwise adding mixed base catalyst is 5-15 ℃.
The time for dripping the mixed base catalyst is 0.5-1.5 h.
The mixed base catalyst is a mixture of sodium methoxide (content: 30%), Dimethylaminopyridine (DMAP) and Tetramethylethylenediamine (TMEDA). The mass ratio of the sodium methoxide to the 2-methyl thiosemicarbazide is 2.5: 1-3.5: 1; the mass ratio of the dimethylaminopyridine to the 2-methylaminothiourea is 0.001: 1-0.005: 1; the mass ratio of the tetramethylethylenediamine to the 2-methylaminothiourea is 0.001: 1-0.005: 1.
The cyclization reaction time is 2.5-4 h.
The pH value of the hydrochloric acid is 0.5-1.
The mass ratio of the distilled water to the 2-methyl thiosemicarbazide is 5: 1-6: 1.
Compared with the prior art, the invention has the following beneficial effects:
(1) the use of the mixed alkali adjusts the alkalinity of the catalyst system and improves the selectivity of the reaction.
(2) By using the mixed solvent, the polarity of the solvent system is adjusted, the viscosity of the solvent system in the reaction process is improved, local over-alkali is avoided, the selectivity of the reaction is improved, and meanwhile, a new solvent is not introduced, and the difficulty in solvent recovery is avoided.
(3) The invention has high selectivity, less side reaction, easy recovery of solvent system, high purity up to 99.5% and high yield up to 92% (calculated on 2-methyl thiosemicarbazide).
(4) The raw materials adopted by the invention are cheap and easily available, the cost is low, and the method is suitable for industrial amplification.
Detailed Description
The present invention is further illustrated by the following specific examples.
The raw materials used in the examples were all commercially available materials except for those specifically mentioned.
Example 1
Adding 10.5g of 2-methyl thiosemicarbazide, 15.3g of diethyl oxalate, 31.5g of methanol and 31.5g of ethanol into a reaction bottle, cooling to 15 ℃, dropwise adding a mixed base catalyst (wherein 36.8g of sodium methoxide, 0.05g of DMAP and 0.05g of TMEDA) for 1.5h, heating to 55 ℃ after dropwise adding to perform cyclization reaction for 2.5h, acidifying with hydrochloric acid to pH 1.0, cooling to 5 ℃, performing suction filtration to obtain a triazine ring crude product, dissolving 63g of the crude product in distilled water at 70 ℃, cooling to 15 ℃ to perform crystallization, performing suction filtration to obtain a triazine ring wet product, drying at 100 ℃ for 3h to obtain 14.75g of a triazine ring dry product with the purity of 99.6% and the yield of 92.7%.
Example 2
Adding 10.5g of 2-methyl thiosemicarbazide, 16.1g of diethyl oxalate, 15.8g of methanol and 36.8g of ethanol into a reaction bottle, cooling to 5 ℃, dropwise adding a mixed base catalyst (wherein 26.3g of sodium methoxide, 0.01g of DMAP and 0.01g of TMEDA) for 0.5h, heating to 45 ℃ after dropwise adding to perform cyclization reaction for 4h, acidifying with hydrochloric acid to pH of 0.5, cooling to 0 ℃, performing suction filtration to obtain a crude triazine ring product, dissolving the crude product in distilled water at 65 ℃ of 52.5g, cooling to 10 ℃ to perform crystallization, performing suction filtration to obtain a wet triazine ring product, drying at 90 ℃ for 5h to obtain a dry triazine ring product of 14.66g, the purity of 99.7% and the yield of 92.1%.
Example 3
Adding 10.5g of 2-methyl thiosemicarbazide, 15.6g of diethyl oxalate, 24g of methanol and 36g of ethanol into a reaction bottle, cooling to 10 ℃, dropwise adding a mixed base catalyst (wherein 30g of sodium methoxide, 0.02g of DMAP and 0.03g of TMEDA) for 1h, heating to 50 ℃ after dropwise adding to perform cyclization reaction for 3h, acidifying with hydrochloric acid until the pH value is 0.7, cooling to 3 ℃, performing suction filtration to obtain a triazine ring crude product, dissolving the crude product in 60g of distilled water at 68 ℃, cooling to 13 ℃, performing crystallization, performing suction filtration to obtain a triazine ring wet product, drying at 95 ℃ for 4h to obtain 14.72g of a triazine ring dry product, the purity is 99.6%, and the yield is 92.5%.
Comparative example 1
Adding 10.5g of 2-methyl thiosemicarbazide, 15.3g of diethyl oxalate and 63g of methanol into a reaction bottle, cooling to 15 ℃, dropwise adding a mixed base catalyst (wherein 36.8g of sodium methoxide, 0.05g of DMAP and 0.05g of TMEDA) for 1.5h, heating to 55 ℃ after dropwise adding to perform cyclization reaction for 2.5h, acidifying with hydrochloric acid to pH 1.0, cooling to 5 ℃, performing suction filtration to obtain a triazine ring crude product, dissolving the crude product in 63g of distilled water at 70 ℃, cooling to 15 ℃, performing crystallization, performing suction filtration to obtain a triazine ring wet product, drying at 100 ℃ for 3h to obtain 12.45g of a triazine ring dry product, the purity of 98.9% and the yield of 78.2%.
Comparative example 2
Adding 10.5g of 2-methyl thiosemicarbazide, 15.3g of diethyl oxalate and 63g of ethanol into a reaction bottle, cooling to 15 ℃, dropwise adding a mixed base catalyst (wherein 36.8g of sodium methoxide, 0.05g of DMAP and 0.05g of TMEDA) for 1.5h, heating to 55 ℃ after dropwise adding to perform cyclization reaction for 2.5h, acidifying with hydrochloric acid to pH 1.0, cooling to 5 ℃, performing suction filtration to obtain a triazine ring crude product, dissolving the crude product in 63g of distilled water at 70 ℃, cooling to 15 ℃, performing crystallization, performing suction filtration to obtain a triazine ring wet product, drying at 100 ℃ for 3h to obtain 12.85g of a triazine ring dry product, the purity of 98.7% and the yield of 80.8%.
Comparative example 3
Adding 10.5g of 2-methyl thiosemicarbazide, 15.3g of diethyl oxalate, 31.5g of methanol and 31.5g of ethanol into a reaction bottle, cooling to 15 ℃, dropwise adding 36.9g of a sodium methoxide catalyst for 1.5h, heating to 55 ℃ after dropwise adding to perform cyclization reaction for 2.5h, acidifying with hydrochloric acid until the pH value is 1.0, cooling to 5 ℃, performing suction filtration to obtain a triazine ring crude product, dissolving the crude product in 63g of distilled water at 70 ℃, cooling to 15 ℃, performing crystallization, performing suction filtration to obtain a triazine ring wet product, drying at 100 ℃ for 3h to obtain 13.75g of a triazine ring dry product with the purity of 99.5% and the yield of 86.4%.
Comparative example 4
Adding 10.5g of 2-methyl thiosemicarbazide, 15.3g of diethyl oxalate, 31.5g of methanol and 31.5g of ethanol into a reaction bottle, cooling to 15 ℃, dropwise adding 36.9g of DMAP catalyst for 1.5h, heating to 55 ℃ after dropwise adding to perform cyclization reaction for 2.5h, acidifying with hydrochloric acid until the pH value is 1.0, cooling to 5 ℃, performing suction filtration to obtain a crude triazine ring product, dissolving the crude product in 63g of distilled water at 70 ℃, cooling to 15 ℃, performing crystallization, performing suction filtration to obtain a wet triazine ring product, drying at 100 ℃ for 3h to obtain a dry triazine ring product 2.1g, the purity is 85.5%, and the yield is 13.2%.
Comparative example 5
Adding 10.5g of 2-methyl thiosemicarbazide, 15.3g of diethyl oxalate, 31.5g of methanol and 31.5g of ethanol into a reaction bottle, cooling to 15 ℃, dropwise adding 36.9g of TMEDA catalyst for 1.5h, heating to 55 ℃ after dropwise adding to perform cyclization reaction for 2.5h, acidifying with hydrochloric acid until the pH value is 1.0, cooling to 5 ℃, performing suction filtration to obtain a crude triazine ring product, dissolving the crude product in 63g of distilled water at 70 ℃, cooling to 15 ℃, performing crystallization, performing suction filtration to obtain a wet triazine ring product, drying at 100 ℃ for 3h to obtain a dry triazine ring product of 1.9g, the purity of 84.9% and the yield of 11.9%.
Claims (9)
1. A method for preparing triazine ring is characterized in that: the method comprises the following steps:
adding 2-methyl thiosemicarbazide, diethyl oxalate and mixed alcohol solvent into a reaction bottle, dropwise adding a mixed base catalyst, carrying out cyclization reaction at 45-55 ℃, acidifying with hydrochloric acid, cooling to 0-5 ℃, and carrying out suction filtration to obtain a triazine ring crude product;
dissolving the crude triazine ring product in distilled water at 65-70 ℃, cooling to 10-15 ℃ for crystallization to obtain a wet triazine ring product, and drying at 90-100 ℃ for 3-5 hours to obtain a dry triazine ring product;
wherein:
the mixed alcohol solvent is a mixed solution of methanol and ethanol, and the mass ratio of the methanol to the ethanol is 3: 7-5: 5.
The mixed base catalyst is a mixture of sodium methoxide, dimethylaminopyridine and tetramethylethylenediamine.
2. The process for producing a triazine ring according to claim 1, characterized in that: the molar ratio of the 2-methyl thiosemicarbazide to the diethyl oxalate is 1: 1.05-1: 1.1.
3. The process for producing a triazine ring according to claim 1, characterized in that: the mass ratio of the mixed alcohol solvent to the 2-methyl thiosemicarbazide is 5: 1-6: 1.
4. The process for producing a triazine ring according to claim 1, characterized in that: the temperature of the dropwise adding mixed base catalyst is 5-15 ℃.
5. The process for producing a triazine ring according to claim 1, characterized in that: the time for dripping the mixed base catalyst is 0.5-1.5 h.
6. The process for producing a triazine ring according to claim 1, characterized in that: the mass ratio of the sodium methoxide to the 2-methyl thiosemicarbazide is 2.5: 1-3.5: 1; the mass ratio of the dimethylaminopyridine to the 2-methylaminothiourea is 0.001: 1-0.005: 1; the mass ratio of the tetramethylethylenediamine to the 2-methylaminothiourea is 0.001: 1-0.005: 1.
7. The process for producing a triazine ring according to claim 1, characterized in that: the cyclization reaction time is 2.5-4 h.
8. The process for producing a triazine ring according to claim 1, characterized in that: the pH value of the hydrochloric acid is 0.5-1.
9. The process for producing a triazine ring according to claim 1, characterized in that: the mass ratio of the distilled water to the 2-methyl thiosemicarbazide is 5: 1-6: 1.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113214176A (en) * | 2021-05-17 | 2021-08-06 | 山东汇海医药化工有限公司 | Preparation method of triazine ring product |
| CN113735790A (en) * | 2021-09-24 | 2021-12-03 | 山东汇海医药化工有限公司 | Method for recovering triazine ring from triazine ring cyclization mother liquor |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113214176A (en) * | 2021-05-17 | 2021-08-06 | 山东汇海医药化工有限公司 | Preparation method of triazine ring product |
| CN113735790A (en) * | 2021-09-24 | 2021-12-03 | 山东汇海医药化工有限公司 | Method for recovering triazine ring from triazine ring cyclization mother liquor |
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