CN109369530B - Preparation method of 2, 4-dioxo-3-aza-spiro [5,5] undecane-1, 5-dinitrile - Google Patents
Preparation method of 2, 4-dioxo-3-aza-spiro [5,5] undecane-1, 5-dinitrile Download PDFInfo
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- CN109369530B CN109369530B CN201811358356.7A CN201811358356A CN109369530B CN 109369530 B CN109369530 B CN 109369530B CN 201811358356 A CN201811358356 A CN 201811358356A CN 109369530 B CN109369530 B CN 109369530B
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- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
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Abstract
The invention provides a preparation method of 2, 4-dioxo-3-aza-spiro [5,5] undecane-1, 5-dinitrile, which comprises the following steps: dropwise adding the ammonia methanol solution into the mixed solution of cyclohexanone and methyl cyanoacetate, and carrying out heat preservation reaction to obtain 2, 4-dioxo-3-aza-spiro [5,5] undecane-1, 5-dinitrile ammonium salt solution; then adding water and mixing evenly, dripping sulfuric acid solution, keeping warm and reacting, separating and washing to obtain the 2, 4-dioxo-3-aza-spiro [5,5] undecane-1, 5-dinitrile. The preparation method of the 2, 4-dioxo-3-aza-spiro [5,5] undecane-1, 5-dinitrile provided by the invention has the advantages of simple process, low energy consumption, less side reaction, product yield of more than 98.5%, ammonia nitrogen content of the product of less than 0.3%, and unit consumption of methyl cyanoacetate of 0.85-1.1 t/t, and is suitable for large-scale industrial production.
Description
Technical Field
The invention relates to the technical field of chemical production, in particular to a preparation method of 2, 4-dioxo-3-aza-spiro [5,5] undecane-1, 5-dinitrile.
Background
2, 4-dioxo-3-aza-spiro [5,5] undecane-1, 5-dinitrile is an intermediate in the preparation of 1, 1-cyclohexyldiacetic acid, while 1, 1-cyclohexyldiacetic acid is an important pharmaceutical intermediate, such as gabapentin. Gabapentin is an antiepileptic drug commonly used for the treatment of neuropathic pain and anxiolytic disorders.
The existing method for preparing 2, 4-dioxo-3-aza-spiro [5,5] undecane-1, 5-dinitrile is to add cyclohexanone and ethyl cyanoacetate into ammonia or isopropanol solution of ammonia, and then to acidify to obtain a product, but the process is easy to generate side reaction, so that the product has more impurities and lower purity, and the process can cause waste of raw materials, increase the production cost and also influence the quality of the subsequent 1, 1-cyclohexyldiacetic acid.
Disclosure of Invention
Aiming at the problems of lower product yield and purity in the existing process for preparing 2, 4-dioxo-3-aza-spiro [5,5] undecane-1, 5-dinitrile, the invention provides a preparation method of 2, 4-dioxo-3-aza-spiro [5,5] undecane-1, 5-dinitrile.
In order to solve the technical problems, the technical scheme provided by the invention is as follows:
step one, dropwise adding an ammonia methanol solution into a mixed solution of cyclohexanone and methyl cyanoacetate, and carrying out heat preservation reaction to obtain a 2, 4-dioxo-3-aza-spiro [5,5] undecane-1, 5-dinitrile ammonium salt solution, wherein the reaction equation is as follows:
step two, adding water into the 2, 4-dioxo-3-aza-spiro [5,5] undecane-1, 5-dinitrile ammonium salt solution, uniformly mixing, then dropwise adding a sulfuric acid solution, carrying out heat preservation reaction, centrifuging, and washing to obtain the 2, 4-dioxo-3-aza-spiro [5,5] undecane-1, 5-dinitrile, wherein the reaction equation is as follows:
compared with the prior art, the preparation method of the 2, 4-dioxo-3-aza-spiro [5,5] undecane-1, 5-dinitrile provided by the invention has mild reaction conditions, the system is always in a neutral condition in the process of preparing the 2, 4-dioxo-3-aza-spiro [5,5] undecane-1, 5-dinitrile ammonium salt, the methyl cyanoacetate is not easy to decompose, and the by-products in the reaction process are few. According to the preparation method of the 2, 4-dioxo-3-aza-spiro [5,5] undecane-1, 5-dinitrile, the yield of the prepared 2, 4-dioxo-3-aza-spiro [5,5] undecane-1, 5-dinitrile product is over 98.5%, the content of ammonia nitrogen in the product is lower than 0.3%, the unit consumption of methyl cyanoacetate is 0.85-1.1 t/t, the consumption of raw materials is reduced, the production process is simplified, the production efficiency is improved, and the preparation method is suitable for large-scale industrial production.
Preferably, in the first step, the molar ratio of the cyclohexanone to the methyl cyanoacetate to the ammonia in the ammonia-methanol solution is 1: 2.03-2.1: 2.2-2.8.
The optimized raw material ratio can improve the utilization rate of the methyl cyanoacetate, reduce the unit consumption of the methyl cyanoacetate and improve the yield of the 2, 4-dioxo-3-aza-spiro [5,5] undecane-1, 5-dinitrile product.
Preferably, in the first step, the mass concentration of ammonia in the ammonia methanol solution is 5-10%.
The preparation method of the ammonia methanol solution comprises the following steps: and (3) introducing ammonia gas into the methanol at the temperature of 15-35 ℃, wherein the introduction time is 2-5 h, and finally preparing the ammonia methanol solution with the content of 5-10%.
The adoption of the ammonia methanol solution can ensure that the reaction raw materials are mixed more uniformly and the reaction is easier to carry out, and the methanol is used as the solvent of ammonia gas, so that only one methanol is contained in the waste water after the product centrifugation, and the separation and the treatment are easy.
Preferably, in the step one, the dropwise adding time of the ammonia methanol solution is 7-15 h, and the dropwise adding temperature is-10-0 ℃.
The ammonia methanol solution is slowly dripped into the mixed solution of the cyclohexanone and the methyl cyanoacetate, so that the reaction system is always in a neutral condition, the decomposition of the methyl cyanoacetate is avoided, the generation of byproducts is reduced, and the purity of the 2, 4-dioxo-3-aza-spiro [5,5] undecane-1, 5-dinitrile product is improved.
Preferably, in the step one, the temperature of the heat preservation reaction is-5 to 5 ℃, and the reaction time is 13 to 25 hours.
The preferable reaction temperature and reaction time can make the reaction fully proceed and reduce the occurrence of side reaction.
Preferably, in the second step, the mass ratio of the water to the 2, 4-dioxo-3-aza-spiro [5,5] undecane-1, 5-dinitrile ammonium salt solution is 0.4-0.65: 1.
The preferred amount of water added is such that the ammonium sulfate formed by the reaction of the 2, 4-dioxo-3-aza-spiro [5,5] undecane-1, 5-dinitrile salt with sulfuric acid is sufficiently dissolved, meanwhile, the pH measurement is more accurate, the reaction is more sufficient, side reactions are reduced, the phenomenon that the feed liquid is too thick and difficult to rotate after the 2, 4-dioxo-3-aza-spiro [5,5] undecane-1, 5-dinitrile product is separated out, the sulfuric acid and the 2, 4-dioxo-3-aza-spiro [5,5] undecane-1, 5-dinitrile ammonium salt are mixed unevenly, the raw material reaction is incomplete, thereby causing the problem of low product yield of 2, 4-dioxo-3-aza-spiro [5,5] undecane-1, 5-dinitrile.
Preferably, in the second step, the mass concentration of the sulfuric acid solution is 40-60%.
Preferably, in the second step, the dropwise adding time of the sulfuric acid solution is 1-2.5 hours, and the dropwise adding temperature is 30-70 ℃.
The sulfuric acid is slowly dripped into the 2, 4-dioxo-3-aza-spiro [5,5] undecane-1, 5-dinitrile ammonium salt solution, so that the reaction can be fully carried out, and the occurrence of side reactions is reduced.
Preferably, in the second step, the sulfuric acid solution is gradually added dropwise until the pH is 1 to 3.
The optimal pH value can not only completely separate out the 2, 4-dioxo-3-aza-spiro [5,5] undecane-1, 5-dinitrile product, but also avoid the waste of the raw material sulfuric acid, improve the product yield and reduce the loss of the raw material.
Preferably, in the second step, the time of the heat preservation reaction is 0.5-2.5 h, and the temperature of the heat preservation reaction is 50-70 ℃.
The preferable reaction temperature and reaction time can make the reaction fully proceed and reduce the occurrence of side reaction.
Preferably, the centrifugal temperature is controlled to be 40-50 ℃.
The high centrifugal temperature is adopted, so that the separation of ammonium sulfate generated by reaction can be avoided, and the purity of the product is improved.
Preferably, the mass ratio of the addition amount of the washing water to the ammonium salt solution of the 2, 4-dioxo-3-aza-spiro [5,5] undecane-1, 5-dinitrile in the first step is 0.3-0.6: 1.
The washing water can be evenly divided into a plurality of portions according to actual needs to wash the product for a plurality of times.
The mass ratio of the washing water to the 2, 4-dioxo-3-aza-spiro [5,5] undecane-1, 5-dinitrile ammonium salt solution in the first step can effectively wash off the mother liquor on the surface of the 2, 4-dioxo-3-aza-spiro [5,5] undecane-1, 5-dinitrile product and the precipitated ammonium sulfate inorganic salt, thereby improving the purity of the product.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
Example 1
A method for preparing 2, 4-dioxo-3-aza-spiro [5,5] undecane-1, 5-dinitrile:
1000kg of cyclohexanone and 2100kg of methyl cyanoacetate are added into a reaction kettle, stirred and cooled to-10 ℃, and 4900kg of ammonia methanol solution with the ammonia content of 8.6 wt% is dripped at a constant speed. The temperature of the reaction kettle is controlled to be-10 ℃ in the dripping process, the dripping time is 15 hours, and the temperature is kept for 13 hours at 5 ℃ after the dripping is finished.
After the heat preservation, 5200kg of water was added, and after stirring for 10min, 53.64% sulfuric acid was added dropwise until the pH became 1.2, the dropwise addition time was 2 hours, and the temperature was controlled to 70 ℃. After the completion of the dropwise addition, the mixture was kept at 50 ℃ for 2.5 hours. The centrifugation was carried out in 4 small batches, the centrifuge feed temperature being 40 ℃ and the washing being carried out twice with 800kg of water per small batch.
2814kg of final product is obtained, the drying weight loss of the product is 17.23%, the ammonia nitrogen content is 0.015%, the yield is 98.94%, and the unit consumption of methyl cyanoacetate is 0.90 t/t.
Example 2
A method for preparing 2, 4-dioxo-3-aza-spiro [5,5] undecane-1, 5-dinitrile:
1000kg of cyclohexanone and 2050kg of methyl cyanoacetate are added into a reaction kettle, stirred and cooled to-5 ℃, and 3900kg of ammonia methanol solution with the ammonia content of 9.8 wt% is dripped at a constant speed. The temperature of the reaction kettle is controlled to be 0 ℃ in the dripping process, the dripping time is 7 hours, and the temperature is kept for 18 hours at 3 ℃ after the dripping is finished.
After the heat preservation is finished, 2880kg of water is added, stirring is carried out for 10min, sulfuric acid with the mass concentration of 40.33% is added dropwise until the pH value is 2, the dropwise adding time is 2.5h, and the temperature is controlled to be 30 ℃ during dropwise adding. After the completion of the dropwise addition, the mixture was kept at 70 ℃ for 0.5 hour. Then the temperature is reduced to 50 ℃ and centrifugation is carried out in 4 small batches, the centrifugal feeding temperature is 45 ℃, and each small batch is washed twice by 540kg of water.
2602kg of final product is obtained, the drying weight loss of the product is 10.65%, the ammonia nitrogen content is 0.226%, the yield is 98.52%, and the unit consumption of the methyl cyanoacetate is 0.88 t/t.
Example 3
A method for preparing 2, 4-dioxo-3-aza-spiro [5,5] undecane-1, 5-dinitrile:
1000kg of cyclohexanone and 2120kg of methyl cyanoacetate are added into a reaction kettle, stirred and cooled to 0 ℃, and 9341kg of ammonia methanol solution with 5.2 wt% of ammonia content is dropwise added at a constant speed. The temperature of the reaction kettle is controlled to be 5 ℃ in the dripping process, the dripping time is 12 hours, and the temperature is kept for 25 hours at the temperature of minus 5 ℃ after the dripping is finished.
6232kg of water is added after the heat preservation is finished, sulfuric acid with the mass concentration of 59.78% is added dropwise after stirring for 10min until the pH value is 3, the dropwise adding time is 1h, and the temperature is controlled to be 50 ℃ when the dropwise adding is carried out. After the completion of the dropwise addition, the mixture was kept at 60 ℃ for 1.5 hours. Then the temperature was reduced to 50 ℃ and centrifugation was started in 4 small batches with a centrifuge feed temperature of 50 ℃ with three washes of 1870kg water per small batch.
Finally, 3115kg of product is obtained, the drying weight loss of the product is 25.33%, the ammonia nitrogen content is 0.101%, the yield is 98.68%, and the unit consumption of the methyl cyanoacetate is 0.91 t/t.
In conclusion, the preparation method of the 2, 4-dioxo-3-aza-spiro [5,5] undecane-1, 5-dinitrile provided by the invention has the advantages of simple process, no need of special equipment, low energy consumption and less side reaction, the yield of the prepared 2, 4-dioxo-3-aza-spiro [5,5] undecane-1, 5-dinitrile product can reach more than 98.5%, the content of ammonia nitrogen in the product is lower than 0.3%, the unit consumption of methyl cyanoacetate is 0.85-1.1 t/t, and the preparation method is suitable for large-scale industrial production and has wide application prospect.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents or improvements made within the spirit and principle of the present invention should be included in the scope of the present invention.
Claims (1)
1. A process for the preparation of 2, 4-dioxo-3-aza-spiro [5,5] undecane-1, 5-dinitrile, comprising the steps of:
step one, dropwise adding an ammonia methanol solution into a mixed solution of cyclohexanone and methyl cyanoacetate, and carrying out heat preservation reaction to obtain a 2, 4-dioxo-3-aza-spiro [5,5] undecane-1, 5-dinitrile ammonium salt solution;
wherein the molar ratio of the cyclohexanone to the methyl cyanoacetate to the ammonia in the ammonia-methanol solution is 1: 2.03-2.1: 2.2-2.8; the mass concentration of ammonia in the ammonia methanol solution is 5-10%; the dropwise adding time of the ammonia methanol solution is 7-15 h, and the dropwise adding temperature is-10-0 ℃; the temperature of the heat preservation reaction is-5 ℃, and the reaction time is 13-25 h;
step two, adding water into the 2, 4-dioxo-3-aza-spiro [5,5] undecane-1, 5-dinitrile ammonium salt solution, uniformly mixing, then dropwise adding a sulfuric acid solution until the pH value is = 1-3, carrying out heat preservation reaction, separating and washing to obtain 2, 4-dioxo-3-aza-spiro [5,5] undecane-1, 5-dinitrile; the mass ratio of the water to the 2, 4-dioxo-3-aza-spiro [5,5] undecane-1, 5-dinitrile ammonium salt solution is 0.4-0.65: 1; the time of the heat preservation reaction is 0.5-2.5 h, and the temperature of the heat preservation reaction is 50-70 ℃;
wherein the mass concentration of the sulfuric acid solution is 40-60%; the dropping time of the sulfuric acid solution is 1-2.5 h, and the dropping temperature is 30-70 ℃; a centrifugal method is adopted during separation, and the centrifugal temperature is 40-50 ℃; during washing, the mass ratio of the addition amount of washing water to the ammonium salt solution of the 2, 4-dioxo-3-aza-spiro [5,5] undecane-1, 5-dinitrile in the first step is 0.3-0.6: 1.
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| CN103333081A (en) * | 2013-06-27 | 2013-10-02 | 南通泰通化学科技有限公司 | Preparation method of 1,1-cyclohexanediacetic acid mono amide |
| CN105061241A (en) * | 2015-08-18 | 2015-11-18 | 太仓运通生物化工有限公司 | Gabapentin preparation method |
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- 2018-11-15 CN CN201811358356.7A patent/CN109369530B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001096334A2 (en) * | 2000-06-15 | 2001-12-20 | Pharmacia Corporation | Heteroarylalkanoic acids as integrin receptor antagonists |
| CN1740161A (en) * | 2005-08-19 | 2006-03-01 | 徐州恩华药业集团有限责任公司 | Gabapentin hydrochloride preparing process |
| CN101417975A (en) * | 2008-12-01 | 2009-04-29 | 太仓市运通化工厂 | Method for preparing gabapentin intermediate |
| CN101475466A (en) * | 2009-01-04 | 2009-07-08 | 曹桂东 | Preparation method of 1,1-cyclohexanediacetic acid |
| CN103333081A (en) * | 2013-06-27 | 2013-10-02 | 南通泰通化学科技有限公司 | Preparation method of 1,1-cyclohexanediacetic acid mono amide |
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