CN109369530A - A kind of preparation method of 2,4- dioxy -3- aza-spiro [5,5] hendecane -1,5- dintrile - Google Patents
A kind of preparation method of 2,4- dioxy -3- aza-spiro [5,5] hendecane -1,5- dintrile Download PDFInfo
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- CN109369530A CN109369530A CN201811358356.7A CN201811358356A CN109369530A CN 109369530 A CN109369530 A CN 109369530A CN 201811358356 A CN201811358356 A CN 201811358356A CN 109369530 A CN109369530 A CN 109369530A
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- aza
- spiro
- hendecane
- dioxy
- dintrile
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D221/20—Spiro-condensed ring systems
Abstract
The present invention provides one kind 2,4- dioxy -3- aza-spiro [5,5] hendecane -1, the preparation method of 5- dintrile, comprising the following steps: be added dropwise to methanolic ammonia solution in the mixed solution of cyclohexanone and methyl cyanoacetate, insulation reaction, obtain 2,4- dioxy -3- aza-spiro [5,5] hendecane -1,5- dintrile ammonium salt solution；Then water is added to be uniformly mixed, sulfuric acid solution is added dropwise, insulation reaction separates, and washing obtains 2,4- dioxy -3- aza-spiro [5,5] hendecane -1,5- dintrile.Provided by the invention 2,4- dioxy -3- aza-spiro [5,5] preparation method of hendecane -1,5- dintrile, simple process, low energy consumption, side reaction is few, and product yield can reach 98.5% or more, and the content of ammonia nitrogen is lower than 0.3% in product, the unit consumption of methyl cyanoacetate is 0.85~1.1t/t, is suitble to large-scale industrial production.
Description
Technical field
The present invention relates to chemical production technical fields, more particularly to one kind 2,4- dioxy -3- aza-spiro [5,5] hendecane -
The preparation method of 1,5- dintrile.
Background technique
2,4- dioxy -3- aza-spiro [5,5] hendecane -1,5- dintrile is the centre for preparing 1,1 1 cyclohexanediacetic acids
Body, and 1,1 one cyclohexanediacetic acid is important medicine intermediate, for example is the important intermediate of Gabapentin.Gabapentin
It is a kind of antiepileptic, is usually used in treating neurogenic pain and antianxiety disease.
The method for preparing 2,4- dioxy -3- aza-spiro [5,5] hendecane -1,5- dintrile at present is cyclohexanone, cyanoacetic acid
Ethyl ester is added in the aqueous isopropanol of ammonia or ammonia, is then acidified to obtain product again, but side reaction easily occurs for this technique, causes
Impurity is more in product, and product purity is lower, but also will cause the waste of raw material, increases production cost, also will affect subsequent
The quality of 1,1 1 cyclohexanediacetic acids.
Summary of the invention
For existing preparation 2,4- dioxy -3- aza-spiro [5,5] hendecane -1,5- dintrile technique there are product yield and
The lower problem of purity, the present invention provide the preparation side of one kind 2,4- dioxy -3- aza-spiro [5,5] hendecane -1,5- dintrile
Method.
In order to solve the above technical problems, present invention provide the technical scheme that
Step 1: methanolic ammonia solution is added dropwise in the mixed solution of cyclohexanone and methyl cyanoacetate, insulation reaction obtains 2,
4- dioxy -3- aza-spiro [5,5] hendecane -1,5- dintrile ammonium salt solution, reaction equation are as follows:
Step 2: adding water into 2,4- dioxy -3- aza-spiro [5,5] hendecane -1,5- dintrile ammonium salt solution, mix
It closes uniformly, sulfuric acid solution is then added dropwise, insulation reaction is centrifuged, and washing obtains 2,4- dioxy -3- aza-spiro [5,5] hendecane -1,
5- dintrile, reaction equation are as follows:
Compared with the existing technology, the system of 2,4- dioxy -3- aza-spiro [5,5] hendecane -1,5- dintrile provided by the invention
Preparation Method, reaction condition is mild, and during preparation 2,4- dioxy -3- aza-spiro [5,5] hendecane -1,5- dintrile ammonium salt
System is in neutrallty condition always, and methyl cyanoacetate is not easily decomposed, and the by-product in reaction process is few, prepares work by optimization
Skill, so that the unit consumption of raw material is low, product purity and yield are higher.2,4- dioxy -3- aza-spiro [5,5] provided by the invention
The preparation method of hendecane -1,5- dintrile, 2,4- dioxy -3- aza-spiro [5,5] hendecane -1,5- dintrile product obtained
Yield is up to 98.5% or more, and the content of ammonia nitrogen is lower than 0.3% in product, and the unit consumption of methyl cyanoacetate is 0.85~1.1t/t, drop
The low consumption of raw material, simplifies production technology, improves production efficiency, is suitble to large-scale industrial production.
Preferably, in step 1, the molar ratio of ammonia in the cyclohexanone, the methyl cyanoacetate and the methanolic ammonia solution
For 1:2.03~2.1:2.2~2.8.
Preferred raw material ratio, can be improved the utilization rate of methyl cyanoacetate, reduce the unit consumption of methyl cyanoacetate, improve 2,4-
The yield of dioxy -3- aza-spiro [5,5] hendecane -1,5- dintrile product.
Preferably, in step 1, the mass concentration of ammonia is 5~10% in the methanolic ammonia solution.
The methanolic ammonia solution the preparation method comprises the following steps: temperature be 15~35 DEG C under conditions of, ammonia is passed through in methanol,
Being passed through the time is 2~5h, and the methanolic ammonia solution of 5~10% contents is finally made.
Reaction raw materials mixing can be made more evenly using methanolic ammonia solution, reaction is easier to carry out, and using methanol as ammonia
The solvent of gas, can make product be centrifuged after waste water in only a kind of alcohol of methanol, easily separated processing.
Preferably, in step 1, the time for adding of the methanolic ammonia solution is 7~15h, and dropping temperature is -10~0 DEG C.
Methanolic ammonia solution is slowly added dropwise into the mixed solution of cyclohexanone and methyl cyanoacetate, reaction system can be made always
In neutrallty condition, methyl cyanoacetate is avoided to decompose, reduce the generation of by-product, improved 2,4- dioxy -3- aza-spiro [5,5]
The purity of hendecane -1,5- dintrile product.
Preferably, in step 1, the temperature of the insulation reaction is -5~5 DEG C, and the reaction time is 13~25h.
Preferred reaction temperature and reaction time can react fully progress, reduce the generation of side reaction.
Preferably, in step 2, the water and 2,4- dioxy -3- aza-spiro [5,5] hendecane -1,5- dintrile ammonium
The mass ratio of salting liquid is 0.4~0.65:1.
The additional amount of preferred water can make 2,4- dioxy -3- aza-spiro [5,5] hendecane -1,5- dintrile ammonium salt and sulfuric acid
The ammonium sulfate that reaction generates sufficiently dissolves, while pH measurement can also be made more acurrate, keeps reaction more abundant, reduces side reaction, and
Also being avoided that after 2,4- dioxy -3- aza-spiro [5,5] hendecane -1,5- dintrile product is precipitated leads to the feeding-up more difficult rotation of feed liquid,
Lead to sulfuric acid and 2, the mixing of 4- dioxy -3- aza-spiro [5,5] hendecane -1,5- dintrile ammonium salt is uneven, and raw material reaction is not thorough
Bottom, so as to cause the appearance of the lower problem of 2,4- dioxy -3- aza-spiro [5,5] hendecane -1,5- dintrile product yield.
Preferably, in step 2, the mass concentration of the sulfuric acid solution is 40~60%.
Preferably, in step 2, the time for adding of the sulfuric acid solution is 1~2.5h, and dropping temperature is 30~70 DEG C.
Sulfuric acid is slowly added dropwise into 2,4- dioxy -3- aza-spiro [5,5] hendecane -1,5- dintrile ammonium salt solution, can be made
Reaction sufficiently carries out, and reduces the generation of side reaction.
Preferably, in step 2, sulfuric acid solution is gradually added dropwise to pH=1~3.
Preferred pH value can be such that 2,4- dioxy -3- aza-spiro [5,5] hendecane -1,5- dintrile product is all precipitated,
The waste that can avoid raw material sulphuric acid again, improves product yield, reduces material loss.
Preferably, in step 2, the time of the insulation reaction is 0.5~2.5h, and the temperature of insulation reaction is 50~70
℃。
Preferred reaction temperature and reaction time can react fully progress, reduce the generation of side reaction.
Preferably, centrifuging temperature control is 40~50 DEG C.
Using higher centrifuging temperature, it can avoid the ammonium sulfate that reaction generates and be precipitated, improve the purity of product.
Preferably, the hendecane-of 2,4- dioxy -3- aza-spiro [5,5] described in the additional amount and step 1 of slurry 1,
The mass ratio of 5- dintrile ammonium salt solution is 0.3~0.6:1.
The slurry can according to actual needs, and amount is divided into more parts and is repeatedly washed to product.
2,4- dioxy -3- aza-spiro [5,5] hendecane -1,5- dintrile ammonium described in preferred slurry and step 1
The mass ratio of salting liquid can effectively wash away the mother liquor of 2,4- dioxy -3- aza-spiro [5,5] hendecane -1,5- dintrile product surface
With the ammonium sulfate inorganic salts of precipitation, the purity of product is improved.
Specific embodiment
In order to make the objectives, technical solutions, and advantages of the present invention clearer, with reference to embodiments, to the present invention
It is further elaborated.It should be appreciated that the specific embodiments described herein are merely illustrative of the present invention, it is not used to
Limit the present invention.
Embodiment 1
A kind of preparation method of 2,4- dioxy -3- aza-spiro [5,5] hendecane -1,5- dintrile:
1000kg cyclohexanone and 2100kg methyl cyanoacetate are added in reaction kettle, stir and are cooled to -10 DEG C, it is then even
It is 8.6wt% methanolic ammonia solution 4900kg that ammonia content, which is added dropwise, in speed.Control temperature of reaction kettle is -10 DEG C, when dropwise addition during being added dropwise
Between 15h, in 5 DEG C of heat preservation 13h after being added dropwise to complete.
Water 5200kg, the sulfuric acid that dropwise addition mass concentration is 53.64% after stirring 10min to pH=are added after heat preservation
1.2, time for adding 2h, controlled at 70 DEG C when dropwise addition.In 50 DEG C of heat preservation 2.5h after being added dropwise to complete.Divide 4 small quantities of centrifugations, centrifugation
Feeding temperature is 40 DEG C, every to be washed twice with moisture of 800kg in small batches.
It is final to obtain product 2814kg, product drying weightlessness 17.23%, ammonia nitrogen 0.015%, yield 98.94%, cyanoacetic acid first
The unit consumption of ester is 0.90t/t.
Embodiment 2
A kind of preparation method of 2,4- dioxy -3- aza-spiro [5,5] hendecane -1,5- dintrile:
1000kg cyclohexanone and 2050kg methyl cyanoacetate are added in reaction kettle, stir and are cooled to -5 DEG C, it is then even
It is 9.8wt% methanolic ammonia solution 3900kg that ammonia content, which is added dropwise, in speed.Control temperature of reaction kettle is 0 DEG C during being added dropwise, time for adding
7h, in 3 DEG C of heat preservation 18h after being added dropwise to complete.
Water 2880kg is added after heat preservation, stirs and the sulfuric acid that mass concentration is 40.33% is added dropwise after 10min to pH=2,
Time for adding 2.5h, controlled at 30 DEG C when dropwise addition.In 70 DEG C of heat preservation 0.5h after being added dropwise to complete.Then 50 DEG C of beginnings are cooled to
Divide 4 small quantities of centrifugations, centrifugation feeding temperature is 45 DEG C, every to wash twice with moisture of 540kg in small batches.
It is final to obtain product 2602kg, product drying weightlessness 10.65%, ammonia nitrogen 0.226%, yield 98.52%, cyanoacetic acid first
The unit consumption of ester is 0.88t/t.
Embodiment 3
A kind of preparation method of 2,4- dioxy -3- aza-spiro [5,5] hendecane -1,5- dintrile:
1000kg cyclohexanone and 2120kg methyl cyanoacetate are added in reaction kettle, stirs and is cooled to 0 DEG C, then at the uniform velocity
Dropwise addition ammonia content is 5.2wt% methanolic ammonia solution 9341kg.Control temperature of reaction kettle is 5 DEG C during being added dropwise, time for adding
12h, in -5 DEG C of heat preservation 25h after being added dropwise to complete.
Water 6232kg is added after heat preservation, stirs and the sulfuric acid that mass concentration is 59.78% is added dropwise after 10min to pH=3,
Time for adding 1h, controlled at 50 DEG C when dropwise addition.In 60 DEG C of heat preservation 1.5h after being added dropwise to complete.Then 50 DEG C are cooled to start point
4 small quantities of centrifugations, centrifugation feeding temperature is 50 DEG C, every to be washed three times with moisture of 1870kg in small batches.
It is final to obtain product 3115kg, product drying weightlessness 25.33%, ammonia nitrogen 0.101%, yield 98.68%, cyanoacetic acid first
The unit consumption of ester is 0.91t/t.
In conclusion the preparation side of 2,4- dioxy -3- aza-spiro [5,5] hendecane -1,5- dintrile provided by the invention
Method, simple process do not need special equipment, and low energy consumption, and side reaction is few, 2,4- dioxy -3- aza-spiro [5,5] ten obtained
One alkane -1,5- dintrile product yield can reach 98.5% or more, and the content of ammonia nitrogen is lower than 0.3% in product, methyl cyanoacetate
Unit consumption is 0.85~1.1t/t, is suitble to large-scale industrial production, has broad application prospects.
The foregoing is merely illustrative of the preferred embodiments of the present invention, is not intended to limit the invention, all in essence of the invention
Made any modification, equivalent replacement or improvement etc., should all be included in the protection scope of the present invention within mind and principle.
Claims (10)
1. one kind 2, the preparation method of 4- dioxy -3- aza-spiro [5,5] hendecane -1,5- dintrile, which is characterized in that including with
Lower step:
Step 1: methanolic ammonia solution is added dropwise in the mixed solution of cyclohexanone and methyl cyanoacetate, insulation reaction, 2,4- bis- is obtained
Oxygen -3- aza-spiro [5,5] hendecane -1,5- dintrile ammonium salt solution；
Step 2: adding water into 2,4- dioxy -3- aza-spiro [5,5] hendecane -1,5- dintrile ammonium salt solution, mixing is equal
It is even, sulfuric acid solution is then added dropwise, insulation reaction separates, and washing obtains 2,4- dioxy -3- aza-spiro [5,5] hendecane -1,5- bis-
Nitrile.
2. the preparation method of 2,4- dioxy -3- aza-spiro [5,5] hendecane -1,5- dintrile as described in claim 1, special
Sign is, in step 1, the molar ratio of ammonia is 1:2.03~2.1 in the cyclohexanone, methyl cyanoacetate and methanolic ammonia solution:
2.2~2.8.
3. the preparation method of 2,4- dioxy -3- aza-spiro [5,5] hendecane -1,5- dintrile as described in claim 1, special
Sign is, in step 1, the mass concentration of ammonia is 5~10% in the methanolic ammonia solution.
4. the preparation method of 2,4- dioxy -3- aza-spiro [5,5] hendecane -1,5- dintrile as described in claim 1, special
Sign is, in step 1, the time for adding of the methanolic ammonia solution is 7~15h, and dropping temperature is -10~0 DEG C.
5. the preparation method of 2,4- dioxy -3- aza-spiro [5,5] hendecane -1,5- dintrile as described in claim 1, special
Sign is, in step 1, the temperature of the insulation reaction is -5~5 DEG C, and the reaction time is 13~25h.
6. the preparation method of 2,4- dioxy -3- aza-spiro [5,5] hendecane -1,5- dintrile as described in claim 1, special
Sign is, in step 2, the water and 2,4- dioxy -3- aza-spiro [5,5] hendecane -1,5- dintrile ammonium salt solution
Mass ratio is 0.4~0.65:1.
7. the preparation method of 2,4- dioxy -3- aza-spiro [5,5] hendecane -1,5- dintrile as described in claim 1, special
Sign is, in step 2, the mass concentration of the sulfuric acid solution is 40~60%；And/or
The time for adding of the sulfuric acid solution is 1~2.5h, and dropping temperature is 30~70 DEG C.
8. the preparation method of 2,4- dioxy -3- aza-spiro [5,5] hendecane -1,5- dintrile as described in claim 1, special
Sign is, in step 2, sulfuric acid solution is gradually added dropwise to pH=1~3.
9. the preparation method of 2,4- dioxy -3- aza-spiro [5,5] hendecane -1,5- dintrile as described in claim 1, special
Sign is, in step 2, the time of the insulation reaction is 0.5~2.5h, and the temperature of insulation reaction is 50~70 DEG C.
10. the preparation method of 2,4- dioxy -3- aza-spiro [5,5] hendecane -1,5- dintrile as described in claim 1, special
Sign is, in step 2, using the method for centrifugation when separation, centrifuging temperature is 40~50 DEG C；And/or
When washing, the hendecane -1,5- of 2,4- dioxy -3- aza-spiro [5,5] described in the additional amount and step 1 of slurry bis-
The mass ratio of nitrile ammonium salt solution is 0.3~0.6:1.
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| CN201811358356.7A CN109369530B (en) | 2018-11-15 | 2018-11-15 | Preparation method of 2, 4-dioxo-3-aza-spiro [5,5] undecane-1, 5-dinitrile |
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| CN201811358356.7A CN109369530B (en) | 2018-11-15 | 2018-11-15 | Preparation method of 2, 4-dioxo-3-aza-spiro [5,5] undecane-1, 5-dinitrile |
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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 |
| CN105061241A (en) * | 2015-08-18 | 2015-11-18 | 太仓运通生物化工有限公司 | Gabapentin preparation method |
-
2018
- 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 |
| 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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