CN107602481A - A kind of 2 methyl 4 amino 5 (formyl aminomethyl) pyrimidine hydrolysis process - Google Patents
A kind of 2 methyl 4 amino 5 (formyl aminomethyl) pyrimidine hydrolysis process Download PDFInfo
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- CN107602481A CN107602481A CN201710789557.1A CN201710789557A CN107602481A CN 107602481 A CN107602481 A CN 107602481A CN 201710789557 A CN201710789557 A CN 201710789557A CN 107602481 A CN107602481 A CN 107602481A
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- methyl
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- pyrimidine
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Abstract
The present invention relates to the technique that a kind of 2 methyl 4 amino 5 (formyl aminomethyl) pyrimidine hydrolysis prepares 2 methyl 4 amino 5 (amino methyl) pyrimidine, that is two kinds of raw material alternating excessive responses, the product of generation is come out by solvent extraction, cooling separates out product, 2 methyl 4 amino 5 (formyl aminomethyl) pyrimidine hydrolysis process that solvent is applied mechanically repeatedly with water.Compared with prior art, can be fully hydrolyzed using 2 methyl of technique 4 amino 5 (formyl aminomethyl) pyrimidine, product content is high；Byproduct sodium formate is separable out.In addition, the method emits no waste water, solvent does not also consume.
Description
Technical field
The present invention relates to a kind of preparation method of vitamin B 1 intermediate, and specifically one kind is by 2- methyl -4- amino -5-
The method that the hydrolysis of (formyl aminomethyl) pyrimidine prepares 2- methyl -4- amino -5- (amino methyl) pyrimidine.
Background technology
2- methyl -4- amino -5- (formyl aminomethyl) pyrimidine hydrolysis generation 2- methyl -4- amino -5- (amino methyl) are phonetic
Pyridine is one of important procedure of vitamin B1 synthesis, and its reaction is as follows：
The main technique that industrialization uses at present is 2- methyl -4- amino -5- (formyl aminomethyl) pyrimidine in sodium hydroxide
Hydrolyzed in the aqueous solution.Because product 2- methyl -4- amino -5- (amino methyl) pyrimidine has certain solubility in water, it is difficult to
Separate, so after hydrolysis, be directly used in without separation and react in next step, the byproduct sodium formate of the step, excessive hydrogen
Sodium oxide molybdena and water, which are brought in next step, is used as wastewater treatment, so not only has an impact to next step reaction, separating technology, and
The treating capacity of waste water is very big.With raising of the society to environmental requirement, also increasingly severe, the relevant enterprise the problem of technique
Explore after 2- methyl -4- amino -5- (formyl aminomethyl) pyrimidine hydrolyzes in sodium hydrate aqueous solution, separated out by cooling
Product 2- methyl -4- amino -5- (amino methyl) pyrimidine of generation, but due to 2- methyl -4- amino -5- (amino methyl) pyrimidine
There is certain solubility in water, dissolved solution degree is up to 22.0g, and relatively more, byproduct formic acid sodium is remained in mother liquor
Cannot separating-purifying come out, wastewater treatment difficulty or bigger.
The content of the invention
It is an object of the invention to overcome above-mentioned existing 2- methyl -4- amino -5- (formyl aminomethyl) pyrimidine hydrolysis process
The deficiency of method, there is provided a kind of two kinds of raw materials are alternately excessive, and the product of generation is come out by solvent extraction, and solvent covers repeatedly with water
2- methyl -4- amino -5- (carbamoylmethyl) pyrimidine hydrolysis process.
The realization of the object of the invention, concrete technology step are as follows：
(1) excessive 2- methyl -4- amino -5- (formyl aminomethyl) pyrimidines and sodium hydrate aqueous solution hydrolysis, instead
Major product 2- methyl -4- amino -5- (amino methyl) pyrimidine is extracted with organic solvent after having answered, and isolates organic phase and water
Phase.
(2) the organic phase cooling that step (1) is isolated separates out product 2- methyl -4- amino -5- (amino methyl) pyrimidine, Gu
Liquid separates to obtain product.
(3) 2- methyl -4- amino -5- (formyl aminomethyl) pyrimidine complete dissolved with unreacted the step of in (1) aqueous phase plus
Enter 2- methyl -4- amino -5- (formyl aminomethyl) pyrimidines and reaction is hydrolyzed in sodium hydroxide, keep sodium hydroxide excessive, instead
Major product 2- methyl -4- amino -5- (amino methyl) pyrimidine is extracted with organic solvent after having answered, isolates organic phase and aqueous phase.
(4) the organic phase cooling that step (3) is isolated separates out major product 2- methyl -4- amino -5- (amino methyl) pyrimidine,
Separation of solid and liquid obtains major product.
(5) the aqueous phase cooling that step (3) obtains separates out byproduct sodium formate, and separation of solid and liquid obtains byproduct sodium formate and water
Phase.
(6) aqueous phase that step (5) obtains adds 2- methyl -4- amino -5- (formyl ammonia dissolved with the complete sodium hydroxide of unreacted
Methyl) reaction is hydrolyzed in pyrimidine and sodium hydroxide, and keep 2- methyl -4- amino -5- (formyl aminomethyl) pyrimidine excessive, repeat
Step (1) operates.
Organic extractant is one or more combinations in benzene, toluene, ethylbenzene, dimethylbenzene in the step (1), (3),
Hydrolysising reacting temperature is 80~120 DEG C.
The temperature that organic phase cooling separates out product in the step (2), (4) is 0~25 DEG C.
Preferably, in above-mentioned processing step, selected organic solvent is toluene in the step (1), (3).
Preferably, in above-mentioned processing step, hydrolysising reacting temperature is 110~120 DEG C in the step (1), (3).
The addition mole of sodium hydroxide and 2- methyl -4- amino -5- (formoxyl first in step (1) in the step (3)
Base) pyrimidine add mole it is preferably equal；The addition mole of 2- methyl -4- amino -5- (carbamoylmethyl) pyrimidine in step (3)
Amount and sodium hydroxide addition mole in step (1) are preferably equal.
Step (1) can circulate down always to (6), can also be started the cycle in due course from newly, can be from (1)
Start the cycle over, can also be started the cycle over from (3).Solvent, or water can be augmented when appropriate in cyclic process.
2- methyl -4- amino -5- (carbamoylmethyl) pyrimidine of the present invention hydrolyzes circulation technology, compared with prior art, 2-
Methyl -4- amino -5- (carbamoylmethyl) pyrimidine can be fully hydrolyzed, and product content is high；In addition, in theory it can be said that the method
Emit no waste water, solvent does not also consume, and the production of actual industrial metaplasia, consumption solvent is seldom, and waste water is also seldom.Reduce sewage disposal
Difficulty, it is cost-effective.
Brief description of the drawings
Fig. 1 is that a kind of 2- methyl -4- amino -5- (formyl aminomethyl) pyrimidine pilot scales recycled hydrolyzes flow chart；
Shown in figure：1st, 4- back flow reaction kettles；2nd, 5- pans；3rd, 8- aqueous phases storage tank；6th, 9- cooling reactors；7th, 10- is filtered
Device；11- reclaims organic solvent fluid reservoir；12- organic solvent tanks.
Embodiment
It is illustrative to the application and further understand below in conjunction with specific embodiment, but embodiment is only used as example
Son provides, and is not intended as whole technical schemes of the present invention, is not limited overall technical solution.It is all have it is identical or
Similar technique feature simply changes or replaced, and belongs to the scope of the present invention.
Embodiment 1
Experiment flow figure such as patent accompanying drawing illustrates Fig. 1：A kind of 2- methyl -4- amino -5- (carbamoylmethyl) pyrimidine pilot scale
Shown in recycled hydrolysis flow chart, comprise the following steps：
(1) 400L distilled water is added in back flow reaction kettle 1, by feeding-in solid body mouth by 375.75kg 2- methyl -4- ammonia
Base -5- (formyl aminomethyl) pyrimidines and 80.00kg sodium hydroxide add, and open stirring, temperature control is at 110 DEG C or so, instead
Answer 2 hours.After having reacted, toluene 2000L is added in reactor 1, it is phonetic to principal product 2- methyl -4- amino -5- (amino methyl)
Pyridine is extracted.Stop stirring after half an hour, stratification, release organic phase and aqueous phase.
(2) aqueous phase is put into aqueous phase storage tank 3 through pans 2；Toluene is mutually put into cooling reactor 9 through pans 2, is cooled to 0
DEG C or so, product is separated out after 2 hours, isolates solid by filter 10, drying obtains 2- methyl -4- amino -5- (amino first
Base) pyrimidine 260.30kg, filtrate, which is put into, reclaims organic solvent fluid reservoir 11, extractant can be used as to reuse.
(3) by aqueous phase fluid reservoir 3 dissolved with the aqueous phase of unreacted 2- methyl -4- amino -5- (carbamoylmethyl) pyrimidine
Back flow reaction kettle 4 is put into, adds 292.25kg 2- methyl -4- amino -5- (formyl aminomethyl) pyrimidines and 90.00kg hydrogen-oxygens
Change sodium, stir and, temperature rises to 110 DEG C or so, reacts 2 hours.After having reacted, by recovery organic solvent fluid reservoir 11
2000L recovery toluene is put into reactor 4 and extracted；Stratification after having extracted, aqueous phase are put into cooling reactor 6 through pans 5
In；Organic phase is put into cooling reactor 9 through pans 5, is cooled to 0 DEG C or so, is crystallized, and is separated after 2 hours through filter 10
Go out solid, drying obtains 2- methyl -4- amino -5- (amino methyl) pyrimidine 265.41kg, and filtrate is put into recovery organic solvent storage
Flow container 11.
(4) aqueous phase being put into cooling reactor 6 cools to 10 DEG C or so crystallizations, is isolated after 2 hours by filter 7
Solid, dries to obtain byproduct sodium formate 204.01kg, and filtrate water is sent to the deposit of aqueous phase storage tank 8 and treated dissolved with excessive sodium hydrate
Apply mechanically.
In above-mentioned process example：Merge 2 2- methyl -4- amino -5- (amino methyl) pyrimidines isolated to obtain
525.71kg, the content that obtained product detects 2- methyl -4- amino -5- (amino methyl) pyrimidine through HPLC is 99.00%.
Embodiment 2
The 400L aqueous solution dissolved with excessive sodium hydrate left in the aqueous phase storage tank 8 of embodiment 1 is transported to reactor 1
In, applied mechanically instead of 400L distilled water as solvent, other process conditions and operating process such as embodiment 1, raw material addition
Lattice 1 are shown in Table with product obtained quantity.
In above-mentioned process example：Merge 2 2- methyl -4- amino -5- (amino methyl) pyrimidines isolated to obtain
550.01kg, the content that obtained product detects 2- methyl -4- amino -5- (amino methyl) pyrimidine through HPLC is 99.20%.
Embodiment 3
The 400L aqueous solution dissolved with excessive sodium hydrate left in the aqueous phase storage tank 8 of embodiment 2 is transported to reactor 1
In, applied mechanically instead of 400L distilled water as solvent, other process conditions and operating process such as embodiment 1, raw material addition
Lattice 1 are shown in Table with product obtained quantity
In above-mentioned process example：Merge 2 2- methyl -4- amino -5- (amino methyl) pyrimidines isolated to obtain
551.32kg, the content that obtained product detects 2- methyl -4- amino -5- (amino methyl) pyrimidine through HPLC is 99.30%.
Embodiment 4
The 400L aqueous solution dissolved with excessive sodium hydrate left in the aqueous phase storage tank 8 of embodiment 3 is transported to reactor 1
In, applied mechanically instead of 400L distilled water as solvent, other process conditions and operating process such as embodiment 1, raw material addition
Lattice 1 are shown in Table with product obtained quantity
In above-mentioned process example：Merge 2 2- methyl -4- amino -5- (amino methyl) pyrimidines isolated to obtain
552.24kg, the content that obtained product detects 2- methyl -4- amino -5- (amino methyl) pyrimidine through HPLC is 99.20%.
Embodiment 5
The 400L aqueous solution dissolved with excessive sodium hydrate left in the aqueous phase storage tank 8 of embodiment 4 is transported to reactor 1
In, applied mechanically instead of 400L distilled water as solvent, other process conditions and operating process such as embodiment 1, raw material addition
Lattice 1 are shown in Table with product obtained quantity.
In above-mentioned process example：Merge 2 2- methyl -4- amino -5- (amino methyl) pyrimidines isolated to obtain
552.29kg, the content that obtained product detects 2- methyl -4- amino -5- (amino methyl) pyrimidine through HPLC is 99.30%.
After circulation 5 times, the aqueous solution in aqueous phase fluid reservoir 8 dissolved with excessive sodium hydrate, which can still continue cycling through, to be applied mechanically.
Form 1:Material condition and product yield
Claims (4)
1. a kind of 2- methyl -4- amino -5- (formyl aminomethyl) pyrimidine hydrolysis process, it is characterised in that comprise the following steps：
(1) excessive 2- methyl -4- amino -5- (formyl aminomethyl) pyrimidines and sodium hydrate aqueous solution hydrolysis, have reacted
Carried out extracting major product 2- methyl -4- amino -5- (amino methyl) pyrimidine with organic solvent afterwards, and isolate organic phase and water
Phase；
(2) the organic phase cooling that step (1) is isolated separates out product 2- methyl -4- amino -5- (amino methyl) pyrimidine, solid-liquid point
From product；
(3) 2- is added in (1) aqueous phase 2- methyl -4- amino -5- (formyl aminomethyl) pyrimidine complete dissolved with unreacted the step of
Reaction is hydrolyzed in methyl -4- amino -5- (formyl aminomethyl) pyrimidines and sodium hydroxide, keeps sodium hydroxide excessive, has reacted
Organic extractant phase product 2- methyl -4- amino -5- (amino methyl) pyrimidine is used afterwards, isolates organic phase and aqueous phase；
(4) the organic phase cooling that step (3) is isolated separates out product 2- methyl -4- amino -5- (amino methyl) pyrimidine, solid-liquid point
From product；
(5) the aqueous phase cooling that step (3) obtains separates out byproduct sodium formate, and separation of solid and liquid obtains byproduct sodium formate and aqueous phase；
(6) aqueous phase that step (5) obtains adds 2- methyl -4- amino -5- (formyl ammonia first dissolved with the complete sodium hydroxide of unreacted
Base) reaction is hydrolyzed in pyrimidine and sodium hydroxide, and keep 2- methyl -4- amino -5- (formyl aminomethyl) pyrimidine excessive, repeat to walk
Suddenly (1) operates.
2. a kind of 2- methyl -4- amino -5- (formyl aminomethyl) pyrimidine hydrolysis process according to claim 1, its feature
It is：Organic extractant is one or more combinations in benzene, toluene, ethylbenzene, dimethylbenzene in step (1), (3).
3. a kind of 2- methyl -4- amino -5- (formyl aminomethyl) pyrimidine hydrolysis process according to claim 1, its feature
It is：Hydrolysising reacting temperature is 80~120 DEG C in step (1), (3).
4. a kind of 2- methyl -4- amino -5- (formyl aminomethyl) pyrimidine hydrolysis process according to claim 1, its feature
It is：Step (1) to (6) circulates always, starts the cycle over from newly when appropriate, is started the cycle over from (1), or is opened from (3)
Begin to circulate, appropriate supplement solvent or water in cyclic process.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108546249A (en) * | 2018-02-28 | 2018-09-18 | 东北制药集团股份有限公司 | A method of preparing diamine pyrimidine |
| CN109503497A (en) * | 2018-12-24 | 2019-03-22 | 江苏兄弟维生素有限公司 | A kind of method of purification of aminopyrimidine |
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| WO2008087021A1 (en) * | 2007-01-19 | 2008-07-24 | Dsm Ip Assets B.V. | Synthesis of 4-amino-pyrimidines |
| CN103012282A (en) * | 2012-12-03 | 2013-04-03 | 华中药业股份有限公司 | Synthetic method of vitamin B1 intermediate |
| CN103420918A (en) * | 2013-07-22 | 2013-12-04 | 新发药业有限公司 | Simple and convenient preparation method of key intermediate (2-methyl-4-amino-5-amino methyl pyrimidine) for vitamin B1 |
| CN103435556A (en) * | 2013-08-26 | 2013-12-11 | 新发药业有限公司 | Simple and quick method for synthesizing improved vitamin B1 intermediate 2-methyl-4-amino-5-aminomethylpyrimidine |
| CN104059023A (en) * | 2013-03-18 | 2014-09-24 | 新发药业有限公司 | Environment-friendly preparation method for key intermediate 2-methyl-4-amino-5-aminomethyl pyrimidine of vitamin B1 |
| CN104326989A (en) * | 2014-11-26 | 2015-02-04 | 江西天新药业有限公司 | Preparation method of 2-methyl-4-amino-5-(aminomethyl) pyrimidine |
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Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008087021A1 (en) * | 2007-01-19 | 2008-07-24 | Dsm Ip Assets B.V. | Synthesis of 4-amino-pyrimidines |
| CN103012282A (en) * | 2012-12-03 | 2013-04-03 | 华中药业股份有限公司 | Synthetic method of vitamin B1 intermediate |
| CN104059023A (en) * | 2013-03-18 | 2014-09-24 | 新发药业有限公司 | Environment-friendly preparation method for key intermediate 2-methyl-4-amino-5-aminomethyl pyrimidine of vitamin B1 |
| CN103420918A (en) * | 2013-07-22 | 2013-12-04 | 新发药业有限公司 | Simple and convenient preparation method of key intermediate (2-methyl-4-amino-5-amino methyl pyrimidine) for vitamin B1 |
| CN103435556A (en) * | 2013-08-26 | 2013-12-11 | 新发药业有限公司 | Simple and quick method for synthesizing improved vitamin B1 intermediate 2-methyl-4-amino-5-aminomethylpyrimidine |
| CN104326989A (en) * | 2014-11-26 | 2015-02-04 | 江西天新药业有限公司 | Preparation method of 2-methyl-4-amino-5-(aminomethyl) pyrimidine |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108546249A (en) * | 2018-02-28 | 2018-09-18 | 东北制药集团股份有限公司 | A method of preparing diamine pyrimidine |
| CN108546249B (en) * | 2018-02-28 | 2021-10-01 | 东北制药集团股份有限公司 | Method for preparing bisamine pyrimidine |
| CN109503497A (en) * | 2018-12-24 | 2019-03-22 | 江苏兄弟维生素有限公司 | A kind of method of purification of aminopyrimidine |
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