CN108017561A - A kind of method of refined card glutamic acid - Google Patents
A kind of method of refined card glutamic acid Download PDFInfo
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- CN108017561A CN108017561A CN201610973321.9A CN201610973321A CN108017561A CN 108017561 A CN108017561 A CN 108017561A CN 201610973321 A CN201610973321 A CN 201610973321A CN 108017561 A CN108017561 A CN 108017561A
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- glutamic acid
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- card glutamic
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C273/00—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C273/18—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas
- C07C273/189—Purification, separation, stabilisation, use of additives
Abstract
The present invention relates to a kind of method of refined card glutamic acid.Described method includes following steps：(1 1) card glutamic acid crude product reacts to obtain card glutamate in containing the alcoholic solvent that carbon number is 1 to 5 with alkali；The card glutamate that (2 1) step (1) obtains retrieves card glutamic acid with acid reaction.Solve the problems, such as that traditional handicraft product purity is relatively low, improve the product quality of card glutamic acid；The product content refined using this method can reach more than 99.5%, and impurity is respectively less than 0.1%, meet the product quality of bulk pharmaceutical chemicals.
Description
Technical field
The present invention relates to a kind of method of refined card glutamic acid, further after more particularly to being reacted using crude product with alkali
The method of card glutamic acid is made again with acid reaction.
Background technology
It is reported that finding, between 1980 to 2001, there are 42 from 28 families children to be diagnosed as NAGS (N-
Acetylglutamate synthetase) deficiency disease, wherein 8 people are dead because not given treatment in time.NAGS deficiency diseases, are a kind of congenital
Urea cycle disorder disease.Patient often makes in blood that ammonia density is excessive, there is the possibility for causing acute death due to lacking NAGS
Property.And NAGS deficiency diseases are less as a kind of rare disease, its medicine, patient is often difficult to obtain effective treatment.
Card glutamic acid, chemical name：N- carbamyls-Pidolidone or (2S) -2- (carbamyl amino) glutaric acid, chemistry
Formula：C6H10N2O5.This product mainly treat children and adult human liver N-acetylglutamate synthetase (NAGS) lack induced Acute or
Chronic hyperammonemia.Mechanism of action is a synthesis compound similar with N-acetylglutamat (NAG) structure for card glutamic acid,
It is the important allosteric activation agent of carbamyl phosphate synthesis (CPS1) in liver mitochondrion.And CPS1 is the bird that ammonia is changed into urea
The primary enzyme of propylhomoserin circulation.NAG is the product of cyclophorase acetylglutamate synthase (NAGS).Therefore card glutamic acid passes through activation
CPS1 substitutions NAGS lacks the NAG of patient.The medicine lists abroad at present, and the country there is no company to produce.Card glutamic acid
Structural formula is：
The synthesis technique of card glutamic acid reports less that traditional handicraft is using Pidolidone as raw material, in alkaline conditions
With cyanic acid nak response, gained card glutamic acid crude product is refined with water, got product, but the finished product that the process for purification obtains is pure
Spend relatively low, particularly maximum single impurity (single miscellaneous) can not meet the needs of being less than 0.1%, therefore be unable to reach the matter of bulk pharmaceutical chemicals
Amount requires.
The content of the invention
Known in those skilled in the art, the purity requirement to the target compound in bulk pharmaceutical chemicals, it is total will not only to pay close attention to its
Purity, and the single impurity (single miscellaneous) of the target compound in bulk pharmaceutical chemicals will also reach less than some limit, be typically less than
0.1%；And traditional process for purification can not make the maximum single impurity (single miscellaneous) in card glutamic acid be less than 0.1%, therefore utilize
Tradition can not obtain the card glutamic acid finished product for meeting standards of the application.And the present invention is mainly to the later stage process for refining of card glutamic acid
Be improved, solve the problems, such as that traditional handicraft product purity is relatively low, particularly by maximum single miscellaneous content be reduced to 0.1% with
Under level, bulk pharmaceutical chemicals quality is further declared related drugs product.Therefore, with conventional method there is this in this process for purification
The difference of matter, thus there is extremely important realistic meaning.
In addition, since the raw material Pidolidone of this product is very cheap, and have extensive source.And final products Ka Gu
If propylhomoserin is again higher as the price of medicine, therefore from the economic viewpoint, although the yield of the present invention is compared with conventional method
It has been declined that, but the purity of the target compound in bulk pharmaceutical chemicals improves 0.5% or so, and particularly maximum single miscellaneous content drops to
Level less than 0.1%, therefore consider using the method for the present invention to prepare the card glutamic acid of purity higher be to have very much
Necessity, and be worth.
Specifically, the present invention provides a kind of method of refined card glutamic acid, described method includes following steps：
(1-1) card glutamic acid crude product reacts to obtain card glutamic acid in containing the alcoholic solvent that carbon number is 1 to 5 with alkali
Salt；
The card glutamate that (2-1) step (1-1) obtains retrieves card glutamic acid with acid reaction.
The alcohol containing carbon number 1 to 5, refers to that the carbon number in alcohol molecule (can be abbreviated as C for 1 to 51-C5
Alcohol).
In a detailed embodiment, the card glutamic acid brine is the card glutamate of dissolubility.
In a detailed embodiment, it is described to be selected from methanol, ethanol, isopropyl containing the alcoholic solvent that carbon number is 1 to 5
At least one of alcohol and normal propyl alcohol.
In a detailed embodiment, the alkali is selected from sodium hydroxide, potassium hydroxide, ammonia, lithium hydroxide, magnesium hydroxide
At least one of with calcium hydroxide.
In a detailed embodiment, it is described acid in hydrochloric acid, sulfuric acid, acetic acid, hydrobromic acid, phosphoric acid and carbonic acid extremely
Few one kind.Wherein, it will be understood to those skilled in the art that the salt of generation should be water miscible in step (2-1), such as
Sodium chloride, potassium chloride, ammonium chloride, magnesium chloride, calcium chloride, sodium sulphate, potassium sulfate, ammonium sulfate, magnesium sulfate, calcium sulfate, sodium acetate,
Potassium acetate, ammonium acetate, sodium bromide, potassium bromide, ammonium bromide, sodium phosphate, potassium phosphate and ammonium phosphate etc..Otherwise, if in the step
The salt of middle generation will be unfavorable for the crystallization purifying of follow-up card glutamic acid if water-insoluble.
In a preferred embodiment, the acid is selected from least one of hydrochloric acid, sulfuric acid and acetic acid.
In a detailed embodiment, in step (1-1), react and carried out under conditions of temperature is 30 DEG C to 50 DEG C
10 minutes to 3 hours.
In a preferred embodiment, in step (1-1), react in the condition that temperature is 35 DEG C to 45 DEG C
20 minutes to 1 hours of lower progress.
In a detailed embodiment, after step (1-1), before step (2-1), further including step (1-2) will
Reaction solution in step (1) is adjusted to 5 DEG C to 30 DEG C, 2 hours of crystallization to 30 hours.
In a preferred embodiment, the step of after the step (1-1) and before step (2-1)
In (1-2), the reaction solution in step (1) is adjusted to 10 DEG C to 25 DEG C, 10 hours of crystallization to 20 hours.
In a detailed embodiment, after step (2-1), step (2-2) is further included by the reaction solution in step (2)
0 DEG C to 20 DEG C is adjusted to, 2 hours of crystallization to 30 hours.
In a preferred embodiment, the step of after the step (2-1) in (2-2), by step (2)
Reaction solution is adjusted to 0 DEG C to 10 DEG C, 10 hours of crystallization to 20 hours.
In a detailed embodiment, the molar ratio of the card glutamic acid crude product and alkali is less than 1:1；It is preferred that the Ka Gu
The molar ratio of propylhomoserin crude product and alkali is 1:2 to 1:4.
In a detailed embodiment, the molar ratio of the card glutamic acid crude product and acid is less than 1:1；It is preferred that the Ka Gu
The molar ratio of propylhomoserin crude product and acid is 1:2 to 1:4.
In a detailed embodiment, the concentration of the card glutamate is 10wt% to 20wt%.
In a detailed embodiment, concentration of the card glutamic acid crude product in alcoholic solvent for 10% (wt/v) extremely
30% (wt/v).
In a detailed embodiment, concentration of the card glutamic acid crude product in alcoholic solvent for 10% (wt/v) extremely
20% (wt/v).
In a detailed embodiment, concentration of the card glutamic acid crude product in alcoholic solvent for 20% (wt/v) extremely
25% (wt/v).
In a detailed embodiment, the step of further including the card glutamic acid that last drying retrieves；It is preferred that
The dry card glutamic acid retrieved under conditions of 20 DEG C to 40 DEG C.
Embodiment
The present invention is described in detail with reference to embodiment, but the invention is not limited in these embodiments.
Unless otherwise instructed, the raw material in the embodiment of the present invention is bought by commercial sources.Used in the present invention
Card glutamic acid crude product can be obtained by traditional handicraft or purchase, such as using Pidolidone as raw material, in alkaline conditions with cyanogen
Sour nak response is made.
Card glutamic acid process for purification comprises the following steps：
(1) card glutamic acid crude product (wherein card glutamic acid is 1 compound of formula) is dissolved in suitable alcohols solvent, adduction
Suitable alkali (AOH, A therein are cation) is reacted, and obtains compound 2.
(2) compound 2, react with suitable acid, obtain card glutamic acid fine work.
Wherein：The alcohols solvent that step 1 uses can be methanol, ethanol, isopropanol, normal propyl alcohol, and the alkali used is hydrogen-oxygen
Change sodium, potassium hydroxide, ammonium hydroxide.
The acid that step 2 uses can be hydrochloric acid, sulfuric acid and acetic acid.
With the purity of HPLC methods detection card glutamic acid.
The yield of card glutamic acid=card glutamic acid fine work must measure/card glutamic acid crude product amount × 100%
Embodiment 1
The card glutamic acid crude product of 1.47kg and 5L ethanol are mixed in 10L there-necked flasks, stirs and is warming up to 35 DEG C, Xiang Qi
The solution that the sodium hydroxide and 3200g purified waters of middle addition 800g is prepared.Add, stirring clarifies reaction solution.Again 35 DEG C it
Between insulated and stirred 0.5h, be cooled to 15 DEG C, crystallization 10h.Filter to doing, drying, obtains the card sodium glutamate of 700g.Will be upper
State ammonium salt to mix with 6L purified waters and in 10L there-necked flasks, stir dissolved clarification, then with acid for adjusting pH=1-2, be cooled to 0 DEG C, crystallization
10h.Crystallization finishes, and filters to dry, 30 DEG C of dryings, maximum single miscellaneous up to card glutamic acid fine work 370g, product purity 99.8%
Less than 0.1%；Product yield is 25.2%.
Embodiment 2
The card glutamic acid crude product of 4.8kg and 20.4L ethanol are mixed in 50L reaction kettles, stirs and is warming up to 45 DEG C, to
Concentrated ammonia liquor 13.7kg is wherein added dropwise.Add, continue to add the purified water of 1.1kg, reaction solution clarification.Keep the temperature and stir between 45 DEG C again
0.5h is mixed, is cooled to 25 DEG C, crystallization 20h.Filter to doing, drying, obtains the card glutamic acid ammonium salt of 2.3kg.By above-mentioned ammonium salt
Mixed with 19L purified waters and in 50L reaction kettles, stir dissolved clarification, then with acid for adjusting pH=1-2, be cooled to 10 DEG C, crystallization 20h.Analysis
Crystalline substance finishes, centrifuge dripping, 30 DEG C of dryings, and up to card glutamic acid fine work 1.4kg, product content 99.7%, maximum list is miscellaneous to be less than
0.1%；Product yield is 29.2%.
Embodiment 3
The card glutamic acid crude product of 4.8kg and 20.4L ethanol are mixed in 50L reaction kettles, stirs and is warming up to 30 DEG C, to
Concentrated ammonia liquor 13.7kg is wherein added dropwise.Add, continue to add the purified water of 1.1kg, reaction solution clarification.Keep the temperature and stir between 30 DEG C again
1h is mixed, is cooled to 5 DEG C, crystallization 10h.Filter to doing, drying, obtains the card glutamic acid ammonium salt of 2.3kg.By above-mentioned ammonium salt with
19L purified waters mix and in 50L reaction kettles, stir dissolved clarification, then with acid for adjusting pH=1-2, are cooled to 0 DEG C, crystallization 20h.Crystallization
Finish, centrifuge dripping, 30 DEG C of dryings, up to card glutamic acid fine work 1.24kg, product content 99.8%, maximum list is miscellaneous to be less than
0.1%；Product yield is 25.8%.
Embodiment 4
The card glutamic acid crude product of 4.8kg and 20.4L ethanol are mixed in 50L reaction kettles, stirs and is warming up to 50 DEG C, to
Concentrated ammonia liquor 13.7kg is wherein added dropwise.Add, continue to add the purified water of 1.1kg, reaction solution clarification.Keep the temperature and stir between 50 DEG C again
0.5h is mixed, is cooled to 30 DEG C, crystallization 30h.Filter to doing, drying, obtains the card glutamic acid ammonium salt of 2.3kg.By above-mentioned ammonium salt
Mixed with 19L purified waters and in 50L reaction kettles, stir dissolved clarification, then with acid for adjusting pH=1-2, be cooled to 10 DEG C, crystallization 20h.Analysis
Crystalline substance finishes, centrifuge dripping, 30 DEG C of dryings, and up to card glutamic acid fine work 1.32kg, product content 99.7%, maximum list is miscellaneous to be less than
0.1%；Product yield is 27.5%.
Embodiment 5
The card glutamic acid crude product of 4.8kg and 20.4L ethanol are mixed in 50L reaction kettles, stirs and is warming up to 50 DEG C, to
Concentrated ammonia liquor 13.7kg is wherein added dropwise.Add, continue to add the purified water of 1.1kg, reaction solution clarification.Keep the temperature and stir between 50 DEG C again
Mix 10 minutes, be cooled to 30 DEG C, crystallization 30h.Filter to doing, drying, obtains the card glutamic acid ammonium salt of 2.3kg.By above-mentioned ammonium
Salt mixes with 19L purified waters and in 50L reaction kettles, stirs dissolved clarification, then with acid for adjusting pH=1-2, is cooled to 20 DEG C, crystallization 30h.
Crystallization finishes, centrifuge dripping, 30 DEG C of dryings, maximum single miscellaneous small up to card glutamic acid fine work 1.36kg, product content 99.7%
In 0.1%；Product yield is 28.3%.
Embodiment 6
The card glutamic acid crude product of 4.8kg and 20.4L ethanol are mixed in 50L reaction kettles, stirs and is warming up to 50 DEG C, to
Concentrated ammonia liquor 13.7kg is wherein added dropwise.Add, continue to add the purified water of 1.1kg, reaction solution clarification.Keep the temperature and stir between 50 DEG C again
Mix 10 minutes, be cooled to 10 DEG C, crystallization 2h.Filter to doing, drying, obtains the card glutamic acid ammonium salt of 2.3kg.By above-mentioned ammonium salt
Mixed with 19L purified waters and in 50L reaction kettles, stir dissolved clarification, then with acid for adjusting pH=1-2, be cooled to 0 DEG C, crystallization 10h.Analysis
Crystalline substance finishes, centrifuge dripping, 30 DEG C of dryings, and up to card glutamic acid fine work 1.38kg, product content 99.7%, maximum list is miscellaneous to be less than
0.1%；Product yield is 28.8%.
Embodiment 7
The card glutamic acid crude product of 4.8kg and 20.4L ethanol are mixed in 50L reaction kettles, stirs and is warming up to 45 DEG C, to
Concentrated ammonia liquor 13.7kg is wherein added dropwise.Add, continue to add the purified water of 1.1kg, reaction solution clarification.Keep the temperature and stir between 50 DEG C again
3 hours are mixed, are cooled to 10 DEG C, crystallization 2h.Filter to doing, drying, obtains the card glutamic acid ammonium salt of 2.3kg.By above-mentioned ammonium
Salt mixes with 19L purified waters and in 50L reaction kettles, stirs dissolved clarification, then with acid for adjusting pH=1-2, is cooled to 0 DEG C, crystallization 2h.Analysis
Crystalline substance finishes, centrifuge dripping, 30 DEG C of dryings, and up to card glutamic acid fine work 1.33kg, product content 99.7%, maximum list is miscellaneous to be less than
0.1%；Product yield is 27.7%.
Comparative example 1
The card glutamic acid crude product of 4.8kg is mixed with 100L reaction kettles, stirring and being warming up to the purified water of 62.4kg
60 DEG C, stirring is until dissolved clarification.After dissolved clarification, continue to stir and be cooled to 15-25 DEG C, the stirring and crystallizing 6h at 15-25 DEG C, blowing,
Centrifuge dripping, 40 DEG C of dryings, obtain card glutamic acid fine work 2.6kg, product content 99.3%, maximum list is miscellaneous to be more than 0.1%, product
Yield 54.2%.
The above, is only several embodiments of the present invention, any type of limitation is not done to the present invention, although this hair
It is bright with preferred embodiment disclose as above, but and be not used to limitation the present invention, any person skilled in the art, is not taking off
In the range of technical solution of the present invention, make a little variation using the technology contents of the disclosure above or modification is equal to
Case study on implementation is imitated, is belonged in the range of technical solution.
Claims (10)
- A kind of 1. method of refined card glutamic acid, it is characterised in that described method includes following steps：(1-1) card glutamic acid crude product reacts to obtain card glutamate in containing the alcoholic solvent that carbon number is 1 to 5 with alkali；The card glutamate that (2-1) step (1-1) obtains retrieves card glutamic acid with acid reaction.
- 2. according to the method described in claim 1, it is characterized in that, described be selected from first containing the alcoholic solvent that carbon number is 1 to 5 At least one of alcohol, ethanol, isopropanol and normal propyl alcohol.
- 3. according to the method described in claim 1, it is characterized in that, the alkali is selected from sodium hydroxide, potassium hydroxide, ammonia, hydrogen-oxygen Change at least one of lithium, magnesium hydroxide and calcium hydroxide；And/orThe acid is selected from least one of hydrochloric acid, sulfuric acid, acetic acid, hydrobromic acid, phosphoric acid and carbonic acid.
- 4. according to the method described in claim 1, it is characterized in that, in step (1-1), it is 30 DEG C to 50 DEG C to react in temperature Under conditions of carry out 10 minutes to 3 hours；It is preferred that in step (1-1), react under conditions of temperature is 35 DEG C to 45 DEG C Carry out 20 minutes to 1 hours.
- 5. according to the method described in claim 1, it is characterized in that, after step (1-1), before step (2-1), further include Reaction solution in step (1) is adjusted to 5 DEG C to 30 DEG C by step (1-2), 2 hours of crystallization to 30 hours；It is preferred that by step (1) reaction solution in is adjusted to 10 DEG C to 25 DEG C, 10 hours of crystallization to 20 hours.
- 6. according to the method described in claim 1, it is characterized in that, after step (2-1), step (2-2) is further included by step (2) reaction solution in is adjusted to 0 DEG C to 20 DEG C, 2 hours of crystallization to 30 hours；It is preferred that by the reaction solution tune in step (2) Whole to 0 DEG C to 10 DEG C, 10 hours of crystallization to 20 hours.
- 7. according to the method described in claim 1, it is characterized in that, the molar ratio of the card glutamic acid crude product and alkali is less than 1:1； It is preferred that the molar ratio of the card glutamic acid crude product and alkali is 1:2 to 1:4.
- 8. according to the method described in claim 1, it is characterized in that, the molar ratio of the card glutamic acid crude product and acid is less than 1:1； It is preferred that the molar ratio of the card glutamic acid crude product and acid is 1:2 to 1:4.
- 9. according to the method described in claim 1, it is characterized in that, the concentration of the card glutamate for 10wt% extremely 20wt%.
- 10. according to the method described in claim 1, it is characterized in that, further include the card glutamic acid that last drying retrieves The step of；It is preferred that the dry card glutamic acid retrieved under conditions of 20 DEG C to 40 DEG C.
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| CN201610973321.9A CN108017561B (en) | 2016-11-04 | 2016-11-04 | Method for refining carglutamic acid |
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| CN201610973321.9A CN108017561B (en) | 2016-11-04 | 2016-11-04 | Method for refining carglutamic acid |
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Cited By (3)
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|---|---|---|---|---|
| CN112028794A (en) * | 2019-06-03 | 2020-12-04 | 武汉武药科技有限公司 | High-purity kaglutamic acid and preparation method thereof |
| WO2021170154A1 (en) * | 2020-02-26 | 2021-09-02 | Scale Up Laboratory, S.R.O. | Process for the purification of carglumic acid and intermediate of this process |
| CN114522147A (en) * | 2020-11-23 | 2022-05-24 | 武汉武药科技有限公司 | Carglutamic acid solid preparation and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CZ308924B6 (en) * | 2020-02-26 | 2021-09-08 | Scale Up Laboratory s.r.o. | Process for purifying carglumic acid and semi-product of this process |
| CN114522147A (en) * | 2020-11-23 | 2022-05-24 | 武汉武药科技有限公司 | Carglutamic acid solid preparation and preparation method thereof |
| CN114522147B (en) * | 2020-11-23 | 2023-08-04 | 武汉武药科技有限公司 | Solid preparation of carboglutamic acid and preparation method thereof |
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| Publication number | Publication date |
|---|---|
| CN108017561B (en) | 2021-03-30 |
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