CN105601542A - Method for crystallizing N-carbamylglutamic acid with mixed acid - Google Patents
Method for crystallizing N-carbamylglutamic acid with mixed acid Download PDFInfo
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- CN105601542A CN105601542A CN201610009812.1A CN201610009812A CN105601542A CN 105601542 A CN105601542 A CN 105601542A CN 201610009812 A CN201610009812 A CN 201610009812A CN 105601542 A CN105601542 A CN 105601542A
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- Prior art keywords
- acid
- carbamylglutamic
- carbamylglutamic acid
- crystallization
- reactant liquor
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- LCQLHJZYVOQKHU-VKHMYHEASA-N carglumic acid Chemical compound NC(=O)N[C@H](C(O)=O)CCC(O)=O LCQLHJZYVOQKHU-VKHMYHEASA-N 0.000 title claims abstract description 82
- 238000000034 method Methods 0.000 title claims abstract description 25
- 239000002253 acid Substances 0.000 title claims abstract description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 50
- 238000002425 crystallisation Methods 0.000 claims abstract description 33
- 230000008025 crystallization Effects 0.000 claims abstract description 33
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims abstract description 31
- 239000012043 crude product Substances 0.000 claims abstract description 28
- 239000007787 solid Substances 0.000 claims abstract description 16
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000000967 suction filtration Methods 0.000 claims abstract description 11
- 239000000376 reactant Substances 0.000 claims description 42
- 239000000203 mixture Substances 0.000 claims description 30
- 238000006396 nitration reaction Methods 0.000 claims description 17
- 238000001035 drying Methods 0.000 claims description 2
- 230000020477 pH reduction Effects 0.000 abstract description 30
- 239000000047 product Substances 0.000 abstract description 11
- 238000006243 chemical reaction Methods 0.000 abstract description 10
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 abstract description 4
- 230000000694 effects Effects 0.000 abstract description 4
- 239000012295 chemical reaction liquid Substances 0.000 abstract description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 abstract description 2
- 150000007522 mineralic acids Chemical class 0.000 abstract description 2
- 159000000000 sodium salts Chemical class 0.000 abstract description 2
- 150000002500 ions Chemical class 0.000 abstract 1
- 229910017604 nitric acid Inorganic materials 0.000 abstract 1
- 238000001556 precipitation Methods 0.000 abstract 1
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 238000002360 preparation method Methods 0.000 description 12
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 10
- 235000013922 glutamic acid Nutrition 0.000 description 10
- 239000004220 glutamic acid Substances 0.000 description 10
- GKKCIDNWFBPDBW-UHFFFAOYSA-M potassium cyanate Chemical compound [K]OC#N GKKCIDNWFBPDBW-UHFFFAOYSA-M 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 238000001291 vacuum drying Methods 0.000 description 8
- 239000004475 Arginine Substances 0.000 description 7
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 4
- 239000012153 distilled water Substances 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 3
- 239000004202 carbamide Substances 0.000 description 3
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 2
- 239000004472 Lysine Substances 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- 230000008485 antagonism Effects 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- PXEDJBXQKAGXNJ-QTNFYWBSSA-L disodium L-glutamate Chemical compound [Na+].[Na+].[O-]C(=O)[C@@H](N)CCC([O-])=O PXEDJBXQKAGXNJ-QTNFYWBSSA-L 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 235000020776 essential amino acid Nutrition 0.000 description 2
- 239000003797 essential amino acid Substances 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 235000013923 monosodium glutamate Nutrition 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 229940073490 sodium glutamate Drugs 0.000 description 2
- DWNBOPVKNPVNQG-LURJTMIESA-N (2s)-4-hydroxy-2-(propylamino)butanoic acid Chemical compound CCCN[C@H](C(O)=O)CCO DWNBOPVKNPVNQG-LURJTMIESA-N 0.000 description 1
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 1
- 102000003960 Ligases Human genes 0.000 description 1
- 108090000364 Ligases Proteins 0.000 description 1
- RFMMMVDNIPUKGG-YFKPBYRVSA-N N-acetyl-L-glutamic acid Chemical compound CC(=O)N[C@H](C(O)=O)CCC(O)=O RFMMMVDNIPUKGG-YFKPBYRVSA-N 0.000 description 1
- JSJWCHRYRHKBBW-UHFFFAOYSA-N N-carbamoyl-beta-alanine Chemical compound NC(=O)NCCC(O)=O JSJWCHRYRHKBBW-UHFFFAOYSA-N 0.000 description 1
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 1
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 235000020256 human milk Nutrition 0.000 description 1
- 210000004251 human milk Anatomy 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 238000005935 nucleophilic addition reaction Methods 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- -1 salt compounds Chemical class 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- 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
- C07C273/1854—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 by reactions not involving the formation of the N-C(O)-N- moiety
- C07C273/1863—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 by reactions not involving the formation of the N-C(O)-N- moiety from urea
-
- 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 invention discloses a method for crystallizing N-carbamylglutamic acid with mixed acid. According to the method, two or more types of acid are sequentially added to an N-carbamylglutamic acid reaction solution for acidification; an obtained solution stands still at the temperature of 0-4 DEG C and stays overnight, and crystallization is conducted; suction filtration is conducted, obtained solid is dried, and a crude product of the N-carbamylglutamic acid is obtained. The acid is two or more of concentrated hydrochloric acid, concentrated nitric acid, concentrated sulfuric acid, concentrated phosphoric acid and other types of inorganic acid. Compared with an acidification method with a single type of acid, the method for crystallizing N-carbamylglutamic acid with mixed acid has the advantages that the mixed acid acidification reaction liquid is adopted, and the common ion effect caused by single acid acidification can be avoided, so that precipitation of sodium salt along with a product is avoided, crystallization purity of the product, namely the N-carbamylglutamic acid is effectively improved, and the maximum one-time crystallization purity of the product can reach 98.3%.
Description
Technical field
The invention belongs to the field of chemical synthesis, be specifically related to a kind of method of nitration mixture crystallization N-carbamylglutamic acid.
Background technology
Arginine is mammiferous essential amino acid in children's age, because breast milk provides the arginine synthetic with cub self notCan meet its nutritional need, must additionally provide. For adults, arginine is a kind of conditionally essential amino acid. ForPoultry, because there not being carbamyl phosphate synthetase in its mitochondria, can not be by the ornithine endogenous synthetic arginine that circulates,Need in feed, absorb. But arginine price is high and have antagonism and fail to add as feed with lysine, histidineAgent large-scale popularization in animal produces is used.
Recently on market, occurred that a kind of Inner source promotes arginine synthetics N-carbamylglutamic acid (N-CarbamylglutAmate, NCG), it is the analog of N-acetylglutamat, has similar biological function, can promote the endogenous essence of animal bodyThe generation of propylhomoserin, low price, and not with lysine, histidine generation antagonism. Therefore a small amount of NCG just can effectively promote to moveThe endogenous synthetic arginine of thing, has very high economic worth.
The preparation method of at present more existing NCG, for example: print imperial grade of chance and within 2007, disclose a kind of NCG preparation method, withGlutamic acid, potassium cyanate and potassium hydroxide are raw material, at 20～25 DEG C of room temperatures, place 16～20h, and then hcl acidifying, in ureido propionic acidLeave standstill after 2～3h, filter, from water, recrystallization is separated out NCG(patent publication No.: CN101168518A); Watchtower bodyguard men of virtue and ability etc. are with paddy ammoniaAcid, ammonium formate and NaOH are raw material, back flow reaction 30～55 minutes at 98～110 DEG C, and product is cooled to room temperature, uses firstAldehyde washing, filters, and adds concentrated hydrochloric acid acidifying, then leaves standstill in-4～2 DEG C, and crystallization is filtered and obtained NCG(patent publication No.:CN101440042B); Liu Yaqian etc. are taking glutamic acid and potassium cyanate as raw material, and ureido propionic acid is catalyst, at glutamic acid and potassium cyanateUnder the condition of mol ratio 1:1.2, reaction temperature 60-65 DEG C, through nucleophilic addition, recrystallization obtains sterling NCG(Liu YaPretty .N-carbamylglutamic acid study on the synthesis [J]. fine-chemical intermediate, 2011,41 (1): 29-31); Giancarlo etc. exist2007 time, propose, can, with the auxiliary synthetic NCG of microwave, first generate sodium glutamate with glutamic acid and alkali and carry out carboxyl guarantorProtect, then and urea reaction, under 1000W power, react 4min, slough the NH of a part3Thereby, obtain the sodium salt of NCG, make reactionMixture is cooled to 0 DEG C, and methanol wash is removed unnecessary urea, and last concentrated hydrochloric acid acidifying, filters to obtain solid, and sodium chloride is removed in washingObtain NCG sterling (VerardoG, GeattiP, StrazzoliniP.Rapidandefficientmicrowave-assistedsynthesisofN-carbamoyl-L-aminoacids[J].SyntheticCommmunications, 2007,37 (11): 1833-1844.); It is synthetic continuously that Cao Fei etc. disclose a kind of micro passage reactionThe method of N-carbamylglutamic acid, taking sodium glutamate and urea as substrate, successively through the reaction of series connection in micro passage reactionDevice I and reactor II are reacted 10-95min at 100-150 DEG C, micro passage reaction discharging by saltout and refine after obtainN-carbamylglutamic acid finished product (patent publication No.: CN103980163B); Etc..
No matter utilize which kind of synthetic method to prepare NCG, its post processing all adopts concentrated hydrochloric acid acidification reaction liquid. The method existsCertain defect: the salt compounds producing after (1) acidifying solubility in water is not high; (2) solely draw with concentrated hydrochloric acid acidifying meetingPlay common-ion effect, thereby while causing crystallization, sodium chloride or potassium chloride are separated out with product, the NCG crude product purity obtaining is notHeight, although improved product purity by being recrystallized, causes yield to decline.
Summary of the invention
For the defect of N-carbamylglutamic acid method for crystallising in above-mentioned preparation process, the object of the present invention is to provide oneThe method of planting nitration mixture crystallization N-carbamylglutamic acid, the method can effectively improve product primary crystallization purity.
The method of a kind of nitration mixture crystallization N-carbamylglutamic acid provided by the invention, comprises the following steps:
A method for nitration mixture crystallization N-carbamylglutamic acid, is characterized in that, it comprises the following steps:
1) to adding successively in N-carbamylglutamic acid reactant liquor two kinds or two or more acid to carry out acidifying;
2) by the solution of step 1) gained hold over night at 0-4 DEG C, crystallization;
3) suction filtration, by gained solid drying, obtains N-carbamylglutamic acid crude product;
Acid described in step 1) is two or more in the inorganic acids such as concentrated hydrochloric acid, red fuming nitric acid (RFNA), the concentrated sulfuric acid, SPA.
In the present invention, N-carbamylglutamic acid reactant liquor can be by current published any one N-carbamyl paddy ammoniaThe preparation method of acid prepares, and in the N-carbamylglutamic acid reactant liquor preparing, the concentration of N-carbamylglutamic acid is200g/L-1000g/L, being preferably best is 400g/L-600g/L.
When N-carbamylglutamic acid reactant liquor adds in acid acidifying, acid is (1-3) with the mol ratio of raw material glutamic acid: 1.
In step 1), souring temperature is 0-50 DEG C, and acidifying pH value is 0.5-4. Being preferably souring temperature is 0-20 DEG C, acidifyingPH value is 2-3.
In step 1), in N-carbamylglutamic acid reactant liquor, add successively two kinds of acid to carry out acidifying, and the sour order addingResult is had no significant effect to two kinds of sour volume ratio 1:0.3-1:2; Preferably two kinds of sour volume ratio 1:1.
Concentrated hydrochloric acid described in the present invention, red fuming nitric acid (RFNA), the concentrated sulfuric acid, SPA are technology art well known to those skilled in the artLanguage, such as concentrated hydrochloric acid is that mass fraction exceedes 36% hydrochloric acid; Red fuming nitric acid (RFNA) mass fraction is about 65%; The concentrated sulfuric acid is that mass fraction is largeIn or equal 70% sulfuric acid solution; SPA is that mass fraction is 85% phosphoric acid solution.
Beneficial effect:
The method of nitration mixture crystallization N-carbamylglutamic acid provided by the invention has the following advantages compared with single sour acidization tool:
1, the common-ion effect causing when the method for employing nitration mixture acidification reaction liquid can be avoided single acidifying, thus avoidSodium salt is separated out with product, has effectively improved the purity of product N-carbamylglutamic acid crystallization.
2, product primary crystallization purity of the present invention exceedes 90%, reaches as high as 98%.
3, nitration mixture method for crystallising of the present invention has general applicability, treats impurity composition in treatment fluid and does not limit, directlyReactant liquor is passed through to nitration mixture crystallization, without reactant liquor being done to removal of impurities processing.
Detailed description of the invention
According to following embodiment, the present invention may be better understood. But the described content of embodiment is only for explanationThe present invention, and should can not limit the present invention described in detail in claims yet.
Concentrated hydrochloric acid mass fraction 37% in following examples, red fuming nitric acid (RFNA) mass fraction 69.8%, concentrated sulfuric acid mass fraction 98%,SPA mass fraction is 85%.
Embodiment 1
(1) adopt the disclosed N-carbamylglutamic acid of the patent preparation method that publication number is CN101168518A, by 1mol paddy ammoniaAcid, 1mol potassium cyanate, 1mol potassium hydroxide fully mix, and obtain mixture, this mixture is dissolved in 250mL distilled water, inThe lower 16-20 hour that places of room temperature (20-25 DEG C), obtains the N-carbamylglutamic acid reactant liquor that 250mL concentration is 558.3g/L;
(2) under 20 DEG C of conditions of temperature, add successively 75mL concentrated hydrochloric acid (mass fraction 37%), 75mL red fuming nitric acid (RFNA) (mass fraction69.8%) reactant liquor of acidification step (1) gained, pH value of solution to 3;
(3) solution of step (2) gained is placed in to 0-4 DEG C of refrigerator hold over night, crystallization;
(4) suction filtration, gained solid, in 70 DEG C of vacuum drying 24 hours, obtains N-carbamylglutamic acid crude product, and one time yield is81.33%, purity is 98.28%.
Reference examples 1
The present embodiment is all identical with embodiment 1 other conditions, and difference is only: step 2) in add 150mL concentrated hydrochloric acid (quality dividedSeveral 37%) reactant liquor of acidification step (1) gained, obtains N-carbamylglutamic acid crude product, and one time yield is 104.6%, purityBe 78.7%.
Embodiment 2
(1) adopt the disclosed N-carbamylglutamic acid of the patent preparation method that publication number is CN101440042B, take 1mol paddyPropylhomoserin, 1mol ammonium formate and 3mol NaOH, be dissolved in the glutamic acid having taken, NaOH in 0.5L distilled water, stirs,In the mixture obtaining, add the ammonium formate having taken again, fully stir, in 110 DEG C of backflows 30 minutes, obtain 500mL concentrationFor the N-carbamylglutamic acid reactant liquor of 401.45g/L;
(2), under temperature 45 C condition, add successively 167mL (2mol) concentrated hydrochloric acid (mass fraction 37%), 125mL(2mol) dense nitreAcid (mass fraction 69.8%), the reactant liquor of acidification step (1) gained, pH value of solution to 3;
(3) solution of step (2) gained is placed in to 0-4 DEG C of refrigerator hold over night, crystallization;
(4) suction filtration, gained solid, in 70 DEG C of vacuum drying 24 hours, obtains N-carbamylglutamic acid crude product, and one time yield is98.08%, purity is 90.12%.
Reference examples 2
The present embodiment is all identical with embodiment 2 other conditions, and difference is only: step 2) in add 335mL concentrated hydrochloric acid (quality dividedSeveral 37%) reactant liquor of acidification step (1) gained, obtains N-carbamylglutamic acid crude product, and one time yield is 98.5%, and purity is75.9%。
Reference examples 3
The present embodiment is all identical with embodiment 2 other conditions, and difference is only: step 2) in add 250mL red fuming nitric acid (RFNA) (quality dividedSeveral 69.8%) reactant liquor of acidification step (1) gained, obtains N-carbamylglutamic acid crude product, and one time yield is 90.1%, purityBe 79.3%.
Embodiment 3
(1) adopt the report such as Liu Yaqian article (Liu Yaqian .N-carbamylglutamic acid study on the synthesis [J]. in the middle of fine chemistry industryBody, 2011,41 (1): 29-31) disclosed N-carbamylglutamic acid preparation method, in 1mol glutamic acid, add 300mL distillationWater, 1mol potassium cyanate, 1mol potassium hydroxide, fully mix, and heating makes dissolution of solid and in 65 DEG C of stirring reactions 2 hours, obtains300mL concentration is the N-carbamylglutamic acid reactant liquor of 649.5g/L;
(2), under 30 DEG C of conditions of temperature, add successively 75mL concentrated hydrochloric acid (mass fraction 37%), the 75mL concentrated sulfuric acid (mass fraction 98%)The reactant liquor of acidification step (1) gained, pH value of solution to 1;
(3) solution of step (2) gained is placed in to 0-4 DEG C of refrigerator hold over night, crystallization;
(4) suction filtration, gained solid, in 70 DEG C of vacuum drying 24 hours, obtains N-carbamylglutamic acid crude product, and one time yield is90.53%, purity is 92.09%.
Reference examples 4
The present embodiment is all identical with embodiment 3 other conditions, and difference is only: step 2) in add 150mL concentrated hydrochloric acid (quality dividedSeveral 37%) reactant liquor of acidification step (1) gained, obtains N-carbamylglutamic acid crude product, and one time yield is 98.7%, purity80.5%。
Reference examples 5
The present embodiment is all identical with embodiment 3 other conditions, and difference is only: step 2) in add the 150mL concentrated sulfuric acid (quality dividedSeveral 98%) reactant liquor of acidification step (1) gained, obtains N-carbamylglutamic acid crude product, and one time yield is 101.6%, purityBe 70.3%.
Embodiment 4
(1) adopt the disclosed N-carbamylglutamic acid of the patent preparation method that publication number is CN101440042B, take 1mol paddyPropylhomoserin, 1mol ammonium formate and 3mol NaOH, be dissolved in the glutamic acid having taken, NaOH in 0.5L distilled water, stirs,In the mixture obtaining, add the ammonium formate having taken again, fully stir, in 110 DEG C of backflows 30 minutes, obtain 508mL concentrationFor the N-carbamylglutamic acid reactant liquor of 607.54g/L;
(2) under 0 DEG C of condition of temperature, add successively the 150mL concentrated sulfuric acid (mass fraction 98%), 150mL red fuming nitric acid (RFNA) (mass fraction69.8%) reactant liquor of acidification step (1) gained, pH value of solution to 1;
(3) solution of step (2) gained is placed in to 0-4 DEG C of refrigerator hold over night, crystallization;
(4) suction filtration, gained solid, in 70 DEG C of vacuum drying 24 hours, obtains N-carbamylglutamic acid crude product, and one time yield is89.13%, purity is 93.53%.
Reference examples 6
The present embodiment is all identical with embodiment 4 other conditions, and difference is only: step 2) in add 150mL red fuming nitric acid (RFNA) (quality dividedSeveral 69.8%) reactant liquor of acidification step (1) gained, obtains N-carbamylglutamic acid crude product, and one time yield is 93.7%, purity81.7%。
Reference examples 7
The present embodiment is all identical with embodiment 4 other conditions, and difference is only: step 2) in add the 150mL concentrated sulfuric acid (quality dividedSeveral 98%) reactant liquor of acidification step (1) gained, obtains N-carbamylglutamic acid crude product, and one time yield is 103.6%, purityBe 71.5%.
Embodiment 5
(1) adopt the report such as Liu Yaqian article (Liu Yaqian .N-carbamylglutamic acid study on the synthesis [J]. in the middle of fine chemistry industryBody, 2011,41 (1): 29-31) disclosed N-carbamylglutamic acid preparation method, in 1mol glutamic acid, add 300mL distillationWater, 1mol potassium cyanate, 1mol potassium hydroxide, fully mix, and heating makes dissolution of solid and in 65 DEG C of stirring reactions 2 hours, obtains314mL concentration is the N-carbamylglutamic acid reactant liquor of 613.92g/L;
(2) under 35 DEG C of conditions of temperature, add successively 100mL concentrated hydrochloric acid (mass fraction 37%), 200mL red fuming nitric acid (RFNA) (mass fraction69.8%) reactant liquor of acidification step (1) gained, pH value of solution to 2;
(3) solution of step (2) gained is placed in to 0-4 DEG C of refrigerator hold over night, crystallization;
(4) suction filtration, gained solid, in 70 DEG C of vacuum drying 24 hours, obtains N-carbamylglutamic acid crude product, and one time yield is92.71%, purity is 90.09%.
Reference examples 8
The present embodiment is all identical with embodiment 5 other conditions, and difference is only: step 2) in add 170mL concentrated hydrochloric acid (quality dividedSeveral 37%) reactant liquor of acidification step (1) gained, obtains N-carbamylglutamic acid crude product, and one time yield is 100.8%, purityBe 76. 7%.
Reference examples 9
The present embodiment is all identical with embodiment 5 other conditions, and difference is only: step 2) in add 125mL red fuming nitric acid (RFNA) (quality dividedSeveral 69.8%) reactant liquor of acidification step (1) gained, obtains N-carbamylglutamic acid crude product, and one time yield is 91.7%, purityBe 80.3%.
Embodiment 6
(1) adopt the disclosed N-carbamylglutamic acid of the patent preparation method that publication number is CN101168518A, by 2mol paddy ammoniaAcid, 2mol potassium cyanate, 2mol potassium hydroxide fully mix, and obtain mixture, this mixture is dissolved in 700mL distilled water, inThe lower 16-20 hour that places of room temperature (20-25 DEG C), obtains the N-carbamylglutamic acid reactant liquor that 745mL concentration is 598.92g/L;
(2), under temperature 50 C condition, add successively 300mL concentrated hydrochloric acid (mass fraction 37%), 150mL red fuming nitric acid (RFNA) (mass fraction69.8%) reactant liquor of acidification step (1) gained, pH value of solution to 3;
(3) solution of step (2) gained is placed in to 0-4 DEG C of refrigerator hold over night, crystallization;
(4) suction filtration, gained solid, in 70 DEG C of vacuum drying 24 hours, obtains N-carbamylglutamic acid crude product, and one time yield is87.49%, purity is 92.08%.
Reference examples 10
The present embodiment is all identical with embodiment 6 other conditions, and difference is only: step 2) in add 350mL concentrated hydrochloric acid (quality dividedSeveral 37%) reactant liquor of acidification step (1) gained, obtains N-carbamylglutamic acid crude product, and one time yield is 98.7%, and purity is77.3%。
Reference examples 11
The present embodiment is all identical with embodiment 6 other conditions, and difference is only: step 2) in add 250mL red fuming nitric acid (RFNA) (quality dividedSeveral 69.8%) reactant liquor of acidification step (1) gained, obtains N-carbamylglutamic acid crude product, and one time yield is 90.6%, purityBe 80.2%.
Embodiment 7
(1) adopt the report such as Liu Yaqian article (Liu Yaqian .N-carbamylglutamic acid study on the synthesis [J]. in the middle of fine chemistry industryBody, 2011,41 (1): 29-31) disclosed N-carbamylglutamic acid preparation method, in 1mol glutamic acid, add 250mL distillationWater, 1mol potassium cyanate, 1mol potassium hydroxide, fully mix, and heating makes dissolution of solid and in 65 DEG C of stirring reactions 2 hours, obtains255mL concentration is the N-carbamylglutamic acid reactant liquor of 640.79g/L;
(2) under 40 DEG C of conditions of temperature, add successively 50mL concentrated hydrochloric acid (mass fraction 37%), 50mL red fuming nitric acid (RFNA) (mass fraction69.8%), the reactant liquor of the 50mL concentrated sulfuric acid (mass fraction 98%) acidification step (1) gained, pH value of solution to 2;
(3) solution of step (2) gained is placed in to 0-4 DEG C of refrigerator hold over night, crystallization;
(4) suction filtration, gained solid, in 70 DEG C of vacuum drying 24 hours, obtains N-carbamylglutamic acid crude product, and one time yield is85.61%, purity is 94.39%.
Reference examples 12
The present embodiment is all identical with embodiment 7 other conditions, and difference is only: step 2) in add 170mL concentrated hydrochloric acid (quality dividedSeveral 37%) reactant liquor of acidification step (1) gained, obtains N-carbamylglutamic acid crude product, and one time yield is 101.5%, purityBe 77.3%.
Reference examples 13
The present embodiment is all identical with embodiment 7 other conditions, and difference is only: step 2) in add 125mL red fuming nitric acid (RFNA) (quality dividedSeveral 69.8%) reactant liquor of acidification step (1) gained, obtains N-carbamylglutamic acid crude product, and one time yield is 87.8%, purityBe 78.3%.
Reference examples 14
The present embodiment is all identical with embodiment 7 other conditions, and difference is only: step 2) in add the 110mL concentrated sulfuric acid (quality dividedSeveral 98%) reactant liquor of acidification step (1) gained, obtains N-carbamylglutamic acid crude product, and one time yield is 99.4%, and purity is72.1%。
Embodiment 8
(1) adopt the report such as Liu Yaqian article (Liu Yaqian .N-carbamylglutamic acid study on the synthesis [J]. in the middle of fine chemistry industryBody, 2011,41 (1): 29-31) disclosed N-carbamylglutamic acid preparation method, in 1mol glutamic acid, add 300mL distillationWater, 1mol potassium cyanate, 1mol potassium hydroxide, fully mix, and heating makes dissolution of solid and in 65 DEG C of stirring reactions 2 hours, obtains315mL concentration is the N-carbamylglutamic acid reactant liquor of 621.54g/L;
(2) under 25 DEG C of conditions of temperature, add successively 100mL concentrated hydrochloric acid (mass fraction 37%), 100mL SPA (mass fraction85%) reactant liquor of acidification step (1) gained, pH value of solution to 2;
(3) solution of step (2) gained is placed in to 0-4 DEG C of refrigerator hold over night, crystallization;
(4) suction filtration, gained solid, in 70 DEG C of vacuum drying 24 hours, obtains N-carbamylglutamic acid crude product, and one time yield is83.9%, purity is 89.02%.
Reference examples 15
The present embodiment is all identical with embodiment 8 other conditions, and difference is only: step 2) in add 170mL concentrated hydrochloric acid (quality dividedSeveral 37%) reactant liquor of acidification step (1) gained, obtains N-carbamylglutamic acid crude product, and one time yield is 100.8%, purityBe 76.7%.
Reference examples 16
The present embodiment is all identical with embodiment 8 other conditions, and difference is only: step 2) in add 150mL SPA (quality dividedSeveral 85%) reactant liquor of acidification step (1) gained, obtains N-carbamylglutamic acid crude product, and one time yield is 90.02%, purityBe 77.38%.
Claims (8)
1. a method for nitration mixture crystallization N-carbamylglutamic acid, is characterized in that, it comprises the following steps:
1) to adding successively in N-carbamylglutamic acid reactant liquor two kinds or two or more acid to carry out acidifying;
2) by the solution of step 1) gained hold over night at 0-4 DEG C, crystallization;
3) suction filtration, by gained solid drying, obtains N-carbamylglutamic acid crude product.
2. the method for a kind of nitration mixture crystallization N-carbamylglutamic acid according to claim 1, is characterized in that, described N-ammoniaIn carbamylglutamic reactant liquor, the concentration of N-carbamylglutamic acid is 200g/L-1000g/L.
3. the method for a kind of nitration mixture crystallization N-carbamylglutamic acid according to claim 1, is characterized in that, in step 1)Souring temperature is 0-50 DEG C, and acidifying pH value is 0.5-4.
4. the method for a kind of nitration mixture crystallization N-carbamylglutamic acid according to claim 1, is characterized in that, in step 1)In N-carbamylglutamic acid reactant liquor, add successively two kinds of acid, two kinds of sour volume ratio 1:0.3-1:2.
5. the method for a kind of nitration mixture crystallization N-carbamylglutamic acid according to claim 1, is characterized in that, in step 1)Described acid is concentrated hydrochloric acid, red fuming nitric acid (RFNA), the concentrated sulfuric acid or SPA.
6. the method for a kind of nitration mixture crystallization N-carbamylglutamic acid according to claim 2, is characterized in that, described N-ammoniaIn carbamylglutamic reactant liquor, the concentration of N-carbamylglutamic acid is 400g/L-600g/L.
7. the method for a kind of nitration mixture crystallization N-carbamylglutamic acid according to claim 3, is characterized in that, in step 1)Souring temperature is 0-20 DEG C, and acidifying pH value is 2-3.
8. the method for a kind of nitration mixture crystallization N-carbamylglutamic acid according to claim 4, is characterized in that, in step 1)Two kinds of sour volume ratio 1:1.
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| CN107033035A (en) * | 2017-06-02 | 2017-08-11 | 河南省科学院高新技术研究中心 | A kind of synthesis of high purity N carbamylglutamic acid and its post-processing approach |
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| CN108484448A (en) * | 2018-04-27 | 2018-09-04 | 湖北泓肽生物科技有限公司 | The method of one pot process N- carbamylglutamic acids |
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| CN106361857A (en) * | 2016-09-29 | 2017-02-01 | 林州亚太兴牧科技有限公司 | N-carbamylglutamic acid (NCG) composite for improving fur quality of rex rabbits and preparation method thereof |
| CN108017561A (en) * | 2016-11-04 | 2018-05-11 | 武汉武药科技有限公司 | A kind of method of refined card glutamic acid |
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| 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 |
| 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 |
| CN112062694A (en) * | 2020-08-07 | 2020-12-11 | 天津全和诚科技有限责任公司 | Preparation process of N-carbamylglutamic acid |
| CN112209854A (en) * | 2020-09-24 | 2021-01-12 | 天津全和诚科技有限责任公司 | Synthesis method of high-purity N-carbamylglutamic acid |
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