CN113045446A - Preparation method of transpeptidase biochemical test reagent substrate - Google Patents
Preparation method of transpeptidase biochemical test reagent substrate Download PDFInfo
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- CN113045446A CN113045446A CN202110332220.4A CN202110332220A CN113045446A CN 113045446 A CN113045446 A CN 113045446A CN 202110332220 A CN202110332220 A CN 202110332220A CN 113045446 A CN113045446 A CN 113045446A
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- transpeptidase
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- 108090000279 Peptidyltransferases Proteins 0.000 title claims abstract description 20
- 239000000758 substrate Substances 0.000 title claims abstract description 20
- 239000003153 chemical reaction reagent Substances 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 238000010876 biochemical test Methods 0.000 title claims abstract description 17
- 238000006243 chemical reaction Methods 0.000 claims abstract description 32
- 239000002904 solvent Substances 0.000 claims abstract description 18
- VOZOQWOUOOVFSB-UHFFFAOYSA-N 6-(trifluoromethyl)-2h-isoquinolin-1-one Chemical compound C1=CNC(=O)C=2C1=CC(C(F)(F)F)=CC=2 VOZOQWOUOOVFSB-UHFFFAOYSA-N 0.000 claims abstract description 15
- 229940126062 Compound A Drugs 0.000 claims abstract description 15
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims abstract description 15
- KZZWQCKYLNIOBT-UHFFFAOYSA-N 5-amino-2-nitrobenzoic acid Chemical compound NC1=CC=C([N+]([O-])=O)C(C(O)=O)=C1 KZZWQCKYLNIOBT-UHFFFAOYSA-N 0.000 claims abstract description 14
- GFABNNMTRVBLPZ-QRPNPIFTSA-N azanium;5-[[(4s)-4-amino-4-carboxybutanoyl]amino]-2-nitrobenzoate Chemical compound N.OC(=O)[C@@H](N)CCC(=O)NC1=CC=C([N+]([O-])=O)C(C(O)=O)=C1 GFABNNMTRVBLPZ-QRPNPIFTSA-N 0.000 claims abstract description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 11
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims abstract description 8
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000002994 raw material Substances 0.000 claims abstract description 7
- 239000003456 ion exchange resin Substances 0.000 claims abstract description 5
- 229920003303 ion-exchange polymer Polymers 0.000 claims abstract description 5
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000002253 acid Substances 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 230000002378 acidificating effect Effects 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- 238000001514 detection method Methods 0.000 claims 2
- 230000008034 disappearance Effects 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 9
- 238000001914 filtration Methods 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 238000006698 hydrazinolysis reaction Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 238000009833 condensation Methods 0.000 description 3
- 230000005494 condensation Effects 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical group [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000004880 explosion Methods 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 2
- KGLPWQKSKUVKMJ-UHFFFAOYSA-N 2,3-dihydrophthalazine-1,4-dione Chemical compound C1=CC=C2C(=O)NNC(=O)C2=C1 KGLPWQKSKUVKMJ-UHFFFAOYSA-N 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000002828 nitro derivatives Chemical class 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
Abstract
The invention relates to a preparation method of a substrate of a transpeptidase biochemical test reagent, belonging to the technical field of chemical synthesis, wherein the preparation method takes 5-amino-2-nitrobenzoic acid and a compound A phthaloyl-L-glutamic anhydride as starting raw materials, and specifically comprises the following steps: step (1): 5-amino-2-nitrobenzoic acid and a compound A, namely phthaloyl-L-glutamic anhydride react in an acid solvent to synthesize an intermediate B; step (2): in a solvent, the intermediate B and hydrazine hydrate are subjected to the following reaction, and ammonium is treated under the action of ion exchange resin to obtain a compound Glupa-C.
Description
Technical Field
The invention relates to the technical field of chemical synthesis, in particular to a preparation method of a substrate of a transpeptidase biochemical test reagent.
Background
Gamma-glutamyl-3-carboxyl-4-nitroaniline monoammonium salt (Glupa-C) is a good substrate for determining transpeptidase, and has important use value in clinical examination. U.S. Pat. No. 5, 3979447A discloses a process for preparing the compound, which comprises condensing 5-amino-2-nitrobenzoic acid with phthaloyl-L-glutamic anhydride (compound A) in the presence of tri-n-butylamine, and hydrazinolysis the condensate to obtain the product. However, detailed condensation and hydrazinolysis conditions are not reported in the patent, the separation method of the product Glupa-C and the phthalhydrazide after hydrazinolysis is difficult, the refining method and the quality standard of the product Glupa-C are not reported, and in addition, the tri-n-butylamine belongs to a highly toxic product and is not suitable for industrial amplification; in the experiment of repeating the preparation process of the preparation document, no desired product is found, and the technical route is shown as the following formula I:
chinese patent CN1076688A discloses a synthetic route of 5-amino-2-nitrobenzoic acid and phthaloyl-L-glutamic anhydride, and the condensation of the two raw materials at 140-142 ℃ and the hydrazinolysis at 40-50 ℃. The nitro compound is easy to explode due to condensation at 140-142 ℃ and cannot realize industrial production, and the product obtained by the synthesis method is not mono-ammonium salt in the form of Glupa-C free alkali. The technical route is shown as the following formula II:
based on the defects of high drug raw material, explosion risk of the process, very low yield, incapability of amplification and the like in the preparation method of the gamma-glutamyl-3-carboxyl-4-nitroaniline monoammonium salt in the alkaline environment, the application provides the preparation method of the transpeptidase biochemical test reagent substrate.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides a preparation method of a substrate of a transpeptidase biochemical test reagent, so as to solve the technical problem of low total yield of the prior method.
The invention is realized by the following technical scheme:
the invention provides a preparation method of a substrate of a transpeptidase biochemical test reagent, which takes 5-amino-2-nitrobenzoic acid and a compound A phthaloyl-L-glutamic anhydride as starting raw materials and specifically comprises the following steps:
step (1): 5-amino-2-nitrobenzoic acid and a compound A, namely phthaloyl-L-glutamic anhydride react in an acid solvent to synthesize an intermediate B;
step (2): reacting the intermediate B with hydrazine hydrate in a solvent, and carrying out ammonium radical treatment under the action of ion exchange resin to obtain a compound Glupa-C;
the general reaction formula from step (1) to step (2) is as follows:
as a further improvement of the invention, in the step (1), the acidic solvent is formic acid or acetic acid, and the volume-to-mass ratio of the used amount of the solvent to the compound A, i.e., the phthaloyl-L-glutamic anhydride, is 1.0-10 mL/g, preferably 4.6 mL/g.
As a further improvement of the invention, in the step (1), the molar ratio of the 5-amino-2-nitrobenzoic acid to the compound A, i.e., the phthaloyl-L-glutamic anhydride, is 0.5:1 to 1:3, preferably 0.5:1 to 1:1.5, and more preferably 0.9: 1.
As a further improvement of the above invention, the reaction temperature in the step (1) is 20 to 200 ℃, preferably 100 ℃.
In a further improvement of the above invention, in the step (1), the reaction progress is detected by TLC, HPLC or NMR, the time when the compound a phthalic anhydride-L-glutamate disappears is used as the reaction end point, and the reaction time is 0.1 to 15 hours, preferably 2 hours.
In a further improvement of the above invention, in the step (2), the solvent is methanol, ethanol, acetonitrile or tetrahydrofuran, and the ratio of the amount of the solvent to the volume mass of the intermediate B is 5.0mL/g to 20.0mL/g, preferably 10 mL/g.
As a further improvement of the invention, in the step (2), the volume mass ratio of the hydrazine hydrate with the volume mass fraction of 28% to the intermediate B is 0.5mL/g to 20.0mL/g, preferably 1.3 mL/g.
As a further improvement of the above invention, the reaction temperature in the step (2) is 0 to 50 ℃, preferably 25 ℃.
In a further improvement of the invention, in the step (2), the reaction progress is detected by TLC, HPLC or NMR, the time when the intermediate B disappears is used as a reaction end point, and the reaction time is 5 to 48 hours, preferably 12 hours.
As a further improvement of the above invention, the post-treatment method of the reaction in the step (2) is a conventional post-treatment method of such a reaction, and is preferably filtration, pH adjustment, crystallization, ammonium ion exchange resin column chromatography, recrystallization or vacuum drying.
Compared with the prior art, the invention has the following advantages: the invention provides a preparation method of a transpeptidase biochemical test reagent substrate, which improves and optimizes the preparation process, reaction conditions and method of gamma-glutamyl-3-carboxyl-4-nitroaniline monoammonium salt, prepares the product in an acidic environment, avoids the hidden danger of explosion in the use and preparation processes of virulent raw materials, reduces the production risk, greatly improves the total yield of the product by 36.9 percent and the purity (99 percent), has simple and convenient preparation process, is easy to amplify and is suitable for industrial production compared with the traditional preparation in an alkaline environment.
Detailed Description
The invention provides a preparation method of a substrate of a transpeptidase biochemical test reagent, which takes 5-amino-2-nitrobenzoic acid and a compound A phthaloyl-L-glutamic anhydride as starting raw materials and specifically comprises the following steps:
step (1): 5-amino-2-nitrobenzoic acid reacts with a compound A, namely phthaloyl-L-glutamic anhydride in a solvent to synthesize an intermediate B;
step (2): in a solvent, carrying out the reaction shown in the specification on the intermediate B and hydrazine hydrate, and carrying out ammonium radical treatment under the action of ion exchange resin to obtain a compound Glupa-C;
the general reaction formula from step (1) to step (2) is as follows:
wherein the molar ratio of the 5-amino-2-nitrobenzoic acid to the compound A phthaloyl-L-glutamic anhydride in the step (1) is 0.5:1-1: 3, the reaction temperature in the step (1) is 20-200 ℃, the reaction process in the step (1) is detected by TLC, HPLC or NMR, the time when the compound A phthaloyl-L-glutamic anhydride disappears is taken as the reaction end point, the reaction time is 0.1-15 hours,
wherein the solvent in the step (2) is methanol, ethanol, acetonitrile or tetrahydrofuran, the volume-to-mass ratio of the solvent to the intermediate B is 5.0 mL/g-20.0 mL/g, the volume-to-mass ratio of 28% hydrazine hydrate to the intermediate B in the step (2) is 0.5 mL/g-20.0 mL/g, the reaction temperature in the step (2) is 0-50 ℃, the reaction process in the step (2) is detected by TLC, HPLC or NMR, the time when the intermediate B disappears is used as a reaction endpoint, and the reaction time is 5-48 hours.
To further verify the effect of the present example, the following experiment was provided as a specific method for preparing a substrate for a transpeptidase biochemical test reagent, and the following experiment was conducted at room temperature (0-35 ℃ C.) without limiting the specific operating temperature.
(1) Synthesis of intermediate B
600 ml of acetic acid, 130g (0.5mol) of the compound A and 82g (0.45mol) of 5-amino-2-nitrobenzoic acid are added in sequence in a 2L reaction bottle under stirring; heating the reaction solution to 100 ℃, and continuing stirring for 2 hours; TLC shows that the reaction is finished, the reaction solution is cooled to room temperature, and crude product 200g is obtained after filtration; the crude product is recrystallized from methanol and water, filtered and dried in vacuum to obtain an intermediate B: 110 g, yield 55%.
(2) Synthesis of compound Glupa-C
15g of intermediate B are dissolved in 150 ml of acetonitrile with stirring at room temperature; 20 ml of 28 percent hydrazine hydrate solution is dripped into the reaction solution and stirred overnight at room temperature; TLC shows that the reaction is finished, filtering is carried out, a filter cake is dissolved by water, the pH is adjusted to 5-6 by 1N hydrochloric acid solution, stirring is carried out for 8 hours at room temperature, filtering is carried out, filtrate is extracted by ethyl acetate for three times, acetonitrile is added into a water phase, stirring is carried out overnight, filtering is carried out, the filter cake is dissolved by water, after an ionic resin column is aminated, a product-containing part is collected and recrystallized, and a compound Glupa-C is obtained: 7.5 g, yield: 67%;
the compound Glupa-C is white powder, HNMR is DMSO-d6, delta 1.95-2.03(m,2H),2.50-2.57(m,2H),3.28-3.35(m,3H),7.57-7.79(m,8H),11.07(brs, 1H).
The above is a detailed embodiment and a specific operation process of the present invention, which are implemented on the premise of the technical solution of the present invention, but the protection scope of the present invention is not limited to the above-mentioned examples.
Claims (9)
1. A preparation method of a substrate of a transpeptidase biochemical test reagent takes 5-amino-2-nitrobenzoic acid and a compound A phthaloyl-L-glutamic anhydride as starting raw materials, and is characterized by comprising the following steps:
step (1): 5-amino-2-nitrobenzoic acid and a compound A, namely phthaloyl-L-glutamic anhydride react in an acid solvent to synthesize an intermediate B;
step (2): reacting the intermediate B with hydrazine hydrate in a solvent, and carrying out ammonium radical treatment under the action of ion exchange resin to obtain a compound Glupa-C;
the general reaction formula from step (1) to step (2) is as follows:
2. the method for preparing a substrate of a transpeptidase biochemical test reagent according to claim 1, wherein the acidic solvent in step (1) is formic acid or acetic acid, and the volume-to-mass ratio of the solvent to the compound A, i.e., phthaloyl-L-glutamic anhydride, is 1.0mL/g to 10 mL/g.
3. The method for preparing a substrate of a transpeptidase biochemical test reagent according to claim 1, wherein the molar ratio of 5-amino-2-nitrobenzoic acid to compound A-phthaloyl-L-glutamic anhydride in step (1) is 0.5:1 to 1: 3.
4. The method for preparing a substrate of a reagent for the biochemical detection of transpeptidase according to claim 1, wherein the reaction temperature in step (1) is 20 ℃ to 200 ℃.
5. The method for preparing a substrate of a transpeptidase biochemical test reagent according to claim 1, wherein the reaction progress in step (1) is detected by TLC, HPLC or NMR, and the reaction time is 0.1-15 hours with the disappearance of the compound A-phthaloyl-L-glutamic anhydride as a reaction end point.
6. The method for preparing a substrate of a transpeptidase biochemical test reagent according to claim 1, wherein the solvent in step (2) is methanol, ethanol, acetonitrile or tetrahydrofuran, and the ratio of the amount of the solvent to the volume-to-mass ratio of the intermediate B is 5.0mL/g to 20.0 mL/g.
7. The method for preparing a substrate of a transpeptidase biochemical test reagent according to claim 1, wherein the volume-to-mass ratio of hydrazine hydrate to intermediate B in step (2) is 0.5mL/g to 20.0 mL/g.
8. The method for preparing a substrate of a reagent for the biochemical detection of transpeptidase according to claim 1, wherein the reaction temperature in step (2) is 0 ℃ to 50 ℃.
9. The method for preparing a substrate of a transpeptidase biochemical test reagent according to claim 1, wherein the reaction progress in the step (2) is detected by TLC, HPLC or NMR, the time when the intermediate B disappears is taken as a reaction end point, and the reaction time is 5-48 hours.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2259512A1 (en) * | 1972-12-05 | 1974-06-27 | Boehringer Mannheim Gmbh | GAMMA-GLUTAMYL-3-CARBOXY-4-NITROANILIDE |
| WO1984000978A1 (en) * | 1982-08-30 | 1984-03-15 | Beckman Instruments Inc | METHOD FOR DETERMINING gamma-GLUTAMYLTRANSFERASE ACTIVITY AND KITS CONTAINING A NOVEL SUBSTRATE SOLUTION FOR USE THEREIN |
| CN1076688A (en) * | 1992-03-21 | 1993-09-29 | 中国药科大学 | The preparation method of gamma-glutamyl-3-carboxyl-4-N-methyl-p-nitroaniline mono-ammonium |
| CN104140382A (en) * | 2014-07-02 | 2014-11-12 | 南京大学 | Hydroximic acid compound as well as preparation method and application thereof |
| KR20180040853A (en) * | 2016-10-13 | 2018-04-23 | 마선영 | Method for lyophilization liver enzyme and lipid |
-
2021
- 2021-03-29 CN CN202110332220.4A patent/CN113045446A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2259512A1 (en) * | 1972-12-05 | 1974-06-27 | Boehringer Mannheim Gmbh | GAMMA-GLUTAMYL-3-CARBOXY-4-NITROANILIDE |
| US3979447A (en) * | 1972-12-05 | 1976-09-07 | Boehringer Mannheim G.M.B.H. | γ-Glutamyl-4-nitroanilide compounds |
| WO1984000978A1 (en) * | 1982-08-30 | 1984-03-15 | Beckman Instruments Inc | METHOD FOR DETERMINING gamma-GLUTAMYLTRANSFERASE ACTIVITY AND KITS CONTAINING A NOVEL SUBSTRATE SOLUTION FOR USE THEREIN |
| EP0118534A1 (en) * | 1982-08-30 | 1984-09-19 | Beckman Instruments Inc | METHOD FOR DETERMINING -g(g)-GLUTAMYLTRANSFERASE ACTIVITY AND KITS CONTAINING A NOVEL SUBSTRATE SOLUTION FOR USE THEREIN. |
| CN1076688A (en) * | 1992-03-21 | 1993-09-29 | 中国药科大学 | The preparation method of gamma-glutamyl-3-carboxyl-4-N-methyl-p-nitroaniline mono-ammonium |
| CN104140382A (en) * | 2014-07-02 | 2014-11-12 | 南京大学 | Hydroximic acid compound as well as preparation method and application thereof |
| KR20180040853A (en) * | 2016-10-13 | 2018-04-23 | 마선영 | Method for lyophilization liver enzyme and lipid |
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Application publication date: 20210629 |