CN104649929A - Preparation method and application of 4-(N-(4-aminobutyryl))-aminobutyric acid - Google Patents
Preparation method and application of 4-(N-(4-aminobutyryl))-aminobutyric acid Download PDFInfo
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- CN104649929A CN104649929A CN201510077458.1A CN201510077458A CN104649929A CN 104649929 A CN104649929 A CN 104649929A CN 201510077458 A CN201510077458 A CN 201510077458A CN 104649929 A CN104649929 A CN 104649929A
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- aminobutyric acid
- solution
- preparation
- acid
- aminobutanonyl
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- 229940124277 aminobutyric acid Drugs 0.000 title claims abstract description 111
- 238000002360 preparation method Methods 0.000 title claims abstract description 41
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 claims abstract description 95
- 238000006243 chemical reaction Methods 0.000 claims abstract description 35
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 33
- 229960003692 gamma aminobutyric acid Drugs 0.000 claims abstract description 23
- 239000007924 injection Substances 0.000 claims abstract description 21
- 238000002347 injection Methods 0.000 claims abstract description 21
- 239000002994 raw material Substances 0.000 claims abstract description 16
- 238000001514 detection method Methods 0.000 claims abstract description 10
- 230000008901 benefit Effects 0.000 claims abstract description 7
- 239000000243 solution Substances 0.000 claims description 66
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 63
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 47
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 30
- 239000007787 solid Substances 0.000 claims description 28
- 239000013558 reference substance Substances 0.000 claims description 25
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 22
- 239000000047 product Substances 0.000 claims description 19
- 150000002148 esters Chemical class 0.000 claims description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 17
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- 238000012360 testing method Methods 0.000 claims description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 12
- 239000007864 aqueous solution Substances 0.000 claims description 10
- 239000007788 liquid Substances 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 9
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 claims description 9
- 238000003756 stirring Methods 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 8
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 claims description 7
- 239000012230 colorless oil Substances 0.000 claims description 7
- 238000000605 extraction Methods 0.000 claims description 7
- 239000012065 filter cake Substances 0.000 claims description 7
- 238000001914 filtration Methods 0.000 claims description 7
- 238000004811 liquid chromatography Methods 0.000 claims description 7
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 7
- RJGROICJTWCHSW-UHFFFAOYSA-N NCCC(CNC(C(=O)O)CC)=O Chemical compound NCCC(CNC(C(=O)O)CC)=O RJGROICJTWCHSW-UHFFFAOYSA-N 0.000 claims description 6
- 229910019142 PO4 Inorganic materials 0.000 claims description 6
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 6
- 238000004440 column chromatography Methods 0.000 claims description 6
- 239000012046 mixed solvent Substances 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 6
- 239000010452 phosphate Substances 0.000 claims description 6
- 229910052700 potassium Inorganic materials 0.000 claims description 6
- 239000011591 potassium Substances 0.000 claims description 6
- QWSZRRAAFHGKCH-UHFFFAOYSA-M sodium;hexane-1-sulfonate Chemical compound [Na+].CCCCCCS([O-])(=O)=O QWSZRRAAFHGKCH-UHFFFAOYSA-M 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 5
- 239000012670 alkaline solution Substances 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- -1 filter Substances 0.000 claims description 4
- 239000000706 filtrate Substances 0.000 claims description 4
- 239000003643 water by type Substances 0.000 claims description 4
- 239000012153 distilled water Substances 0.000 claims description 3
- 238000010812 external standard method Methods 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 239000003960 organic solvent Substances 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 2
- 230000000903 blocking effect Effects 0.000 claims description 2
- 230000006837 decompression Effects 0.000 claims description 2
- 238000005649 metathesis reaction Methods 0.000 claims description 2
- 239000011259 mixed solution Substances 0.000 claims description 2
- 239000003921 oil Substances 0.000 claims description 2
- 239000012086 standard solution Substances 0.000 claims description 2
- OGNSCSPNOLGXSM-UHFFFAOYSA-N (+/-)-DABA Natural products NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 abstract description 10
- 239000008354 sodium chloride injection Substances 0.000 abstract description 6
- 238000009833 condensation Methods 0.000 abstract description 2
- 230000005494 condensation Effects 0.000 abstract description 2
- 238000010511 deprotection reaction Methods 0.000 abstract description 2
- 230000032050 esterification Effects 0.000 abstract description 2
- 238000005886 esterification reaction Methods 0.000 abstract description 2
- 238000011020 pilot scale process Methods 0.000 abstract description 2
- 238000005984 hydrogenation reaction Methods 0.000 abstract 1
- 238000004519 manufacturing process Methods 0.000 abstract 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 abstract 1
- 239000000126 substance Substances 0.000 description 14
- 239000012071 phase Substances 0.000 description 12
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
- 239000012535 impurity Substances 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- IMLHOIPJHRBEBX-UHFFFAOYSA-M sodium 2-aminobutanoic acid chloride Chemical compound [Cl-].[Na+].NC(C(=O)O)CC IMLHOIPJHRBEBX-UHFFFAOYSA-M 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- XUKUURHRXDUEBC-SXOMAYOGSA-N (3s,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-SXOMAYOGSA-N 0.000 description 3
- QGQXAMBOYWULFX-LZWSPWQCSA-N 2-morpholin-4-ylethyl (e)-6-(4,6-dihydroxy-7-methyl-3-oxo-1h-2-benzofuran-5-yl)-4-methylhex-4-enoate Chemical compound OC=1C=2C(=O)OCC=2C(C)=C(O)C=1C\C=C(/C)CCC(=O)OCCN1CCOCC1 QGQXAMBOYWULFX-LZWSPWQCSA-N 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 235000002597 Solanum melongena Nutrition 0.000 description 2
- 244000061458 Solanum melongena Species 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 230000008030 elimination Effects 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 2
- 235000019796 monopotassium phosphate Nutrition 0.000 description 2
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 229910021642 ultra pure water Inorganic materials 0.000 description 2
- 239000012498 ultrapure water Substances 0.000 description 2
- 208000037157 Azotemia Diseases 0.000 description 1
- 208000001408 Carbon monoxide poisoning Diseases 0.000 description 1
- 206010065559 Cerebral arteriosclerosis Diseases 0.000 description 1
- 206010010075 Coma hepatic Diseases 0.000 description 1
- 208000010513 Stupor Diseases 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 210000004720 cerebrum Anatomy 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 201000001059 hepatic coma Diseases 0.000 description 1
- 208000007386 hepatic encephalopathy Diseases 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 201000005851 intracranial arteriosclerosis Diseases 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000013074 reference sample Substances 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 208000009852 uremia Diseases 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a preparation method and application of 4-(N-(4-aminobutyryl))-aminobutyric acid. The preparation method comprises the following steps: by using gamma-aminobutyric acid (GABA) as the initial raw material, carrying out esterification protection, Carter condensation, sodium hydroxide/palladium-carbon hydrogenation reduction deprotection and the like to prepare the 4-(N-(4-aminobutyryl))-aminobutyric acid. The prepared 4-(N-(4-aminobutyryl))-aminobutyric acid is mainly used for detection of the 4-(N-(4-aminobutyryl))-aminobutyric acid content in the GABA raw material and GABA preparation. The GABA preparation comprises a GABA injection, a GABA sodium chloride injection, GABA for injection and the like. The preparation method has the advantages of accessible raw materials, simple reaction conditions and high yield and purity, is convenient to operate, and is suitable for laboratory and pilot-scale industrialized production of the 4-(N-(4-aminobutyryl))-aminobutyric acid. The product has stable properties, and is suitable for detection of GABA and related preparations.
Description
Technical field
The invention belongs to field of medicine preparing technology; relate to the preparation method of 4-(N-(4-aminobutanonyl))-aminobutyric acid, also relate to it in aminobutyric acid and aminobutyric acid related preparations (aminobutyric acid injection liquid, aminobutyric acid sodium chloride injection and Aminobutyric Acid for Injection) to the application that related substance detects.
Background technology
Aminobutyric acid chemical name γ-aminobutyric acid, it is a kind of amino acid drug, be combined with blood ammonia in vivo and generate urea and excrete, there is the effect reducing blood ammonia and promote cerebrum metabolism, be used for the treatment of various types of hepatic coma, also for the stupor caused by brain soldier sequela, cerebral arteriosclerosis, injury of head sequela and uremia, carbon monoxide poisoning etc.Clinically main with the form of injection for patient.The at present both at home and abroad control of quality standard to its related substance is fairly simple, and the report studied its related impurities is few very few especially.In order to ensure the security of aminobutyric acid injection Clinical practice; we have carried out systematic research to the related substance of aminobutyric acid and related preparations; find 4-(N-(4-aminobutanonyl))-aminobutyric acid be topmost impurity in aminobutyric acid, with aminobutyric acid clinical application untoward reaction have very large relation.
-aminobutyric acid is also known as aminobutyric acid impurity II for 4-(N-(4-aminobutanonyl)), and molecular formula is C
8h
16n
2o
3, molecular weight is 188.12, and chemical structural formula is as follows:
Aminobutyric acid impurity II is a kind of pressed powder of white, soluble in water, be the dimer produced in aminobutyric acid building-up process, because physico-chemical property is similar to aminobutyric acid, being difficult to be removed in aminobutyric acid purification refine process, is the potential risk affecting aminobutyric acid quality product and security.In aminobutyric acid related substance research field, the structure of aminobutyric acid impurity II and detection method all belong to and proposing first, and its preparation method and application are showed no domestic and foreign literature report.
Summary of the invention
The object of the invention is, provides the preparation method of a kind of 4-(N-(4-aminobutanonyl))-aminobutyric acid.
Present invention also offers the application of 4-(N-(4-aminobutanonyl))-aminobutyric acid prepared; can be used as reference substance; for detecting the content detection of 4-in aminobutyric acid and aminobutyric acid preparation (N-(4-aminobutanonyl))-aminobutyric acid; for the lifting of aminobutyric acid and preparation quality standard thereof and the security of quality product control to provide technical support and material guarantee; make aminobutyric acid national standard be in world lead level, there is good economic benefit and social benefit.
The present invention is with aminobutyric acid (GABA) for starting raw material, and through esterification protection, block the reactions such as special condensation, sodium hydroxide and palladium hydrocarbonize reduction deprotection, obtained 4-(N-(4-aminobutanonyl))-aminobutyric acid, its synthetic route is as follows:
The preparation method of 4-of the present invention (N-(4-aminobutanonyl))-aminobutyric acid, comprises the following steps:
1) synthetic intermediate 1A-1:
Take GABA, after dissolving with alkaline solution, under ice bath, in 5min, drip chloroformic acid benzyl ester (Cbz-Cl), drip and finish, remove ice bath, 20 ~ 30 DEG C of reaction 1.5 ~ 2.5 h, reaction solution pH to 2 is adjusted with dilute acid soln, be extracted with ethyl acetate three times, merge ester layer, ester layer saturated sodium-chloride is washed once, with anhydrous sodium sulfate drying, column chromatography obtains colorless oil, separates out white solid after placement, i.e. 1A-1;
Raw material GABA: chloroformic acid benzyl ester: the mol ratio of alkali is 1:1.2 ~ 1.8:2 ~ 3;
2) synthetic intermediate 1A-2:
GABA, tosic acid (TsOH), dehydrated alcohol and toluene are mixed, be heated to 110 DEG C, backflow 18 ~ 22 h, after having reacted, be cooled to 20 ~ 30 DEG C, remove solvent under reduced pressure, obtain oily matter, add anhydrous diethyl ether and make dissolving, 20 ~ 24h is placed in-18 ~-20 DEG C, take advantage of cold filtration, obtain white solid, be i.e. 1A-2;
Raw material GABA: tosic acid: dehydrated alcohol: the mol ratio of toluene is 1:1.1 ~ 1.3:1.4 ~ 1.8:9 ~ 10;
3) synthetic intermediate 2A:
By obtained 1A-1 and 1A-2, be dissolved in acetonitrile, then add Et
3n and Ka Te condensing agent (BOP), stirs, in 25 ~ 35 DEG C of reaction 10 ~ 12h, then add the saturated sodium bicarbonate aqueous solution of reaction solution quality 5 ~ 7 times, mix, extraction into ethyl acetate 3 times, merge ester layer, ester layer is used 5% (g/v) aqueous citric acid solution, water, saturated sodium bicarbonate aqueous solution to be washed till TLC successively and is detected inclusion-free point, dry, filter, remove solvent under reduced pressure, obtain colorless oil, leave standstill 0.5 ~ 2h to separate out completely to solid, filter, obtain white solid, i.e. 2A;
1A-1:1A-2:Et
3n: the mol ratio of blocking special condensing agent (BOP) is 1:1:0.8:1; Acetonitrile content is 3 ~ 5 times of 1A-1 and 1A-2 total mass;
4) synthetic intermediate 3A:
The 2A obtained by step 3), with methyl alcohol, THF and H of volume ratio 1:1:1
2the mixed solvent of O dissolves, and then adds NaOH, stirs, and in 25 ~ 35 DEG C of reaction 8 ~ 12h, after having reacted, after removing organic solvent under reduced pressure, adjust pH to 6 ~ 7 with dilute hydrochloric acid, separate out solid, filter, filter cake distilled water wash, obtains white solid, i.e. 3A;
The mol ratio of 2A and NaOH is 1:1 ~ 2; Mixed solvent consumption is the quality 10 times of 2A;
5) synthetic product 4-(N-(4-aminobutanonyl))-aminobutyric acid:
After the 3A dissolve with methanol obtained by step 4), add Pd/C, then use H
2air in metathesis reactor, stir, in 25 ~ 35 DEG C of reaction 30 ~ 40 h, after having reacted, filtering Pd/C, filtrate decompression is steamed and is desolventized, separate out white solid, filter, filter cake ethyl acetate is washed, obtain white solid, i.e. 4-of the present invention (N-(4-aminobutanonyl))-aminobutyric acid;
3A and methanol quality are than being 1:10.
Alkaline solution described in step 1) is the aqueous solution of NaOH or KOH of concentration 1 ~ 4mol/L, the NaOH aqueous solution of preferred 3mol/L;
Dilute acid soln concentration described in step 1) is hydrochloric acid, the sulfuric acid or phosphoric acid etc. of 4 ~ 8mol/L, the hydrochloric acid of preferred 6mol/L;
Column chromatography eluting solvent described in step 1) is petrol ether/ethyl acetate mixed solution, and sherwood oil and ethyl acetate volume ratio are 4:1;
Ethyl acetate consumption described in step 1) is 2 times of reaction solution volume, and saturated sodium-chloride consumption is 1 times of ester layer volume.
Step 2) described in reaction to complete judging criterion be that TLC can't detect GABA.
During step 3) extraction, ethyl acetate consumption is 30 ~ 50% of reaction solution quality.
It is that TLC detects without raw material that reaction described in step 4) completes judging criterion;
The preferred 1mol/L of dilute hydrochloric acid concentration described in step 4).
Filter with being equipped with diatomaceous sand core funnel during step 5) filtering Pd/C.
The application of 4-(N-(4-aminobutanonyl))-aminobutyric acid that the present invention prepares: the detection being mainly used in 4-in aminobutyric acid raw material and aminobutyric acid preparation (N-(4-aminobutanonyl))-Gamma-propalanine content, aminobutyric acid preparation comprises aminobutyric acid injection liquid, aminobutyric acid sodium chloride injection and Aminobutyric Acid for Injection etc.
When 4-of the present invention (N-(4-aminobutanonyl))-aminobutyric acid is used for the detection of 4-(N-(4-aminobutanonyl))-Gamma-propalanine content in aminobutyric acid raw material and aminobutyric acid preparation, method is:
1) preparation of solution
Reference substance solution: get 4-(N-(4-aminobutanonyl))-aminobutyric acid reference substance and adopt water preparation standard solution, concentration is 4-(N-(4-aminobutanonyl))-aminobutyric acid reference substance containing 20 μ g in every 1ml solution;
Need testing solution: get trial-product and adopt water to prepare need testing solution, concentration is containing 4mg aminobutyric acid trial-product in every 1ml solution;
Moving phase: comprise A moving phase and B moving phase, A moving phase and B mobile phase volume are than being 90:10; A moving phase: get potassium primary phosphate l0.0g and sodium hexanesulfonate 1.1g, be dissolved in water and be diluted to 1000ml, by phosphoric acid adjust ph to 2.1; B moving phase: methyl alcohol;
System suitability solution: get aminobutyric acid reference substance, alpha-pyrrolidone reference substance and 4-(N-(4-aminobutanonyl))-aminobutyric acid reference substance, be dissolved in water and dilute the solution made and be respectively 0.4mg, 4 μ g and 20 μ g in every 1ml solution containing aminobutyric acid, alpha-pyrrolidone (impurity A) and 4-(N-(4-aminobutanonyl))-aminobutyric acid (impurity B), as system suitability solution;
2) chromatographic condition
Instrument: Waters e2695 high performance liquid chromatograph, PDA detector, Alliance chromatographic working station;
Chromatographic column: Venusil MP C18 post, specification Ф 4.6mm × 250mm, 5 μm, aperture;
Moving phase: determined wavelength is 210nm, column temperature 30 DEG C, flow velocity 1.0ml/min;
3) measuring method
Get system suitability solution 10 μ l injection liquid chromatography; record color atlas; get need testing solution and each 10 μ l injection liquid chromatographies of reference substance solution more respectively, record color atlas, calculates the content of 4-(N-(4-aminobutanonyl))-aminobutyric acid with external standard method.
In the solution of preparation when present method detects, 4-(N-(4-aminobutanonyl))-Gamma-propalanine content is no more than 0.5% (wt).
When getting the detection of system suitability solution, the resolution at aminobutyric acid peak and alpha-pyrrolidone peak and 4-(N-(4-aminobutanonyl))-aminobutyric acid peak all should meet the requirements, and number of theoretical plate calculates should be not less than 3000 by aminobutyric acid peak.
The preparation method of 4-of the present invention (N-(4-aminobutanonyl))-aminobutyric acid and application, its beneficial effect is:
1) preparation method's raw material is easy to get, and reaction conditions is simple, easy to operate, productive rate and purity high, be suitable for 4-(N-(4-aminobutanonyl))-aminobutyric acid and produce in the industrialization of laboratory and pilot scale.
2) 4-(N-(4-aminobutanonyl))-aminobutyric acid stable in properties prepared, is suitable for aminobutyric acid and related preparations (aminobutyric acid injection liquid, aminobutyric acid sodium chloride injection and Aminobutyric Acid for Injection) Related substances separation uses.
Accompanying drawing explanation
Fig. 1 is 4-(N-(4-aminobutanonyl))-aminobutyric acid of embodiment 1
1h-NMR spectrogram;
Fig. 2 is 4-(N-(4-aminobutanonyl))-aminobutyric acid of embodiment 1
13c-NMR spectrogram;
Fig. 3 is the high resolution mass spectrum figure of 4-(N-(4-aminobutanonyl))-aminobutyric acid of embodiment 1;
Fig. 4 is the system suitability color atlas of aminobutyric acid Related substances separation;
Fig. 5 is the high-efficient liquid phase chromatogram of 4-(N-(4-aminobutanonyl))-aminobutyric acid of embodiment 1;
Fig. 6 is the exemplary potent liquid chromatogram of aminobutyric acid Related substances separation.
Embodiment
Embodiment 1
1) synthetic intermediate 1A-1:
Take GABA(2.0 g, 19.4mmol), dissolve with 20mL 3mol/LNaOH, under ice bath, in 5min, slowly instill chloroformic acid benzyl ester (4mL, 28mmol), drip and finish, remove ice bath; 25 DEG C of reaction 2 h; PH to 2 is adjusted with 6mol/LHCl, separate out a large amount of oily matter, reaction solution is placed in separating funnel, with the extraction into ethyl acetate three times of reaction solution 2 times of volumes, merges ester layer, with the saturated nacl aqueous solution of ester layer 1 times of volume wash ester layer once after, with anhydrous sodium sulfate drying, column chromatography (petrol ether/ethyl acetate=4:1), obtains colorless oil, white solid 3.4g is separated out, i.e. 1A-1 after placing.
C
12H
15NO
4 1H-NMR(400 MHz,DMSO-d6) δ(ppm): 12.039(s, 1H), 7.384～7.268(m, 5H), 5.005(s, 2H), 3.006(q,
J=6.8 Hz, 2H ), 2.215(t,
J= 7.6 Hz, 2H), 1.658～1.586(m, 2H).
2) synthetic intermediate 1A-2:
Add GABA (5.2g, 50mmol) in 100mL eggplant type bottle, tosic acid (TsOH) (10.0g, 58mmol), dehydrated alcohol 5mL and toluene 50mL, mixes, and is heated to 110 DEG C, and backflow 20h, TLC monitor to reacting completely, stopped reaction.Be cooled to 25 DEG C, remove solvent under reduced pressure, add anhydrous diethyl ether 150mL, place 22h in-19 DEG C, take advantage of cold filtration, obtain white solid 14.7g, i.e. 1A-2.
3) synthetic intermediate 2A:
Take 1A-1(2.0g, 8.4mmol) and 1A-2(2.5g, 8.4mmol) in 100mL eggplant type bottle, add acetonitrile 10ml and dissolve, add Et
3n 6mL and Ka Te condensing agent (BOP) (3.7g, 8.4mmol), in 30 DEG C of reaction 11h, reaction solution saturated sodium bicarbonate solution is diluted to 100ml, mixes, with 30ml extraction into ethyl acetate 3 times, merge ester layer, ester layer successively with concentration be 5% (g/v) citric acid, water, saturated sodium bicarbonate solution be washed till TLC and detect inclusion-free point, drying, filter, remove solvent under reduced pressure, obtain colorless oil, leave standstill 1.5h to separate out completely to solid, filter, obtain white solid, i.e. 2A.
C
18H
26N
2O
5 1H-NMR(400 MHz,DMSO-d6) δ(ppm): 7.794(t,
J= 5.6 Hz, 1H), 7.384～7.244(m, 6H), 5.004(s, 2H), 4.042(q,
J= 7.2Hz, 2H), 3.107～2.951(m, 4H), 2.279(t,
J= 7.6 Hz, 2H),2.055(t,
J= 7.6 Hz, 2H), 1.667～1.578(t,
J= 7.2 Hz, 3H).
4) synthetic intermediate 3A:
By methyl alcohol, THF and H of step 3) product 2A with volume ratio 1:1:1
2the mixed solvent of O dissolves, and mixed solvent consumption is the quality 10 times of 2A, then adds NaOH solid (1.0g, 25mmol), stirs, and in 30 DEG C of reaction 10h, after having reacted, namely TLC detects without raw material, stopped reaction.After removing organic solvent under reduced pressure, adjust pH to 6 ~ 7, separate out a large amount of white solid with 1mol/LHCl, filter, filter cake distilled water wash, obtains white solid, i.e. 3A.
C
16H
22N
2O
5 1H-NMR(400MHz,DMSO-d6) δ(ppm): 12.056(s, 1H), 7.817(t,
J= 4.4 Hz, 1H), 7.384～7.250(m, 6H), 5.002(s, 2H), 3.052～3.2.947(m, 4H), 2.198(t,
J= 7.6 Hz, 2H), 2.052(t,
J= 7.6 Hz, 2H), 1.646～1.562(m, 4H).
5) synthetic product 4-(N-(4-aminobutanonyl))-aminobutyric acid:
After the 3A dissolve with methanol obtained by step 4), 3A and methanol quality, than being 1:10, add Pd/C 100mg, are filled with H after then extracting the air in container out
2, stir, in 30 DEG C of reaction 36h, after having reacted, with being equipped with diatomaceous sand core funnel elimination Pd/C, getting filtrate, removing solvent under reduced pressure, separate out white solid; Filter, filter cake ethyl acetate is washed, and obtains white solid, i.e. the present embodiment 4-(N-(4-aminobutanonyl))-aminobutyric acid.
C
8H
16N
2O
3 1H-NMR(400MHz,D
2O-d
2) δ(ppm): 3.091(t,
J= 6.8 Hz, 2H), 2.906(t,
J= 7.6 Hz, 2.256(t,
J= 7.2 Hz, 2H), 2.094(t,
J= 7.2 Hz, 2H), 1.880～1.805(m, 2H), 1.685～1.614(m, 2H).
13C-NMR(400MHz, D
2O-d2) δ(ppm)：182.60(C1), 174.68(C5), 39.21(C8), 38.79(C4), 34.84(C6), 32.56(C2), 25.28(C7), 23.07(C3).HRMS m/z calcd for C
8H
17N
2O
3[M
++H]:189.1239, found 189.1191.
Embodiment 2
1) synthetic intermediate 1A-1:
Take GABA(1.0g, 9.7mmol), dissolve with 10mL 3mol/LNaOH, under ice bath, in 5min, slowly instill chloroformic acid benzyl ester (1.5mL, 10.5mmol), drip and finish, remove ice bath; 25 DEG C of reaction 2 h; PH to 2 is adjusted with 6mol/LHCl, separate out a large amount of oily matter, reaction solution is placed in separating funnel, with the extraction into ethyl acetate three times of reaction solution 2 times of volumes, merges ester layer, with the saturated nacl aqueous solution of ester layer 1 times of volume wash ester layer once after, with anhydrous sodium sulfate drying, column chromatography (petrol ether/ethyl acetate=4:1), obtains colorless oil, white solid 1.1g is separated out, i.e. 1A-1 after placing.
C
12H
15NO
4 1H-NMR(400 MHz,DMSO-d6) δ(ppm): 12.039(s, 1H), 7.384～7.268(m, 5H), 5.005(s, 2H), 3.006(q,
J=6.8 Hz, 2H ), 2.215(t,
J= 7.6 Hz, 2H), 1.658～1.586(m, 2H).
Step 2) ~ 5) with embodiment 1
Embodiment 3
Step 1) ~ 4) with embodiment 1
5) synthetic product 4-(N-(4-aminobutanonyl))-aminobutyric acid:
After the 3A dissolve with methanol obtained by step 4), 3A and methanol quality, than being 1:10, add Pd/C 100mg, are filled with H after then extracting the air in container out
2, stir, in 30 DEG C of reaction 30h, after having reacted, with being equipped with diatomaceous sand core funnel elimination Pd/C, getting filtrate, removing solvent under reduced pressure, separate out white solid; Filter, filter cake ethyl acetate is washed, and obtains white solid, i.e. the present embodiment 4-(N-(4-aminobutanonyl))-aminobutyric acid.
C
8H
16N
2O
3 1H-NMR(400MHz,D
2O-d
2) δ(ppm): 3.091(t,
J= 6.8 Hz, 2H), 2.906(t,
J= 7.6 Hz, 2.256(t,
J= 7.2 Hz, 2H), 2.094(t,
J= 7.2 Hz, 2H), 1.880～1.805(m, 2H), 1.685～1.614(m, 2H).
13C-NMR(400MHz, D
2O-d2) δ(ppm)：182.60(C1), 174.68(C5), 39.21(C8), 38.79(C4), 34.84(C6), 32.56(C2), 25.28(C7), 23.07(C3).HRMS m/z calcd for C
8H
17N
2O
3[M
++H]:189.1239, found 189.1191.
The application of 4-(N-(4-aminobutanonyl))-aminobutyric acid that the present invention prepares:
Experimental group: the mensuration of aminobutyric acid and preparation related substance thereof, 4-(N-(4-aminobutanonyl))-aminobutyric acid using the embodiment of the present invention 1 to prepare compares product.
1) reference substance, trial-product and reagent
Reference substance: aminobutyric acid reference substance (National Institute for Food and Drugs Control, lot number: 140723-200501)
Alpha-pyrrolidone (Northeast Pharmaceutical Group Co., Ltd. provides)
4-(N-(4-aminobutanonyl))-aminobutyric acid (the invention provides, content 99%)
Trial-product formulation: aminobutyric acid raw material, aminobutyric acid sodium chloride injection, Aminobutyric Acid for Injection, aminobutyric acid injection liquid
Reagent: methyl alcohol (chromatographically pure), potassium primary phosphate (chemical pure), sodium hexanesulfonate, ultrapure water.
2) preparation of solution
Need testing solution: get trial-product (being equivalent to aminobutyric acid 0.2g) respectively, put in 50ml measuring bottle, be dissolved in water and be diluted to scale, shaking up.
Reference substance solution: get 4-(N-(4-aminobutanonyl))-aminobutyric acid reference substance, is dissolved in water and dilutes the solution made about containing 20 μ g in every 1ml.
System suitability solution: get aminobutyric acid reference substance, alpha-pyrrolidone (impurity A) and 4-(N-(4-aminobutanonyl))-aminobutyric acid (impurity B); accurately weighed; be dissolved in water and dilute the solution made and be about respectively 0.4mg, 4 μ g and 20 μ g in every 1ml containing aminobutyric acid, alpha-pyrrolidone (impurity A) and 4-(N-(4-aminobutanonyl))-aminobutyric acid (impurity B), as system suitability solution.
3) chromatographic condition
Instrument: Waters e2695 high performance liquid chromatograph, PDA detector, Alliance chromatographic working station, column oven.Chromatographic column: Venusil MP C18 post 4.6mm × 250mm 5 μm, moving phase: (get potassium primary phosphate l0.0g and sodium hexanesulfonate 1.1g with potassium dihydrogen phosphate, be dissolved in water and be diluted to 1000ml, by phosphoric acid adjust ph to 2.1)-methyl alcohol (90:10) is moving phase, determined wavelength is 210nm, column temperature 30 DEG C, flow velocity 1.0ml/min.
4) assay method
Get system suitability solution 10 μ l injection liquid chromatography; record color atlas; the resolution at aminobutyric acid peak and alpha-pyrrolidone peak and 4-(N-(4-aminobutanonyl))-aminobutyric acid peak all should meet the requirements, and number of theoretical plate calculates should be not less than 3000 by aminobutyric acid peak.Get need testing solution and each 10 μ l injection liquid chromatographies of reference substance solution more respectively; record color atlas; calculate the content of 4-(N-(4-aminobutanonyl))-aminobutyric acid with external standard method, 4-(N-(4-aminobutanonyl))-aminobutyric acid must not cross 0.5%.
5) measurement result, in table 1
Control group: the mensuration (4-(N-(4-aminobutanonyl))-aminobutyric acid not using the present invention to prepare compares product) of aminobutyric acid and preparation related substance thereof
1) reference substance, sample and reagent
Sample: aminobutyric acid, aminobutyric acid sodium chloride injection, Aminobutyric Acid for Injection, aminobutyric acid injection liquid
Reagent: methyl alcohol (chromatographically pure), potassium primary phosphate (chemical pure), sodium hexanesulfonate, ultrapure water.
2) preparation of solution
Need testing solution: sample thief appropriate (being equivalent to aminobutyric acid 0.2g), puts in 50ml measuring bottle, is dissolved in water and is diluted to scale, shaking up, as need testing solution.
Contrast solution: get need testing solution 2ml, puts in 100ml measuring bottle, is diluted with water to scale, shake up, in contrast solution.
3) chromatographic condition
Instrument: Waters e2695 high performance liquid chromatograph, PDA detector, Alliance chromatographic working station, column oven.Chromatographic column: Venusil MP C18 post 4.6mm × 250mm 5 μm, moving phase: (get potassium primary phosphate l0.0g and sodium hexanesulfonate 1.1g with potassium dihydrogen phosphate, be dissolved in water and be diluted to 1000ml, by phosphoric acid adjust ph to 2.1)-methyl alcohol (90:10) is moving phase, determined wavelength is 210nm, column temperature 30 DEG C, flow velocity 1.0ml/min.
4) assay method
Get need testing solution and each 10 μ l of reference substance solution respectively, according to above-mentioned 3) chromatographic condition, injection liquid chromatography, record color atlas.Need testing solution is if any impurity peaks, and its peak area must not be greater than the peak area (2.0%) of reference substance solution.
5) measurement result, in table 1.
Table 1 experimental group trial-product measurement result different from control group
Known according to table 1; the advantage of product of the present invention is adopted to be to control 4-(N-(4-aminobutanonyl))-Gamma-propalanine content in aminobutyric acid related products; impurity control method is more scientific, and Control of Impurities precision improves, and foreign matter content is closer to actual value.
Claims (10)
1. a preparation method for 4-(N-(4-aminobutanonyl))-aminobutyric acid, is characterized in that, comprise the following steps:
1) synthetic intermediate 1A-1:
Take GABA, after dissolving with alkaline solution, under ice bath, in 5min, drip chloroformic acid benzyl ester, drip and finish, remove ice bath, 20 ~ 30 DEG C of reaction 1.5 ~ 2.5 h, reaction solution pH to 2 is adjusted with dilute acid soln, be extracted with ethyl acetate three times, merge ester layer, ester layer saturated sodium-chloride is washed once, with anhydrous sodium sulfate drying, column chromatography obtains colorless oil, separates out white solid after placement, i.e. 1A-1;
Raw material GABA: chloroformic acid benzyl ester: the mol ratio of alkali is 1:1.2 ~ 1.8:2 ~ 3;
2) synthetic intermediate 1A-2:
GABA, tosic acid, dehydrated alcohol and toluene are mixed, be heated to 110 DEG C, backflow 18 ~ 22 h, after having reacted, be cooled to 20 ~ 30 DEG C, remove solvent under reduced pressure, obtain oily matter, add anhydrous diethyl ether and make dissolving, 20 ~ 24h is placed in-18 ~-20 DEG C, take advantage of cold filtration, obtain white solid, be i.e. 1A-2;
Raw material GABA: tosic acid: dehydrated alcohol: the mol ratio of toluene is 1:1.1 ~ 1.3:1.4 ~ 1.8:9 ~ 10;
3) synthetic intermediate 2A:
By obtained 1A-1 and 1A-2, be dissolved in acetonitrile, then add Et
3n and Ka Te condensing agent, stirs, in 25 ~ 35 DEG C of reaction 10 ~ 12h, then add the saturated sodium bicarbonate aqueous solution of reaction solution quality 5 ~ 7 times, mix, extraction into ethyl acetate 3 times, merge ester layer, ester layer is used 5% (g/v) aqueous citric acid solution, water, saturated sodium bicarbonate aqueous solution to be washed till TLC successively and is detected inclusion-free point, dry, filter, remove solvent under reduced pressure, obtain colorless oil, leave standstill 0.5 ~ 2h to separate out completely to solid, filter, obtain white solid, i.e. 2A;
1A-1:1A-2:Et
3n: the mol ratio of blocking special condensing agent is 1:1:0.8:1; Acetonitrile content is 3 ~ 5 times of 1A-1 and 1A-2 total mass;
4) synthetic intermediate 3A:
The 2A obtained by step 3), with methyl alcohol, THF and H of volume ratio 1:1:1
2the mixed solvent of O dissolves, and then adds NaOH, stirs, and in 25 ~ 35 DEG C of reaction 8 ~ 12h, after having reacted, after removing organic solvent under reduced pressure, adjust pH to 6 ~ 7 with dilute hydrochloric acid, separate out solid, filter, filter cake distilled water wash, obtains white solid, i.e. 3A;
The mol ratio of 2A and NaOH is 1:1 ~ 2; Mixed solvent consumption is the quality 10 times of 2A;
5) synthetic product 4-(N-(4-aminobutanonyl))-aminobutyric acid:
After the 3A dissolve with methanol obtained by step 4), add Pd/C, then use H
2air in metathesis reactor, stir, in 25 ~ 35 DEG C of reaction 30 ~ 40 h, after having reacted, filtering Pd/C, filtrate decompression is steamed and is desolventized, separate out white solid, filter, filter cake ethyl acetate is washed, obtain white solid, i.e. 4-of the present invention (N-(4-aminobutanonyl))-aminobutyric acid;
3A and methanol quality are than being 1:10.
2. preparation method according to claim 1, is characterized in that: the alkaline solution described in step 1) is the aqueous solution of NaOH or KOH of concentration 1 ~ 4mol/L; Described dilute acid soln concentration is the hydrochloric acid of 4 ~ 8mol/L, sulfuric acid or phosphoric acid.
3. preparation method according to claim 2, is characterized in that: described alkaline solution is the NaOH aqueous solution of 3mol/L; Described dilute acid soln is the hydrochloric acid of 6mol/L.
4. preparation method according to claim 1, is characterized in that: the column chromatography eluting solvent described in step 1) is petrol ether/ethyl acetate mixed solution, and sherwood oil and ethyl acetate volume ratio are 4:1.
5. preparation method according to claim 1, is characterized in that: the ethyl acetate consumption described in step 1) is 2 times of reaction solution volume, and saturated sodium-chloride consumption is 1 times of ester layer volume; During step 3) extraction, ethyl acetate consumption is 30 ~ 50% of reaction solution quality.
6. preparation method according to claim 1, is characterized in that: the dilute hydrochloric acid concentration described in step 4) is 1mol/L.
7. preparation method according to claim 1, is characterized in that: filter with being equipped with diatomaceous sand core funnel during step 5) filtering Pd/C.
8. the application of 4-(N-(4-aminobutanonyl))-aminobutyric acid for preparing of preparation method according to claim 1, is characterized in that: for the detection of 4-in aminobutyric acid raw material and aminobutyric acid preparation (N-(4-aminobutanonyl))-Gamma-propalanine content.
9. application according to claim 8, is characterized in that: during detection for 4-in aminobutyric acid raw material and aminobutyric acid preparation (N-(4-aminobutanonyl))-Gamma-propalanine content, method is:
1) preparation of solution
Reference substance solution: get 4-(N-(4-aminobutanonyl))-aminobutyric acid reference substance and adopt water preparation standard solution, concentration is 4-(N-(4-aminobutanonyl))-aminobutyric acid reference substance containing 20 μ g in every 1ml solution;
Need testing solution: get trial-product and adopt water to prepare need testing solution, concentration is containing 4mg aminobutyric acid trial-product in every 1ml solution;
Moving phase: comprise A moving phase and B moving phase, A moving phase and B mobile phase volume are than being 90:10; A moving phase: get potassium primary phosphate l0.0g and sodium hexanesulfonate 1.1g, be dissolved in water and be diluted to 1000ml, by phosphoric acid adjust ph to 2.1; B moving phase: methyl alcohol;
System suitability solution: get aminobutyric acid reference substance, alpha-pyrrolidone reference substance and 4-(N-(4-aminobutanonyl))-aminobutyric acid reference substance, be dissolved in water and dilute the solution made and be respectively 0.4mg, 4 μ g and 20 μ g in every 1ml solution containing aminobutyric acid, alpha-pyrrolidone and 4-(N-(4-aminobutanonyl))-aminobutyric acid, as system suitability solution;
2) chromatographic condition
Instrument: Waters e2695 high performance liquid chromatograph, PDA detector, Alliance chromatographic working station;
Chromatographic column: Venusil MP C18 post, specification Ф 4.6mm × 250mm, 5 μm, aperture;
Moving phase: determined wavelength is 210nm, column temperature 30 DEG C, flow velocity 1.0ml/min;
3) measuring method
Get system suitability solution 10 μ l injection liquid chromatography; record color atlas; get need testing solution and each 10 μ l injection liquid chromatographies of reference substance solution more respectively, record color atlas, calculates the content of 4-(N-(4-aminobutanonyl))-aminobutyric acid with external standard method.
10. application according to claim 9, is characterized in that: in the solution prepared during detection, 4-(N-(4-aminobutanonyl))-Gamma-propalanine content is no more than 0.5% (wt).
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| US20140045808A1 (en) * | 2012-08-13 | 2014-02-13 | of Nevada, Las Vegas | Reducing Risk of Contracting Clostridium-Difficile Associated Disease |
| CN103601651A (en) * | 2013-11-25 | 2014-02-26 | 华东理工大学 | Multi-dendritic quaternary ammonium compound, and preparation and use thereof |
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| US20140045808A1 (en) * | 2012-08-13 | 2014-02-13 | of Nevada, Las Vegas | Reducing Risk of Contracting Clostridium-Difficile Associated Disease |
| CN103601651A (en) * | 2013-11-25 | 2014-02-26 | 华东理工大学 | Multi-dendritic quaternary ammonium compound, and preparation and use thereof |
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