CN1257885C - Carbon 13 labeled ledocaine and its salts preparations and uses - Google Patents
Carbon 13 labeled ledocaine and its salts preparations and uses Download PDFInfo
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- CN1257885C CN1257885C CN 03150579 CN03150579A CN1257885C CN 1257885 C CN1257885 C CN 1257885C CN 03150579 CN03150579 CN 03150579 CN 03150579 A CN03150579 A CN 03150579A CN 1257885 C CN1257885 C CN 1257885C
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- lidocaine
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- nuclide
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- 150000003839 salts Chemical class 0.000 title claims abstract description 25
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- OKTJSMMVPCPJKN-OUBTZVSYSA-N Carbon-13 Chemical compound [13C] OKTJSMMVPCPJKN-OUBTZVSYSA-N 0.000 title 1
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 claims abstract description 37
- 229960004194 lidocaine Drugs 0.000 claims abstract description 34
- 238000001514 detection method Methods 0.000 claims abstract description 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 9
- 210000004185 liver Anatomy 0.000 claims abstract description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 23
- 229910052799 carbon Inorganic materials 0.000 claims description 23
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 15
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- 239000003054 catalyst Substances 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 8
- 229960004393 lidocaine hydrochloride Drugs 0.000 claims description 7
- YECIFGHRMFEPJK-UHFFFAOYSA-N lidocaine hydrochloride monohydrate Chemical compound O.[Cl-].CC[NH+](CC)CC(=O)NC1=C(C)C=CC=C1C YECIFGHRMFEPJK-UHFFFAOYSA-N 0.000 claims description 7
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- QUPDWYMUPZLYJZ-UHFFFAOYSA-N ethyl Chemical compound C[CH2] QUPDWYMUPZLYJZ-UHFFFAOYSA-N 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Substances OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- CBPYOHALYYGNOE-UHFFFAOYSA-M potassium;3,5-dinitrobenzoate Chemical compound [K+].[O-]C(=O)C1=CC([N+]([O-])=O)=CC([N+]([O-])=O)=C1 CBPYOHALYYGNOE-UHFFFAOYSA-M 0.000 claims description 5
- 238000003756 stirring Methods 0.000 claims description 5
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 4
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- 230000002378 acidificating effect Effects 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 239000007795 chemical reaction product Substances 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 239000000047 product Substances 0.000 claims description 3
- 239000007787 solid Substances 0.000 claims description 3
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 2
- 238000007796 conventional method Methods 0.000 claims description 2
- 229910017053 inorganic salt Inorganic materials 0.000 claims description 2
- 239000003550 marker Substances 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 2
- 239000001384 succinic acid Substances 0.000 claims 1
- BPYKTIZUTYGOLE-IFADSCNNSA-N Bilirubin Chemical compound N1C(=O)C(C)=C(C=C)\C1=C\C1=C(C)C(CCC(O)=O)=C(CC2=C(C(C)=C(\C=C/3C(=C(C=C)C(=O)N\3)C)N2)CCC(O)=O)N1 BPYKTIZUTYGOLE-IFADSCNNSA-N 0.000 abstract description 4
- 206010067482 No adverse event Diseases 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- 230000005856 abnormality Effects 0.000 abstract description 2
- 208000019423 liver disease Diseases 0.000 abstract 1
- 238000010189 synthetic method Methods 0.000 abstract 1
- 230000006870 function Effects 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 238000001035 drying Methods 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- WRMRXPASUROZGT-UHFFFAOYSA-N monoethylglycinexylidide Chemical compound CCNCC(=O)NC1=C(C)C=CC=C1C WRMRXPASUROZGT-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 206010067125 Liver injury Diseases 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 239000003416 antiarrhythmic agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 238000005251 capillar electrophoresis Methods 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- HDITUCONWLWUJR-UHFFFAOYSA-N diethylazanium;chloride Chemical compound [Cl-].CC[NH2+]CC HDITUCONWLWUJR-UHFFFAOYSA-N 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000002875 fluorescence polarization Methods 0.000 description 1
- 231100000234 hepatic damage Toxicity 0.000 description 1
- 210000005161 hepatic lobe Anatomy 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- -1 lithium aluminum hydride Chemical compound 0.000 description 1
- 230000008818 liver damage Effects 0.000 description 1
- 230000003908 liver function Effects 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000002271 resection Methods 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention discloses a <13>C nuclein labeled lidocaine, salts, a preparation method and an application thereof. In the present invention, the <13>C nuclein labeled lidocaine and salts thereof can be applied to the detection of liver reserve function. The adopted reagents of the present invention have the characteristics of simple detection method, no need of expensive detection device and correct detection result, and are free from the interference of the common bilirubin abnormality of patients with hepatosis. <13>C is a stability isotope with no radioactivity and no adverse reaction to patients. <13>C lidocaine and salts thereof have the advantages of convenient synthetic method, considerably lower preparation cost than that of the prior art and easy obtainment of raw materials, and are suitable for industrial production. The <13>C nuclein labeled ledocaine of the present invention is a compound whose structure general formula is disclosed in the specification.
Description
Technical Field
The invention relates to a detection reagentIn particular to a reagent, in particular carbon, for detecting the reserve function of the liver13Nuclide-labeled lidocaine or a salt thereof.
Background
Lidocaine is a local anesthetic and an antiarrhythmic drug, and has been widely used clinically. In recent years, the reagent is used for detecting the liver reserve function. The basic principle is that after lidocaine enters the body, it passes through P in the liver450The liver reserve function is detected by detecting the content of MEGX in blood. The detection method comprises fluorescence polarization method, high performance capillary electrophoresis method and high performance liquid chromatography. The detection methods are long in time, expensive and complex in sample treatment, so that the application has certain limitation.
To overcome the above-mentioned disadvantages of lidocaine, Chinese patent application No. 02112477.9 uses carbon13Nuclides or carbons14Nuclides to replace four carbon atoms of lidocaine, a carbon is disclosed13Nuclides and carbon14Nuclide-labeled lidocaine. Due to the preparation of carbon13Nuclides or carbons14Nuclide-labeled lidocaine requires carbon13Nuclides or carbons14The nuclide-labeled reagent is expensive, so that the technology disclosed in the chinese patent application No. 02112477.9 has a high production cost, and the technology does not provide relevant physicochemical data, and cannot be confirmed, and industrial production has certain difficulty.
Disclosure of Invention
One of the technical problems to be solved by the invention is to disclose a carbon13Nuclide-labeled lidocaine or a salt thereof, so as to overcome the defects in the prior art;
the technical problem to be solved by the invention is to provide the carbon13A preparation method of nuclide-labeled lidocaine or salt thereof.
The invention also discloses the technical problem to be solvedCarbon (C)13Nuclide-labeled LiduokaThe use of a salt thereof.
The idea of the invention is that:
the inventor believes that lidocaine and salts thereof pass through P in the liver450After the MEGX and the acetaldehyde are firstly generated by the systemic metabolism, the acetaldehyde is metabolized to generate CO2And is discharged from the body through respiration. With carbon13After the carbon atom of ethyl group in lidocaine and its salt molecule is labeled by nuclide, the method is used13C expiratory mass spectrometer for timed and quantitative detection of expired gas13CO2The amount of the compound can judge the reserve function of the liver, and the four carbon atoms of the lidocaine and the salt thereof are not required to be completely marked, so that the production cost can be greatly reduced, the preparation is simpler, and the industrialized production is easy to realize.
Carbon of the invention13Nuclide-labeled lidocaine is a compound having the following structural formula:
in the formula (I), the compound is shown in the specification,*c represents carbon13A nuclide marker site.
Said carbon13The nuclide-labeled lidocaine salt is one of inorganic salt and organic salt, preferably hydrochloride, sulfate, citrate or succinate.
Carbon of the invention13The preparation method of the nuclide-labeled lidocaine or the salt thereof comprises the following steps:
(1) to be dissolved in organic solvents13Solutions of C-labelled ethylamine and compounds containing13Reacting C-labeled acetic acid organic solvent for 0.1-1 h in the presence of a catalyst, and collecting N-doped acetic acid from the reaction product13C ethyl radical13And C, acetamide.
The organic solvent is preferably one of tetrahydrofuran, benzene, hexane, cyclohexane or diethyl ether;
the catalyst is preferably one or a mixture of Dicyclohexylcarbodiimide (DCC) or 4-Dimethylaminopyridine (DMAP); the reaction formula is as follows:
(2) the above-mentioned N-13C ethyl radical13C acetamide with LIAlH in solvent4Stirring and reacting for 2-6 hours at room temperature, distilling at normal pressure, collecting distillate, introducing HCl gas until the pH value is 1-3, and cooling to-70-30Collecting the precipitated white solid at the temperature of DEG C,13c diethylamine hydrochloride. The reaction formula is as follows:
the solvent is one of tetrahydrofuran or diethyl ether;
Mp225-60℃,MS M+51;
(3) will be described in detail13C diethylamine hydrochloride and 2, 6-dimethyl chloroacetanilide are subjected to reflux reaction for 1 to 5 hours in the presence of an alkaline catalyst in a solvent, cooled to the temperature of between 5 ℃ below zero and 5 ℃, and products are collected to obtain the compound13C lidocaine.
The solvent is one of benzene, toluene, hexane, cyclohexane or diethyl ether;
the basic catalyst is one of sodium hydroxide, potassium carbonate, pyridine or triethylamine;
the reaction formula is as follows:
the yield is 75 percent, Mp is 68-69 ℃, and MS M+236。
(4) Will be described in detail13Salifying C lidocaine in a solvent by using an acidic substance, adjusting the pH value to 1-3, heating and refluxing, and collecting a reaction product by adopting a conventional method to obtain13C lidocaine salt.
The solvent is one or the mixture of ethanol, isopropanol, acetone, tetrahydrofuran or diethyl ether;
the acidic substance is HCl or H2SO4One of citric acid or succinic acid, and the corresponding salt can be obtained after reaction.
The raw materials involved in the preparation process can adopt commercial products.
Hair brushBright carbon13The nuclide-labeled lidocaine or a salt thereof can be applied to detection of liver reserve function in the same way as the conventional technology.13C is stable isotope, has no radioactivity,therefore, has no adverse reaction to patients.
The invention has the characteristics of simple detection method, no need of expensive detection equipment, correct detection result, no interference from bilirubin abnormality common in hepatopaths,13c is stable isotope and has no radioactivity, so the medicine has no adverse reaction to patients,13the method for synthesizing the C lidocaine and the salt thereof is simple, the preparation cost is greatly lower than that of the prior art, the raw materials are easy to obtain, and the method is suitable for industrial production.
Detailed Description
Example 1
In a reaction flask, add13C acetic acid (3g, 0.05mol), THF (25ml), DCC (10.3g, 0.05mol) DMAP (0.3g) was stirred, and then this solution was added dropwise13C ethylamine (2.15g, 0.05mol) -THF (10ml) solution, which takes about half an hour, is completely dropped, is stirred at room temperature overnight, is filtered, is concentrated to be dry, and then N-13C ethyl radical135g of a crude product of acetamide C;
THF20ml and lithium aluminum hydride (1.9g, 0.05mol) were added to the reaction flask, stirred, and N-13C ethyl radical13C acetamide (4.35g, 0.05mol), stirring at room temperature for 4 hours, distilling at normal pressure until no distillate drips out, introducing HCl gas into the distillate until the pH value is 1, cooling to-5 ℃, separating out white solid, filtering, and drying filter cake in vacuum to obtain the final product133.85g of C diethylamine hydrochloride, yield 70%.
Mp 225-60℃,MS M+51;
2.6-Dimethylchloroacetanilide (9.85g, 0.05mol) and benzene (30ml) were charged into a reaction flask, and after mixing, the mixture was added13Diethylamine hydrochloride (5.5g, 0.05mol), 40% NaOH (4g.0.06mol) was added dropwise to the reaction solution, and after stirring at room temperature for 15 minutes, the reaction solution was heated to refluxRefluxing for 3 hours, cooling to 0 ℃, filtering, washing filter cakes with water, and drying to obtain138.8g of C lidocaine;
the yield is 75 percent, Mp is 68-69 ℃, and MS M+236。
Example 2
In a reaction flask, add13Dissolving 5g of lidocaine C and 20ml of ethanol by stirring, introducing HCl gas until the pH value is 2.5, heating and refluxing after the introduction is finished, adding a little activated carbon for decoloring, filtering, cooling and crystallizing the filtrate, filtering, washing a filter cake with a little acetone, draining, and drying to obtain white lidocaine13C Lidocaine hydrochloride 4.8g, yield83%,Mp 78-90℃。
Example 3
13C lidocaine hydrochloride breath test for liver function assessment
13Dissolving lidocaine hydrochloride in distilled water to obtain 0.1% solution containing lidocaine131mg of lidocaine hydrochloride;
the mice were anesthetized with ether and injected into the abdominal cavity of the mice at a weight of 1mg/kg13C an aqueous solution of lidocaine hydrochloride, to13C exhaled mass spectrometer assay13CO2And the detection result shows that the mouse is normal13CO2Peak at 1.5-2 hours, and in the liver damage or liver lobe resection mouse test13CO2The peak drop and the lag, thus indicating,13the C lidocaine hydrochloride can be applied to the detection of the liver reserve function.
Claims (10)
2. Carbon according to claim 113Nuclide-labeled lidocaine or a salt thereof, characterized in that the salt is an inorganic salt or an organic salt.
3. Carbon according to claim 213Nuclide-labeled lidocaine or a salt thereof, wherein the salt is one of hydrochloride, sulfate, citrate, or succinate.
4. Carbon according to claim 1, 2 or 313The preparation method of the nuclide-labeled lidocaine or the salt thereof is characterized by comprising the following steps of:
(1) to be dissolved in organic solvents13Solutions of C-labelled ethylamine and compounds containing13C-labeled acetic acid organic solvent is reacted in the presence of a catalyst, and N-13C ethyl radical13C acetamide;
the catalyst is one or a mixture of dicyclohexylcarbodiimide and 4-dimethylamino pyridine;
(2) n-13C ethyl radical13C acetamide with LIAlH in solvent4Stirring and reacting at room temperature, distilling, collecting distillate, introducing HCl gas until the pH value is 1-3, cooling, and collecting precipitated white solid, namely13C diethylamine hydrochloride;
(3) will be provided with13C diethylamine hydrochloride and 2, 6-dimethyl chloroacetanilide are refluxed and reacted in the presence of an alkaline catalyst in a solvent, cooled and collected to obtain a product13C lidocaine;
the basic catalyst is one of sodium hydroxide, potassium carbonate, pyridine or triethylamine.
5. The method according to claim 4, wherein the organic solvent in step (1) is one of tetrahydrofuran, benzene, hexane, cyclohexane or diethyl ether.
6. The method according to claim 4, wherein the organic solvent in step (2) is one of tetrahydrofuran and diethyl ether.
7. The method of claim 4, wherein the organic solvent in step (3) is one of benzene, toluene, hexane or cyclohexane.
8. The method according to any one of claims 4 to 7, further comprising the steps of: will be described in detail13C lidocaine reacts with acidic substances in a solvent, the pH value is adjusted to be 1-3, heating reflux is carried out, a conventional method is adopted, and reaction products are collected to obtain the C lidocaine hydrochloride13C lidocaine salt.
9. The method according to claim 8, wherein the solvent is one or a mixture of ethanol, isopropanol, acetone, tetrahydrofuran or diethyl ether; the acidic substance is HCl or H2SO4Citric acid or succinic acid.
10. The carbon as claimed in any one of claims 1 to 313The application of nuclide-labeled lidocaine or salt thereof as a liver reserve function detection reagent.
Priority Applications (1)
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CN 03150579 CN1257885C (en) | 2003-08-26 | 2003-08-26 | Carbon 13 labeled ledocaine and its salts preparations and uses |
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CN 03150579 CN1257885C (en) | 2003-08-26 | 2003-08-26 | Carbon 13 labeled ledocaine and its salts preparations and uses |
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CN1490306A CN1490306A (en) | 2004-04-21 |
CN1257885C true CN1257885C (en) | 2006-05-31 |
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Effective date of registration: 20070629 Address after: 201103 Shanghai City Jinhui road 588 Lane 34, room 702 Patentee after: Cao Yin Address before: 200030 7D, 278 Wuxing Road, Shanghai, China Patentee before: Shanghai Kaiwen Pharmaceutical Co., Ltd. |
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C19 | Lapse of patent right due to non-payment of the annual fee | ||
CF01 | Termination of patent right due to non-payment of annual fee |