CN113501793A - Preparation method of stable isotope labeled nitrazepam internal standard reagent - Google Patents
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- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
- C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
- C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
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- C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
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Abstract
The invention relates to a preparation method of a stable isotope labeled nitrazepam internal standard reagent for food safety detection, belonging to the field of research and development of standard substances for food safety detection. The stable isotope labeled nitrazepam is obtained by using stable isotope labeled phenylboronic acid as a raw material through catalytic addition, acylation, cyclization and separation and purification. The process has the advantages of simple and easily obtained raw materials for synthesis, simple operation, mild reaction conditions, high chemical purity of the final product, no dilution of isotope abundance, no use of toxic and carcinogenic chemical reagents, and effective reduction of the risks of personnel health and environmental pollution. The stable isotope labeled nitrazepam obtained by the preparation method has the chemical purity of more than 98 percent and the isotope abundance of more than 98 percent, and can meet the technical requirements of a stable isotope labeled internal standard reagent required by a liquid chromatography tandem mass spectrometry for food safety detection.
Description
Technical Field
The invention relates to a preparation method of a stable isotope labeled nitrazepam internal standard reagent for food safety detection, belonging to the field of research and development of standard substances for food safety detection.
Background
Miexi (Midicine)Pan is benzodiazepine
The category of drugs is two categories of mental drugs, which are clinically used for treating insomnia, convulsion and myoclonic epilepsy. Because of having the functions of tranquilizing and hypnotizing, antianxiety, anticonvulsant and muscle relaxation, the medicine is often added into Chinese patent medicines and health-care foods for tranquilizing and allaying excitement by illegal manufacturers so as to enhance the curative effect; or the compound is added into feed as a growth promoter by individual livestock husbandry feeders, so that the animals are less sleepy, the nutrient consumption for maintaining physical performance of the animals is reduced, and the weight gain is facilitated; or used in animal transportation and slaughtering process to relieve adverse stimulus reaction of animal body, reduce death rate, and prevent meat quality change. However, overdose of nitrazepam can cause dizziness, somnolence, hypodynamia, coma, respiratory depression and other side effects, and tolerance, dependence and addiction are easy to generate after long-term use. Therefore, the Chinese 'regulations on implementation of drug management law' and 'food sanitation law' definitely stipulate that chemical drug components are prohibited to be added into Chinese patent drugs and health-care food; notice 176 of the Ministry of agriculture also states that the use of benzodiazepines in animal feed and drinking water is strictly prohibited
A quasi drug. The current relevant detection methods are: the detection standard in the feed is benzodiazepine in NY/T1757-2009 feed issued by Ministry of agriculture
Determination of quasi-drugs by liquid chromatography-tandem mass spectrometry; the related detection standard methods in the food are a food supplement inspection method ' detection of 75 illegally added chemical drugs in BJS 201710 health-care food ' issued by the State administration of market supervision and administration and ' determination of residual quantity of benzodiazepine drugs in SN/T3847-2019 export food ' issued by the State administration of customs, liquid chromatography-mass spectrometry/mass spectrometry '. Wherein, the determination of the residual quantity of benzodiazepine drugs in SN/T3847 and 2019 export foods by a liquid chromatography-mass spectrometry/mass spectrometry method adopts a stable isotope internal standard method for quantification and uses nitrazepam (phenyl-D)5) AsIsotopic internal standards were used.
At present, the nitrazepam labeled by the stable isotope is only provided by foreign standard product companies and can only be solved by import, thereby severely restricting the application of the compound in domestic food safety detection. To date, the only synthetic literature on stable isotopically labeled nitrazepam has been the patent published in Karlsen m. salihi, equal to 2014 (WO 2014013063 a 1). The patent is based on the stable isotope labeled benzene-13C6The method is obtained by 3 steps of Friedel-crafts acylation, cyclization, dichromate oxidation and the like, the condition requirement is harsh, toxic and carcinogenic strong oxidant dichromate is needed in the last oxidation step, the health risk of experimenters and the environmental risk of waste liquid treatment are increased, and the treatment cost of the experimental waste liquid is high.
Therefore, the development of a preparation method of stable isotope labeled nitrazepam, which is simple to operate, mild in condition, friendly to personnel and environment, is urgently needed to meet the increasing application requirement of the compound in the aspect of food safety detection.
Disclosure of Invention
The invention aims to provide a preparation method of stable isotope labeled nitrazepam suitable for food safety detection. The synthesis method has the advantages of easily available raw materials, short reaction route, simple operation, mild conditions and no use of toxic and carcinogenic chemical reagents; the final product has high chemical purity, and the isotopic abundance is not diluted, so that the product cost is effectively reduced.
The purpose of the invention can be realized by the following technical scheme:
1. a preparation method of a stable isotope labeling Nitrazepam internal standard reagent is disclosed, wherein the stable isotope labeling Nitrazepam internal standard reagent has a chemical structure shown in a formula (Labeled-Nitrazepam):
wherein R is H or D12C or13C, characterized in that the general route of the preparation steps is as follows:
wherein R is H or D12C or13C, X and Y are respectively one of Cl, Br and I, and the preparation steps are as follows:
(1) under the existence of a catalyst, a ligand, an additive and an organic solvent, adding stable isotope labeled phenylboronic acid, then adding 2-amino-5-nitrobenzonitrile, and reacting for 12-48 hours at the temperature of 30-120 ℃; after TLC tracking reaction raw materials completely react, quenching the reaction mixed solution with water, filtering, extracting the filtrate with an organic solvent, combining organic phases, washing with a saturated sodium bicarbonate solution and a saturated sodium chloride solution in sequence, adding a drying agent for drying, removing the solvent by reduced pressure distillation, and carrying out column chromatography on residues to obtain the stable isotope labeled 2-amino-5-nitrobenzophenone;
the reaction of this step is as follows:
wherein the chemical structure of the stable isotope labeled phenylboronic acid is shown as formula (I), and the chemical structure of the stable isotope labeled 2-amino-5-nitrobenzophenone is shown as formula (II), wherein R is H or D12C or13C；
(2) Dissolving stable isotope labeled 2-amino-5-nitrobenzophenone in an organic solvent, adding halogen acetyl halide, and reacting for 1-10 hours at the temperature of 20-80 ℃; after TLC tracking reaction raw materials completely react, quenching the reaction mixed solution with water, filtering, extracting the filtrate with an organic solvent, combining organic phases, washing with a saturated sodium bicarbonate solution and a saturated sodium chloride solution in sequence, adding a drying agent for drying, removing the solvent by reduced pressure distillation, and carrying out column chromatography on residues to obtain the stable isotope labeled 2-haloacetamido-5-nitrobenzophenone;
the reaction of this step is as follows:
wherein the chemical structure of the stable isotope labeled 2-haloacetamido-5-nitrobenzophenone is shown as the formula (III), wherein R is H or D12C or13C, X and Y are respectively one of Cl, Br and I;
(3) dissolving 2-haloacetamido-5-nitrobenzophenone labeled by a stable isotope in an organic solvent, adding urotropine and ammonium salt, and reacting for 1-8 hours at the temperature of 30-120 ℃; after TLC tracks that the reaction raw materials react completely, the reaction mixed solution is dried by spinning, water is added, organic solvent is used for extraction, organic phases are combined, and the organic phases are washed by saturated sodium bicarbonate solution and saturated sodium chloride solution in turn, and then drying agent is added; and (4) distilling under reduced pressure to remove the solvent, and carrying out column chromatography on the residue to obtain the stable isotope labeled nitrazepam.
The reaction of this step is as follows:
wherein the chemical structure of the stable isotope Labeled Nitrazepam is shown as the formula (Labeled-Nitrazepam), wherein R is H or D12C or13C。
In the step (1), the catalyst is one or more of palladium acetate, palladium chloride, bis (triphenylphosphine) palladium dichloride, tetrakis (triphenylphosphine) palladium, bis (diphenylphosphinophenyl ether) palladium dichloride, bis (diphenylphosphinoferrocene) palladium dichloride, palladium acetylacetonate, palladium trifluoroacetate, bis (diphenylphosphinofethanpalladium dichloride), tris (dibenzylideneacetone) dipalladium and tris (dibenzylideneacetone) dipalladium chloroform adduct; the ligand is one or more of 2,2 ' -bipyridyl, 4 ' -dimethyl-2, 2 ' -bipyridyl, 5 ' -dimethyl-2, 2 ' -bipyridyl, 4 ' -dimethoxy-2, 2 ' -bipyridyl, 1, 10-phenanthroline, 4, 7-dimethyl-1, 10-phenanthroline and 4, 7-diphenyl-1, 10-phenanthroline; the additive is one or more of hydrochloric acid, sulfuric acid, glacial acetic acid, formic acid, trifluoroacetic acid, dichloroacetic acid, methanesulfonic acid, p-toluenesulfonic acid and benzoic acid(ii) a The solvent is one or more of tetrahydrofuran, dioxane, toluene, xylene, 2-methyltetrahydrofuran, N-dimethylformamide, methanol, ethanol, isopropanol, N-propanol, benzene and chlorobenzene; the stable isotope labeled phenylboronic acid is deuterium labeled phenylboronic acid,13One of the C-labeled phenylboronic acids; the reaction temperature is 30-120 ℃; the reaction time is 12-48 hours.
In the step (2), the halogen acetyl halide is one or more of chloroacetyl chloride, chloroacetyl bromide, bromoacetyl chloride, bromoacetyl bromide and iodoacetyl chloride; the organic solvent is one or more of tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, benzene, toluene, xylene, acetonitrile and N, N-dimethylformamide; the reaction temperature is 20-80 ℃; the reaction time is 1-10 hours.
In the step (3), the organic solvent is one or more of methanol, ethanol, n-propanol and isopropanol; the ammonium salt is one or more of ammonium chloride, ammonium formate, ammonium acetate and ammonium sulfate; the reaction temperature is 30-120 ℃; the reaction time is 1-8 hours.
Compared with the prior art, the invention has the beneficial effects that: the synthesis method has the advantages of easily available raw materials, simple operation and mild conditions, avoids using highly toxic and carcinogenic chemical reagents, and effectively reduces the risks of personnel health and environmental pollution. The stable isotope labeled nitrazepam for food safety detection obtained by the preparation method has important significance for relevant food safety supervision and detection work in China.
Description of the drawings:
FIG. 1: 2-amino-5-nitrobenzophenone (phenyl-D)5) Is/are as follows1HNMR picture
FIG. 2: 2-amino-5-nitrobenzophenone (phenyl-D)5) LC-MS diagram of
FIG. 3: 2-chloroacetamido-5-nitrobenzophenone (phenyl-D)5) Is/are as follows1H NMR chart
FIG. 4: nitrazepam (phenyl-D)5) Is/are as follows1H NMR chart
FIG. 5: nitrazepam (phenyl-D)5) LC-MS diagram of
FIG. 6: nitrazepam (benzene)radical-D5) HPLC chart of (1)
Detailed Description
The present invention will be further described with reference to the following examples and the accompanying drawings, which are not intended to limit the scope of the present invention in any way.
Example 1: 2-amino-5-nitrobenzophenone (phenyl-D)5) Preparation of
In a 500mL three-necked flask, deuterated phenylboronic acid (12.71g, 0.1mol), 2-amino-5-nitrobenzophenone (8.15g, 0.05mol), the catalyst tetrakis (triphenylphosphine) palladium (2.89g, 2.5mmol), the ligand 4,4 '-dimethyl-2, 2' -bipyridine (920mg, 5mmol), the additive trifluoroacetic acid (57g, 0.5mol), and tetrahydrofuran were added: water 1: 1 (250 mL); reacting at 90 ℃ for 24 hours; TLC (thin layer chromatography) is used for tracking reaction raw materials to react completely, the reaction liquid is cooled to room temperature, 200mL of water is added, ethyl acetate (3X 300mL) is used for extraction, organic phases are combined, the organic phases are washed by saturated sodium bicarbonate solution and saturated sodium chloride solution in sequence, anhydrous sodium sulfate is added for drying, the solvent is removed through reduced pressure distillation, and the stable isotope labeled 2-amino-5-nitrobenzophenone (phenyl-D) is obtained through column chromatography of residues5) (11.49g, yield 93%).1HNMR(DMSO-D 6600 MHz): δ 8.20(s, 1H), 8.20(s, 2H), 8.12(dd, 1H), 6.97(d, 1H,), see FIG. 1; LC-MS (ESI +)248[ M + H]+See fig. 2.
Example 2: 2-chloroacetamido-5-nitrobenzophenone (phenyl-D)5) Preparation of
In a 100mL three-necked flask, 2-amino-5-nitrobenzophenone (phenyl-D) was added5) (2.37g, 10mmol), chloroacetyl chloride (1.69g, 15mmol) and dried dioxane (20 mL); introducing nitrogen, and reacting for 12 hours at the temperature of 20 ℃; TLC tracking reaction raw material reaction completionAfter completion, the solvent was distilled off under reduced pressure, 20mL of water was added, extraction was performed with ethyl acetate (3X 30mL), the organic phases were combined, washed successively with saturated sodium bicarbonate solution, saturated sodium chloride solution, dried with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography to give stable isotope-labeled 2-chloroacetamido-5-nitrobenzophenone (phenyl-D)5) (2.97g, yield 95%).1H NMR(DMSO-D 6600 MHz): δ 11.0(s, 1H), 8.50(dd, 1H), 8.20(d, 1H), 8.06(d, 1H,), 4.23(s, 2H,), see FIG. 3.
Example 3: nitrazepam (phenyl-D)5) Preparation of
Adding stable isotope labeled 2-chloroacetamido-5-nitrobenzophenone (phenyl-D) into a 50mL three-necked bottle5) (3.23g, 10mmol), urotropin (2.80g, 20mmol), ammonium chloride (1.07g, 20mmol), methanol (20 mL); heating to reflux under the protection of nitrogen, and reacting at the temperature for 24 hours; TLC (thin layer chromatography) is used for tracking reaction raw materials to completely react, the solvent is removed by reduced pressure distillation, 20mL of water is added, ethyl acetate (3X 30mL) is used for extraction, organic phases are combined, the mixture is washed by saturated sodium bicarbonate solution and saturated sodium chloride solution in sequence, anhydrous sodium sulfate is added for drying, the solvent is removed by reduced pressure distillation, and the residue is subjected to column chromatography to obtain the stable isotope labeled nitrazepam (phenyl-D)5) (2.57g, yield 90%).1HNMR(DMSO-D 6600 MHz): δ 11.16(s, 1H), 8.44(dd, 1H), 8.03(d, 1H)7.45(d, 1H), 4.26(s, 2H), see fig. 4; LC-MS (ESI +)287[ M + H]+See fig. 5; chemical purity by HPLC 99.55%, see fig. 6; isotopic abundance 98.56%, see table 1.
TABLE 1 nitrazepam (phenyl-D)5) Isotopic abundance of
The quality standard meets the requirement of an isotope internal standard reagent required by a liquid chromatogram tandem mass spectrometry for food safety detection.
13Synthesis of C-labeled nitrazepam the procedure was the same as for nitrazepam (phenyl-D) in the above example5) The synthesis step (2).
The above description is only for the purpose of illustrating the preferred embodiments of the present invention, and the present invention should not be limited by the disclosure of the preferred embodiments. Therefore, it is intended that all equivalents and modifications which do not depart from the spirit of the invention disclosed herein are deemed to be within the scope of the invention.
Claims (4)
1. A preparation method of a stable isotope labeling Nitrazepam internal standard reagent is disclosed, wherein the stable isotope labeling Nitrazepam internal standard reagent has a chemical structure shown in a formula (Labeled-Nitrazepam):
wherein R is H or D12C or13C, characterized in that the general route of the preparation steps is as follows:
wherein X and Y are respectively one of Cl, Br and I, and the preparation steps are as follows:
(1) under the existence of a catalyst, a ligand, an additive and an organic solvent, adding stable isotope labeled phenylboronic acid, then adding 2-amino-5-nitrobenzonitrile, and reacting for 12-48 hours at the temperature of 30-120 ℃; after TLC tracking reaction raw materials completely react, quenching the reaction mixed solution with water, filtering, extracting the filtrate with an organic solvent, combining organic phases, washing with a saturated sodium bicarbonate solution and a saturated sodium chloride solution in sequence, adding a drying agent for drying, removing the solvent by reduced pressure distillation, and carrying out column chromatography on residues to obtain the stable isotope labeled 2-amino-5-nitrobenzophenone;
the reaction of this step is as follows:
wherein the chemical structure of the stable isotope labeled phenylboronic acid is shown as formula (I), and the chemical structure of the stable isotope labeled 2-amino-5-nitrobenzophenone is shown as formula (II), wherein R is H or D12C or13C；
(2) Dissolving stable isotope labeled 2-amino-5-nitrobenzophenone in an organic solvent, adding halogen acetyl halide, and reacting for 1-10 hours at the temperature of 20-80 ℃; after TLC tracking reaction raw materials completely react, quenching the reaction mixed solution with water, filtering, extracting the filtrate with an organic solvent, combining organic phases, washing with a saturated sodium bicarbonate solution and a saturated sodium chloride solution in sequence, adding a drying agent for drying, removing the solvent by reduced pressure distillation, and carrying out column chromatography on residues to obtain the stable isotope labeled 2-chloroacetamide-5-nitrobenzophenone;
the reaction of this step is as follows:
wherein the chemical structure of the stable isotope labeled 2-chloroacetamide-5-nitrobenzophenone is shown as a formula (III), wherein R is H or D12C or13C; x and Y are respectively one of Cl, Br and I;
(3) dissolving stable isotope labeled 2-chloroacetamide-5-nitrobenzophenone in an organic solvent, adding urotropine and ammonium salt, and reacting for 1-8 hours at 30-120 ℃; after TLC tracks that the reaction raw materials react completely, the reaction mixed solution is dried by spinning, water is added, organic solvent is used for extraction, organic phases are combined, and the organic phases are washed by saturated sodium bicarbonate solution and saturated sodium chloride solution in turn, and then drying agent is added; and (4) distilling under reduced pressure to remove the solvent, and carrying out column chromatography on the residue to obtain the stable isotope labeled nitrazepam.
The reaction of this step is as follows:
wherein the chemical structure of the stable isotope labeled nitrazepam is shown as a formula (IV), wherein R is H or D12C or13C。
2. The method for preparing a stable isotope labeling nitrazepam internal standard reagent according to claim 1, characterized in that in the step (1), the catalyst is one or more of palladium acetate, palladium chloride, bis (triphenylphosphine) palladium dichloride, tetrakis (triphenylphosphine) palladium, bis (diphenylphosphinophenyl ether) palladium dichloride, bis (diphenylphosphinoferrocene) palladium dichloride, palladium acetylacetonate, palladium trifluoroacetate, bis (diphenylphosphino) ethane palladium dichloride, tris (dibenzylideneacetone) dipalladium and tris (dibenzylideneacetone) dipalladium chloroform adduct; the ligand is one or more of 2,2 ' -bipyridyl, 4 ' -dimethyl-2, 2 ' -bipyridyl, 5 ' -dimethyl-2, 2 ' -bipyridyl, 4 ' -dimethoxy-2, 2 ' -bipyridyl, 1, 10-phenanthroline, 4, 7-dimethyl-1, 10-phenanthroline and 4, 7-diphenyl-1, 10-phenanthroline; the additive is one or more of hydrochloric acid, sulfuric acid, glacial acetic acid, formic acid, trifluoroacetic acid, dichloroacetic acid, methane sulfonic acid, p-toluenesulfonic acid and benzoic acid; the solvent is one or more of tetrahydrofuran, dioxane, toluene, xylene, 2-methyltetrahydrofuran, N-dimethylformamide, methanol, ethanol, isopropanol, N-propanol, benzene and chlorobenzene; the stable isotope labeled phenylboronic acid is deuterium labeled phenylboronic acid,13One of the C-labeled phenylboronic acids; the reaction temperature is 30-120 ℃; the reaction time is 12-48 hours.
3. The method for preparing a stable isotope labeled nitrazepam internal standard reagent according to claim 1, characterized in that in the step (2), the haloacetyl halide is one or more of chloroacetyl chloride, chloroacetyl bromide, bromoacetyl chloride, bromoacetyl bromide and iodoacetyl chloride; the organic solvent is one or more of tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, benzene, toluene, xylene, acetonitrile and N, N-dimethylformamide; 20-80 ℃; the reaction time is 1-10 hours.
4. The method for preparing a stable isotope labeling nitrazepam internal standard reagent according to claim 1, characterized in that in the step (3), the organic solvent is one or more of methanol, ethanol, n-propanol and isopropanol; the ammonium salt is one or more of ammonium chloride, ammonium formate, ammonium acetate and ammonium sulfate; the reaction temperature is 30-120 ℃; the reaction time is 1-8 hours.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1098410A (en) * | 1993-12-28 | 1995-02-08 | 湖北制药厂第八分厂 | The preparation method of surem |
| WO2016040822A1 (en) * | 2014-09-12 | 2016-03-17 | Pinpoint Testing, Llc | Ready-to-constitute analytical platforms for chemical analyses and quantification |
| CN112608283A (en) * | 2020-12-22 | 2021-04-06 | 华中药业股份有限公司 | Preparation method of nitrazepam |
| CN113072509A (en) * | 2021-03-01 | 2021-07-06 | 中国科学院成都有机化学有限公司 | Method for synthesizing 7-amino clonazepam compound |
-
2021
- 2021-08-05 CN CN202110898980.1A patent/CN113501793A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1098410A (en) * | 1993-12-28 | 1995-02-08 | 湖北制药厂第八分厂 | The preparation method of surem |
| WO2016040822A1 (en) * | 2014-09-12 | 2016-03-17 | Pinpoint Testing, Llc | Ready-to-constitute analytical platforms for chemical analyses and quantification |
| CN112608283A (en) * | 2020-12-22 | 2021-04-06 | 华中药业股份有限公司 | Preparation method of nitrazepam |
| CN113072509A (en) * | 2021-03-01 | 2021-07-06 | 中国科学院成都有机化学有限公司 | Method for synthesizing 7-amino clonazepam compound |
Non-Patent Citations (3)
| Title |
|---|
| JIUXI CHEN等: "Palladium-catalyzed direct addition of arylboronic acids to 2-aminobenzonitrile derivatives: synthesis, biological evaluation and in silico analysis of 2-aminobenzophenones, 7-benzoyl-2-oxoindolines, and 7-benzoylindoles.", 《 ORGANIC & BIOMOLECULAR CHEMISTRY》 * |
| PANKAJ R. NILKANTH等: "Synthesis and Evaluation of Anticonvulsant Activity of Some Schiff Bases of 7-Amino-1,3-dihydro-2H-1,4-benzodiazepin-2-one.", 《CHEMISTRY & BIODIVERSITY》 * |
| 李安良 等: "硝基安定的合成", 《中国医药工业杂志》 * |
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