CN113325088A - Isotope mental active substance labeled compound and preparation method and application thereof - Google Patents

Isotope mental active substance labeled compound and preparation method and application thereof Download PDF

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CN113325088A
CN113325088A CN202110125205.2A CN202110125205A CN113325088A CN 113325088 A CN113325088 A CN 113325088A CN 202110125205 A CN202110125205 A CN 202110125205A CN 113325088 A CN113325088 A CN 113325088A
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ambica
fluoropentyl
indole
methyl
sample
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陈飚
许浩
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Wuxi Nuoping Pharmaceutical Technology Co ltd
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/04—Preparation or injection of sample to be analysed
    • G01N30/06—Preparation
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/62—Detectors specially adapted therefor
    • G01N30/72—Mass spectrometers
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/86—Signal analysis
    • G01N30/8624—Detection of slopes or peaks; baseline correction
    • G01N30/8631—Peaks
    • G01N30/8634—Peak quality criteria
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/04—Preparation or injection of sample to be analysed
    • G01N2030/042—Standards
    • G01N2030/045—Standards internal

Abstract

The isotopic psychoactive substance labeled compound provided by the invention can be used for an internal standard for measuring the content of a psychoactive substance N- (3-methyl-butanamide-2-yl) -1- (5-fluoropentyl) -indole-3-amide in a hair inspection material, and can be used for qualitatively detecting the N- (3-methyl-butanamide-2-yl) -1- (5-fluoropentyl) -indole-3-amide according to the retention time and ion pair matching, and specifically, quantitatively detecting the corresponding compound according to the chromatographic peak area. The isotope labeled compound is used as an internal standard substance, can reduce the matrix effect of a detection material, and has good application prospect in aspects such as judicial identification and the like.

Description

Isotope mental active substance labeled compound and preparation method and application thereof
Technical Field
The invention belongs to the technical field of preparation and application of standard substances of mental active substances, and particularly relates to an isotopic mental active substance labeled compound, and a preparation method and application thereof.
Background
Aiming at the detection of trace and trace substances in a detected material, an isotope dilution mass spectrometry method of a liquid chromatogram-mass spectrometer combined with an isotope labeling standard substance internal standard is the most common and efficient detection means. The isotope labeled standard substance is used as an internal standard, and the isotope labeled internal standard and a compound to be detected have completely consistent chemical properties except molecular weight, so that the isotope dilution mass spectrometry can achieve high detection precision and sensitivity, and is an indispensable tool for accurately detecting trace psychoactive substances.
The detection of the psychoactive substances and related metabolites in the hair can reflect the condition that a detected object is contacted with the psychoactive substances for a long time, and is an essential detection means for drug addiction judgment, community drug rehabilitation and the like.
At present, the method for trace N- (3-methyl-butanamide-2-yl) -1- (5-fluoropentyl) -indole-3-amide (5F-AMBICA) in the biological test material is generally a liquid phase mass spectrometry, and the content of 5F-AMBICA in the test material is determined by a standard curve method by selecting a compound with similar chemical properties with 5F-AMBICA as an internal standard. The closer the internal standard is to the target, the lower its matrix effect. The currently selected internal standard is typically the more common methoxamine or D5-diazepam.
Therefore, it is an urgent problem to be solved by those skilled in the art to provide an isotopically active substance labeled compound for improving the accuracy and sensitivity of detection of a psychoactive substance 5F-AMBICA in a test material.
Disclosure of Invention
Aiming at the problems of low detection precision and low sensitivity of psychoactive substances in the prior art, the invention provides an isotopically active substance labeled compound, which has the following structural formula:
Figure RE-DEST_PATH_IMAGE001
wherein R is1、R2、R3、R4At least one of which is D, said psychoactive substance comprising N- (3-methyl-butanamide-2-yl) -1- (5-fluoropentyl) -indole-3-amide (5F-AMBICA).
Preferably, the isotopically active substance labeled compound has the structural formula:
Figure RE-DEST_PATH_IMAGE002
。
in another aspect of the present invention, there is provided a method for preparing the isotopically active substance-labeled compound, comprising the steps of:
(1) carrying out Friedel-crafts acylation reaction on N- (3-methyl-butyryl benzylamine-2-yl) formamide and N-5-fluoropentyl indole under the catalysis of aluminum trichloride to generate a benzyl protected 5F-AMBICA intermediate;
(2) deprotection of the intermediate of step (1) under acidic conditions produces N- (3-methyl-butanamide-2-yl) -1- (5-fluoropentyl) -indole-4, 5,6, 7-D4-3-amide (D4-5F-AMBICA).
In another aspect, the invention provides the use of the isotopically active substance labeled compound in detecting the content of the psychoactive substance N- (3-methyl-butanamide-2-yl) -1- (5-fluoropentyl) -indole-3-amide (5F-AMBICA) in biological samples or sewage.
In the above application, the method for detecting the content of the psychoactive substance 5F-AMBICA in the biological test material or the sewage by using the isotopic psychoactive substance labeled compound comprises the following steps:
(1) setting the detection conditions of liquid chromatography-mass spectrometry;
(2) drawing a standard curve: adding 5F-AMBICA and D4-5F-AMBICA standard solutions with different proportions into a negative test material corresponding to a sample to be detected, performing LC-MS/MS detection after the same pretreatment step as the sample to be detected, and making a standard curve for the peak area ratio and the concentration of the 5F-AMBICA and the D4-5F-AMBICA; wherein the internal standard is an isotopically active substance labeled compound of claim 1 or 2;
(3) pretreatment and determination of a sample to be detected: adding the isotopic psychoactive substance labeled compound as described in claim 2 into a sample to be detected as an internal standard, performing LC-MS/MS detection after the same pretreatment steps as those used for drawing a standard curve to obtain quantitative parameters of the sample to be detected and the internal standard, and calculating by using a formula of the standard curve of an internal standard method to obtain the content of the sample to be detected.
Preferably, in step (1), the mobile phase for the liquid chromatography-mass spectrometry detection is: acetonitrile (0.01% formic acid), B: water (0.01% formic acid, 5% ammonium formate), gradient: 1min 10% A, 2min 50% A, 4min 90% A,6min 95% A; a chromatographic column: poroshell120 PFP 3.0 x100mm 1.9.9 um; column temperature: 30 ℃; flow rate: 0.5 mL/min; sample introduction amount: 5 mu L of the solution; an ion source: electrospray ion source, positive mode (ESI +); the spraying voltage is 3500V; ion source temperature: 340 ℃; collision gas: nitrogen gas.
Preferably, in the step (2), the mass concentration of the internal standard substance in the mixed standard solution is 0.1-99.9%.
Preferably, in the step (3), the mass concentration of the internal standard substance in the sample to be tested is 0.1% -99.9%.
Preferably, in step (3), the internal standard method formula is calculated as:
Figure RE-DEST_PATH_IMAGE003
wherein X is the concentration of a sample to be detected, Y is the peak area obtained by liquid chromatography-mass spectrometry detection, b0Is the intercept of the standard curve, b1Is the slope of the standard curve.
Preferably, the mass content of the psychoactive substance 5F-AMBICA in the biological test material or the sewage is 10-7%-10%。
In another aspect, the present invention provides a method for detecting the content of psychoactive substance 5F-AMBICA in biological samples or wastewater, which comprises using isotopically psychoactive substance-labeled compound D4-5F-AMBICA as an internal standard to detect psychoactive substances, wherein the compound has the following structural formula:
Figure RE-DEST_PATH_IMAGE004
、
Figure RE-DEST_PATH_IMAGE005
、
Figure RE-DEST_PATH_IMAGE006
、
Figure RE-DEST_PATH_IMAGE007
、
Figure RE-DEST_PATH_IMAGE008
、
Figure RE-DEST_PATH_IMAGE009
、
Figure RE-DEST_PATH_IMAGE010
、
Figure RE-DEST_PATH_IMAGE011
、
Figure RE-DEST_PATH_IMAGE012
、
Figure RE-DEST_PATH_IMAGE013
、
Figure RE-DEST_PATH_IMAGE014
、
Figure RE-DEST_PATH_IMAGE015
、
Figure RE-DEST_PATH_IMAGE016
、
Figure RE-DEST_PATH_IMAGE017
or
Figure RE-DEST_PATH_IMAGE018
。
The isotopic psychoactive substance labeled compound D4-N- (3-methyl-butanamide-2-yl) -1- (5-fluoropentyl) -indole-3-amide provided by the invention can be used as an internal standard for content determination of a psychoactive substance N- (3-methyl-butanamide-2-yl) -1- (5-fluoropentyl) -indole-3-amide in a sewage detection material, can reduce the matrix effect of the detection material, and has good application prospects in aspects such as judicial identification and the like.
Drawings
The invention is further described below in conjunction with the appended drawings and the detailed description.
FIG. 1 high resolution mass spectrum of D4-5F-AMBICA in example 1.
FIG. 2 1H-NMR spectrum of D4-5F-AMBICA in example 1.
FIG. 3 spectrum 13C-NMR of D4-5F-AMBICA in example 1.
FIG. 4 preparation of D4-5F-AMBICA in example 119F-NMR spectrum.
FIG. 5 detection chromatogram of hair 5F-AMBICA sample in example 2.
FIG. 6 detection chromatogram of hair 5F-AMBICA sample in example 2.
Figure 7 hair 5F-AMBICA standard curve in example 2.
FIG. 8 shows the structural formula of the compound.
Detailed Description
In order to make the technical means, the creation characteristics, the achievement purposes and the effects of the invention easy to understand, the invention is further explained below by combining the specific drawings.
In the present invention, the term "matrix effect" refers to the influence and interference of substances other than the analyte 5F-AMBICA on the analysis process and the detection result.
In the description of the present invention, the mass concentration of 5F-AMBICA in hair is 10-7%-10%。
The isotopically active substance labeled compound D4-N- (3-methyl-butanamide-2-yl) -1- (5-fluoropentyl) -indole-4, 5,6, 7-D4-3-amide provided by the invention has the following structural formula:
Figure RE-571407DEST_PATH_IMAGE002
the invention is further illustrated by the following specific examples.
Example one
Preparation of N- (3-methyl-butanamide-2-yl) -1- (5-fluoropentyl) -indole-4, 5,6, 7-D4-3-amide (D4-5F-AMBICA):
at-20 deg.C, N- (3-methyl-butyrylbenzyl-2-yl) formamide (750 mg, 3 mmol) was dissolved in 50 mL of anhydrous oxygen-free carbon tetrachloride, aluminum trichloride (400 mg, 3 mmol) was added, followed by dropwise addition of N-5-fluoropentylindole (200 mg, 1 mmol) anhydrousWater oxygen free carbon tetrachloride solution (25 mL), stirred and slowly warmed to room temperature, held at room temperature for 12 hours, heated to 40 ℃ and heated for 2 hours. After cooling, the reaction was quenched by addition of ammonium chloride solution, the solvent was removed by rotary evaporation, dissolved in 150 mL of ethyl acetate, and the insoluble material was removed by filtration through celite, eluting with 30 mL of diethyl ether-ethyl acetate 1: 1 solution washing of diatomaceous earth, combining the organic phases, washing with 5% aqueous hydrochloric acid, extraction of the aqueous phase with ethyl acetate, and drying of the combined organic phases with anhydrous magnesium sulphate. The drying agent was removed by filtration and the solvent removed by rotary evaporation. Purification by silica gel column chromatography (petroleum ether: ethyl acetate =4: 1) gave D4-N- (3-methyl-butanamide-2-yl) -1- (5-fluoropentyl) -indole-4, 5,6, 7-D4-3-amide (D4-5F-AMBICA) as a white solid (207 mg, 54%).1H NMR (600 MHz, Methanol-d4) δ 7.99 (s, 1H), 4.48 (d, J = 7.2 Hz, 1H), 4.42 (t, J = 6.0 Hz, 1H), 4.34 (t, J = 6.0 Hz, 1H), 4.23 (t, J = 7.1 Hz, 2H), 2.19 (h, J = 6.8 Hz, 1H), 1.97 – 1.85 (m, 2H), 1.79 – 1.60 (m, 2H), 1.50 – 1.32 (m, 2H), 1.06 (dd, J = 6.8, 4.3 Hz, 6H). 13C NMR (151 MHz, Methanol-d4) δ 176.88, 167.72, 138.04, 132.66, 127.66, 110.61, 85.21, 84.12, 59.60, 47.57, 32.32, 31.20, 31.07, 30.80, 23.82, 23.79, 19.94, 18.91. 19F NMR (564 MHz, Methanol-d4) δ -220.23. HR-MS (ESI/TOF) m/z: Calcd. for C19H23D4FN3O2[M+H]+352.2338, Found 352.2329, shown in figures 1, 2, 3 and 4.
Example two
Detecting the content of N- (3-methyl-butanamide-2-yl) -1- (5-fluoropentyl) -indole-3-amide (5F-AMBICA) in hair by using D4-N- (3-methyl-butanamide-2-yl) -1- (5-fluoropentyl) -indole-4, 5,6, 7-D4-3-amide (D4-5F-AMBICA) as an internal standard; (1) liquid chromatography-mass spectrometry detection conditions:
a) the instrument model is as follows: agilent 1290 and 6470 QQQ;
b) a chromatographic column: poroshell120 PFP 3.0 x100mm 1.9.9 um;
c) column temperature: 30 ℃;
d) mobile phase: acetonitrile (0.01% formic acid), B: water (0.01% formic acid, 5% ammonium formate), gradient: 1min 10% A, 2min 50% A, 4min 90% A,6min 95% A;
e) flow rate: 0.5 mL/min;
f) sample introduction amount: 5 mu L of the solution;
g) an ion source: electrospray ion source, positive mode (ESI +);
h) the spraying voltage is 3500V;
i) ion source temperature: 340 ℃;
j) collision gas: nitrogen gas;
the ion pairs and corresponding conditions are shown in table 1:
TABLE 1
Figure RE-DEST_PATH_IMAGE019
(2) Pretreatment and detection of samples
Cleaning hair sample with ultrapure water, detergent water and acetone, air drying, cutting into pieces, weighing each 20.0 mg, adding 1 mL methanol (containing 10ng/mL D4-5F-AMBICA), grinding, ultrasonic treating in a freezing ultrasonic instrument for 30min, centrifuging at 4000 r for 5 min, collecting supernatant 800 μ L, volatilizing under 60 deg.C water bath air flow, redissolving with 80 μ L methanol, filtering with 0.22 μ L filter membrane,5 μ L was analyzed by LC-MS/MS to obtain the spectra shown in FIGS. 4 and 5.Wherein the quantitative ion pair is 348.2/232.0, and the peak area ratios of the 5F-AMBICA and the internal standard substance D4-5F-AMBICA in the two detections are 4151709/3874411 and 4288356/4026584 respectively;
(3) drawing of standard curve
Cleaning blank negative hair samples with ultrapure water, detergent water and acetone, air drying, cutting into pieces, weighing 20.0 mg of each part, adding 1 mL of methanol (containing 10ng/mL of D4-5F-AMBICA), adding 20 microliter of 5F-AMBICA standard reference substance with the concentration of 200, 500, 1000, 2000 and 5000 ng/mL to prepare hair addition samples with the concentration of 0.2, 0.5, 1.0, 2.0 and 5.0 ng/mg, preparing 3 parts of each concentration in parallel, swirling for 3 min, standing and soaking for 30min at room temperature, treating according to the sample pretreatment process, performing LC-MS/MS detection, and making a standard curve for the peak area ratio and the concentration of the 5F-AMBICA and the D4-5F-AMBICA to obtain the graph shown in figure 6. Formula of standard curveY = 1.443544X-0.060386, wherein X is the concentration of the sample to be detected, Y is the peak area obtained by liquid chromatography-mass spectrometry detection, b0= -0.060386 for standard curve intercept, b1=1.443544 is the slope of the standard curve.
According to the quantitative relation between the peak area ratio and the concentration in the standard curve and the calculation formula:
Figure RE-DEST_PATH_IMAGE020
and calculating the content of the 5F-AMBICA in the sample to be detected to be 0.78 ng/mg.
When the isotopic psychoactive substance labeled compound provided by the invention is used for detecting a psychoactive substance 5F-AMBICA in a detection material, a proper amount of the isotopic psychoactive substance labeled compound D4-5F-AMBICA is added into the detection material, appropriate pretreatment is carried out according to the detection requirement, then liquid chromatography-mass spectrometry (LC-MS/MS) detection is carried out, the isotopic psychoactive substance labeled compound is used as an internal standard, and qualitative and quantitative detection of the substance to be detected is realized by comparing the peak area ratios of a target substance and the substance to be detected under a Multiple Reaction Monitoring (MRM) mode, the detectable psychoactive substance is 5F-AMBICA, the specificity is high, and the sensitivity is high.
The foregoing shows and describes the general principles, essential features, and advantages of the invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are described in the specification and illustrated only to illustrate the principle of the present invention, but that various changes and modifications may be made therein without departing from the spirit and scope of the present invention, which fall within the scope of the invention as claimed. The scope of the invention is defined by the appended claims and equivalents thereof.

Claims (11)

1. An isotopically active substance labelled compound, wherein the compound has the formula:
Figure 645538DEST_PATH_IMAGE001
wherein R is1、R2、R3、R4At least one of which is D, said psychoactive substance comprising N- (3-methyl-butanamide-2-yl) -1- (5-fluoropentyl) -indole-3-amide (5F-AMBICA).
2. The isotopically active substance labeled compound of claim 1, wherein the isotopically active substance labeled compound has the formula:
Figure 733580DEST_PATH_IMAGE002
。
3. a method for preparing an isotopically active substance-labeled compound according to claim 1 or 2, comprising the steps of:
(1) carrying out Friedel-crafts acylation reaction on N- (3-methyl-butyryl benzylamine-2-yl) ammonium formate and N-5-fluoropentyl indole under the catalysis of aluminum trichloride to generate a benzyl protected intermediate;
(2) deprotection of the intermediate of step (1) under acidic conditions produces N- (3-methyl-butanamide-2-yl) -1- (5-fluoropentyl) -indole-4, 5,6, 7-D4-3-amide (D4-5F-AMBICA).
4. Use of an isotopically labelled compound of claim 1 or 2 for detecting the level of drug N- (3-methyl-butanamide-2-yl) -1- (5-fluoropentyl) -indole-3-amide in hair.
5. Use according to claim 4, characterized in that the method for detecting the content of the drug N- (3-methyl-butanamide-2-yl) -1- (5-fluoropentyl) -indole-3-amide in hair using the isotopically labelled compound according to claim 1 or 2 comprises the following steps:
(1) setting the detection conditions of liquid chromatography-mass spectrometry;
(2) drawing a standard curve: adding 5F-AMBICA and D4-5F-AMBICA standard solutions with different proportions into a negative test material corresponding to a sample to be detected, performing LC-MS/MS detection after the same pretreatment step as the sample to be detected, and making a standard curve for the peak area ratio and the concentration of the 5F-AMBICA and the D4-5F-AMBICA; wherein the internal standard is the isotopically drug-labeled compound of claim 1 or 2;
(3) pretreatment and determination of a sample to be detected: adding the isotope drug labeled compound in claim 2 into a sample to be detected as an internal standard, performing LC-MS/MS detection after the same pretreatment steps as those used for drawing a standard curve to obtain quantitative parameters of the sample to be detected and the internal standard, and calculating by using a formula of the standard curve of an internal standard method to obtain the content of the sample to be detected.
6. The use according to claim 4, wherein in step (1), the mobile phase for the liquid chromatography-mass spectrometry detection is: acetonitrile (0.01% formic acid), B: water (0.01% formic acid, 5% ammonium formate), gradient: 1min 10% A, 2min 50% A, 4min 90% A,6min 95% A; a chromatographic column: poroshell120 PFP 3.0 x100mm 1.9.9 um; column temperature: 30 ℃; flow rate: 0.5 mL/min; sample introduction amount: 5 mu L of the solution; an ion source: electrospray ion source, positive mode (ESI +); the spraying voltage is 3500V; ion source temperature: 340 ℃; collision gas: nitrogen gas.
7. The method according to claim 5, wherein in the step (2), the mass concentration of the internal standard substance in the mixed standard solution is 0.1-99.9%.
8. The method according to claim 5, wherein in the step (3), the mass concentration of the internal standard substance in the sample to be tested is 0.1-99.9%.
9. The method of claim 5, wherein in step (3), the internal standard method formula is calculated as:
Figure 70452DEST_PATH_IMAGE003
wherein X is the concentration of the sample to be detected, Y is the peak area obtained by liquid chromatography-mass spectrometry detection, b0 is the intercept of the standard curve, and b1 is the slope of the standard curve.
10. The use according to claim 4, wherein the bioassay material contains N- (3-methyl-butanamide-2-yl) -1- (5-fluoropentyl) -indole-3-amide in an amount of 10-7%-10%。
11. A method for detecting the content of the drug N- (3-methyl-butanamide-2-yl) -1- (5-fluoropentyl) -indole-3-amide in a biological test material, which comprises detecting the drug N- (3-methyl-butanamide-2-yl) -1- (5-fluoropentyl) -indole-3-amide using an isotopically labeled drug compound as an internal standard, which compound has the following structural formula:
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、
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、
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、
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、
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、
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、
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、
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、
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、
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、
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、
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、
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、
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or
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。
CN202110125205.2A 2021-01-29 2021-01-29 Isotope mental active substance labeled compound and preparation method and application thereof Pending CN113325088A (en)

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