CN113325089A - 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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CN113325089A
CN113325089A CN202110133955.4A CN202110133955A CN113325089A CN 113325089 A CN113325089 A CN 113325089A CN 202110133955 A CN202110133955 A CN 202110133955A CN 113325089 A CN113325089 A CN 113325089A
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fubica
fluorobenzyl
indole
methyl
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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
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    • 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
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    • G01N2030/045—Standards internal

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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- (p-fluorobenzyl) -indole-3-amide in a hair inspection material, and can be used for qualitatively detecting the N- (3-methyl-butanamide-2-yl) -1- (p-fluorobenzyl) -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- (p-fluorobenzyl) -indole-3-amide (AB-FUBICA) in the biological material to be detected is generally a liquid phase mass spectrometry, and the content of AB-FUBICA in the material to be detected is determined by a standard curve method by selecting a compound with similar chemical properties with AB-FUBICA 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 the psychoactive substance AB-FUBICA in the 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-800324DEST_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- (p-fluorobenzyl) -indole-3-amide (AB-FUBICA).
Preferably, the isotopically active substance labeled compound has the structural formula:
Figure RE-2635DEST_PATH_IMAGE001
。
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-p-fluorobenzyl indole under the catalysis of aluminum trichloride to generate an AB-FUBICA intermediate protected by benzyl;
(2) and (2) deprotecting the intermediate in the step (1) under acidic conditions to produce N- (3-methyl-butanamide-2-yl) -1- (p-fluorobenzyl) -indole-4, 5,6, 7-D4-3-amide (D4-AB-FUBICA).
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- (p-fluorobenzyl) -indole-3-amide (AB-FUBICA) in biological detection materials or sewage.
In the above application, the method for detecting the content of the psychoactive substance AB-FUBICA in the biological detection 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 AB-FUBICA and D4-AB-FUBICA standard solutions with different proportions into a negative test material corresponding to a sample to be tested, performing LC-MS/MS detection after the same pretreatment step as the sample to be tested, and making a standard curve for the peak area ratio and the concentration of the AB-FUBICA and the D4-AB-FUBICA; 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 step (2), the internal standard substance in the standard solution is mixedThe mass concentration is 0.1-99.9%.
Preferably, in step (3), the internal standard substance in the sample to be tested isThe mass concentration is 0.1-99.9%.
Preferably, in step (3), the internal standard methodIs calculated by the formula：
Figure RE-254756DEST_PATH_IMAGE002
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 quality of the psychoactive substance AB-FUBICA in the biological sample or the sewage isThe content is 10 -7%-10%。
In another aspect, the present invention provides a method for detecting the content of psychoactive substance AB-FUBICA in biological detection material or sewage, which comprises using isotope psychoactive substance labeled compound D4-AB-FUBICA as internal standard substance to detect psychoactive substance, wherein the compound has the following structural formula:
Figure RE-734279DEST_PATH_IMAGE001
、
Figure RE-30131DEST_PATH_IMAGE003
、
Figure RE-595105DEST_PATH_IMAGE004
、
Figure RE-306709DEST_PATH_IMAGE005
、
Figure RE-247595DEST_PATH_IMAGE006
、
Figure RE-386453DEST_PATH_IMAGE007
、
Figure RE-297777DEST_PATH_IMAGE008
、
Figure RE-16334DEST_PATH_IMAGE009
、
Figure RE-80236DEST_PATH_IMAGE010
、
Figure RE-389995DEST_PATH_IMAGE011
、
Figure RE-54194DEST_PATH_IMAGE012
、
Figure RE-310863DEST_PATH_IMAGE013
、
Figure RE-494851DEST_PATH_IMAGE014
、
Figure RE-975511DEST_PATH_IMAGE015
or
Figure RE-595848DEST_PATH_IMAGE016
。
The isotopic psychoactive substance labeled compound D4-N- (3-methyl-butanamide-2-yl) -1- (p-fluorobenzyl) -indole-3-amide provided by the invention can be used as an internal standard for measuring the content of a psychoactive substance N- (3-methyl-butanamide-2-yl) -1- (p-fluorobenzyl) -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.
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-AB-FUBICA in example 1.
FIG. 2 1H-NMR spectrum of D4-AB-FUBICA in example 1.
FIG. 3 13C-NMR spectrum of D4-AB-FUBICA in example 1.
FIG. 4 preparation of D4-AB-FUBICA in example 119F-NMR spectrum.
FIG. 5 AB-FUBICA sample detection chromatogram of hair in example 2.
FIG. 6 AB-FUBICA sample detection chromatogram of hair in example 2.
FIG. 7 AB-FUBICA standard curve for hair 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 description of the present invention, it is,"matrix effect" means that the test material is other than the object to be testedInfluence and interference of substances other than AB-FUBICA on the analysis process and detection results.
In the description of the present invention, the mass concentration of AB-FUBICA in hair is -710%-10%。
The isotopically active substance labeled compound D4-N- (3-methyl-butanamide-2-yl) -1- (p-fluorobenzyl) -indole-4, 5,6, 7-D4-3-amide provided by the invention has the following structural formula:
Figure RE-452946DEST_PATH_IMAGE001
the invention is further illustrated by the following specific examples.
Example 1
A method for preparing N- (3-methyl-butanamide-2-yl) -1- (p-fluorobenzyl) -indole-4, 5,6, 7-D4-amide (D4-AB-FUBICA);
at-20 deg.CNext, 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, and then an anhydrous oxygen-free carbon tetrachloride solution (25 mL) of N-p-fluorobenzyl indole (200 mg, 1 mmol) was added dropwise, stirred and slowly warmed to room temperature, and after 12 hours at room temperature, 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- (p-fluorobenzyl) -indole-4, 5,6, 7-D4-3-amide (D4-AB-FUBICA) as a white solid (223 mg, 60%).1H NMR (600 MHz, Methanol-d4) δ 8.04 (s, 1H), 7.29 – 7.18 (m, 2H), 7.08 – 6.99 (m, 2H), 5.41 (s, 2H), 4.46 (d, J = 7.2 Hz, 1H), 2.17 (h, J = 6.6 Hz, 1H), 1.14 – 0.99 (m, 6H). 13C NMR (151 MHz, Methanol-d4) δ176.85, 167.59, 164.62, 163.00, 138.09, 134.48, 132.90, 130.26, 130.20, 127.85, 116.63, 116.49, 111.29, 59.65, 50.60, 32.28, 19.93, 18.93. 19F NMR (564 MHz, Methanol-d4) δ -116.86. HR-MS (ESI/TOF) m/z: Calcd. for C21H19D4FN3O2[M+H]+372.2025, Found 372.2018, shown in figures 1, 2, 3 and 4.
Example 2
Detecting the content of N- (3-methyl-butanamide-2-yl) -1- (p-fluorobenzyl) -indole-3-amide (AB-FUBICA) in hair by taking D4-N- (3-methyl-butanamide-2-yl) -1- (p-fluorobenzyl) -indole-4, 5,6, 7-D4-3-amide (D4-AB-FUBICA) 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-350495DEST_PATH_IMAGE017
(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-AB-FUBICA), grinding, ultrasonic treating in a refrigerated 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 368.2/248.0, and the peak area ratios of AB-FUBICA and the internal standard substance D4-AB-FUBICA in the two detections are 96354/111903 and 96330/113434 respectively;
(3) drawing of standard curve
Cleaning blank negative 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-AB-FUBICA), adding 20 μ L AB-FUBICA standard reference substance with concentration of 200, 500, 1000, 2000, 5000 ng/mL, preparing into hair addition samples with concentration of 0.2, 0.5, 1.0, 2.0, 5.0 ng/mg, preparing 3 parts each concentration in parallel, vortex for 3 min, standing and soaking at room temperature for 30min, and collecting the samplesAfter the pretreatment process of the product, performing LC-MS/MS detection, making a standard curve for the peak area ratio and the concentration of AB-FUBICA and D4-AB-FUBICA,obtaining the map as shown in figure 6.The formula of the standard curve is Y = 1.171764X-0.014102, wherein X is the concentration of the sample to be detected, Y is the peak area obtained by liquid chromatogram-mass spectrum detection, b0= -0.014102 for standard curve intercept, b1=1.171764 is the slope of the standard curve.
According to peak area ratio and concentration in standard curveQuantitative relationship, according to the calculation formula:
Figure RE-2056DEST_PATH_IMAGE018
and calculating the content of AB-FUBICA in the sample to be detected to be 0.74 ng/mg.
When the isotope psychoactive substance labeled compound provided by the invention is used for detecting a psychoactive substance AB-FUBICA in a detection material, a proper amount of the isotope psychoactive substance labeled compound D4-AB-FUBICA 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 isotope 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 in a Multiple Reaction Monitoring (MRM) mode, the detectable psychoactive substance is AB-FUBICA, the specificity is strong, 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 394156DEST_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- (p-fluorobenzyl) -indole-3-amide (AB-FUBICA).
2. The isotopically active substance labeled compound of claim 1, wherein the isotopically active substance labeled compound has the formula:
Figure 344795DEST_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 a Friedel-crafts acylation reaction on N- (3-methyl-butyryl benzylamine-2-yl) ammonium formate and N-p-fluorobenzyl indole under the catalysis of aluminum trichloride to generate a benzyl protected intermediate;
(2) and (2) deprotecting the intermediate in the step (1) under acidic conditions to produce N- (3-methyl-butanamide-2-yl) -1- (p-fluorobenzyl) -indole-4, 5,6, 7-D4-3-amide (D4-AB-FUBICA).
4. Use of an isotopically labelled compound according to claim 1 or 2 for detecting the level of the drug N- (3-methyl-butanamide-2-yl) -1- (p-fluorobenzyl) -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- (p-fluorobenzyl) -indole-3-amide in hair using the isotopically labelled compound of claim 1 or 2 comprises the following steps:
(1) setting the detection conditions of liquid chromatography-mass spectrometry;
(2) drawing a standard curve: adding AB-FUBICA and D4-AB-FUBICA standard solutions with different proportions into a negative test material corresponding to a sample to be tested, performing LC-MS/MS detection after the same pretreatment step as the sample to be tested, and making a standard curve for the peak area ratio and the concentration of the AB-FUBICA and the D4-AB-FUBICA; 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 step (2), the internal standard substance in the standard solution is mixedThe mass concentration is 0.1-99.9%.
8. The method according to claim 5, wherein in step (3), the internal standard substance in the sample to be tested isMass concentration 0.1 to 99.9 percent.
9. The method according to claim 5, wherein in the step (3), the internal standard methodThe formula is calculated as:
Figure 696142DEST_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.
10. Use according to claim 4, wherein the biological sample comprises N- (3-methyl-butanamide-2-yl) -1- (p-fluorobenzyl) -indole-3-amide -7The content is 10-10%.
11. A method for detecting the content of the drug N- (3-methyl-butanamide-2-yl) -1- (p-fluorobenzyl) -indole-3-amide in a biological test material, which comprises detecting the drug N- (3-methyl-butanamide-2-yl) -1- (p-fluorobenzyl) -indole-3-amide using an isotopically labeled drug compound as an internal standard, wherein the 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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、
Figure 601595DEST_PATH_IMAGE010
、
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、
Figure 681863DEST_PATH_IMAGE012
、
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、
Figure 591231DEST_PATH_IMAGE014
、
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、
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or
Figure 3254DEST_PATH_IMAGE017
。
CN202110133955.4A 2021-02-01 2021-02-01 Isotope mental active substance labeled compound and preparation method and application thereof Pending CN113325089A (en)

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Application publication date: 20210831

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