CN112010782B - 3-deuterated dansyl chloride and preparation method and application thereof - Google Patents

3-deuterated dansyl chloride and preparation method and application thereof Download PDF

Info

Publication number
CN112010782B
CN112010782B CN201910469626.XA CN201910469626A CN112010782B CN 112010782 B CN112010782 B CN 112010782B CN 201910469626 A CN201910469626 A CN 201910469626A CN 112010782 B CN112010782 B CN 112010782B
Authority
CN
China
Prior art keywords
deuterated
dansyl chloride
reaction
amino
preparation
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN201910469626.XA
Other languages
Chinese (zh)
Other versions
CN112010782A (en
Inventor
再帕尔阿不力孜
张瑞萍
汪满江措
王玉成
张国宁
臧清策
贺玖明
刘家兴
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Institute of Materia Medica of CAMS
Original Assignee
Institute of Materia Medica of CAMS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Institute of Materia Medica of CAMS filed Critical Institute of Materia Medica of CAMS
Priority to CN201910469626.XA priority Critical patent/CN112010782B/en
Publication of CN112010782A publication Critical patent/CN112010782A/en
Application granted granted Critical
Publication of CN112010782B publication Critical patent/CN112010782B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/02—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/001—Acyclic or carbocyclic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/02—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof
    • C07C303/22—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof from sulfonic acids, by reactions not involving the formation of sulfo or halosulfonyl groups; from sulfonic halides by reactions not involving the formation of halosulfonyl groups
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/6428—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Physics & Mathematics (AREA)
  • Immunology (AREA)
  • Optics & Photonics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention belongs to the technical field of isotope derivatization reagents, and particularly relates to 3-deuterated dansyl chloride, and a preparation method and application thereof. The preparation method provided by the invention can prepare the 3-deuterated dansyl chloride from the reaction raw materials including 5-amino-1-naphthalenesulfonic acid, paraformaldehyde, sodium borohydride, sodium hydride, deuterated iodomethane, phosphorus oxychloride and phosphorus pentachloride. The preparation method provided by the invention has the advantages that the raw materials are easy to obtain, the intermediate products are few, the 3-deuterated dansyl chloride derivative reagent can be obtained, and the preparation method can be used for fluorescent detection or metabonomics analysis research.

Description

3-deuterated dansyl chloride and preparation method and application thereof
Technical Field
The invention belongs to the technical field of isotope derivatization reagents, and particularly relates to 3-deuterated dansyl chloride, and a preparation method and application thereof.
Background
In metabonomics research, small molecular compounds contained in a biological sample can reflect the metabolic state of an organism, and dansyl chloride can be specifically combined with active hydrogen atoms of the small molecular compounds and is used for enhancing the mass spectrum response of the small molecular compounds. The isotope dansyl chloride derivatization reagent is matched with the dansyl chloride derivatization reagent for use, and has outstanding advantages in the aspects of metabolite qualitative identification, unknown metabolite screening and the like; and the deuterated dansyl chloride derivatization reagent is combined with the standard substance, so that the isotope standard substance of the derivatized standard substance can be more conveniently obtained, and the method is used for supplementing co-outflow and matrix effect in quantitative research, and further obtaining more reliable metabonomics experimental results. Therefore, the isotope dansyl chloride derivatization reagent plays a significant role in the research of metabonomics.
At present, 6 deuterated dansyl chloride derivatization reagents exist, but certain retention time difference still exists due to large mass difference with unlabeled dansyl chloride, the ideal isotope derivatization reagent has a difference of 3 daltons, and 3 deuterated dansyl chloride derivatization reagents are not reported in the prior art. This problem can be avoided and the use in combination with unlabelled reagents can improve the accuracy of qualitative identification.
Disclosure of Invention
The invention aims to provide 3-deuterated dansyl chloride, a preparation method and application thereof.
In order to achieve the above purpose, the invention provides the following technical scheme:
the preparation method provided by the invention can prepare the 3-deuterated dansyl chloride from the reaction raw materials comprising 5-amino-1-naphthalenesulfonic acid, paraformaldehyde, sodium borohydride, sodium hydride, deuterated iodomethane, phosphorus oxychloride and phosphorus pentachloride.
In the invention, the reaction raw material of the 3-deuterated dansyl chloride comprises 5-amino-1-naphthalenesulfonic acid (1-naphthyamine-5-sulfoaic acid). In the invention, the 5-amino-1-naphthalenesulfonic acid is taken as a basic raw material, is easy to obtain, and can reduce the preparation cost of the 3-deuterated dansyl chloride. In the invention, the structure of the 5-amino-1-naphthalene sulfonic acid is shown as a formula a:
Figure BDA0002080450140000021
the source of the 5-amino-1-naphthalenesulfonic acid is not particularly limited in the present invention, and commercially available products well known to those skilled in the art can be used.
In the invention, the reaction raw materials of the 3 deuterated dansyl chloride also comprise paraformaldehyde (paraformaldehyde) and sodium borohydride (NaBH) 4 ) Sodium hydride (NaH), deuterated iodomethane (CD) 3 I) Phosphorus oxychloride (POCl) 3 ) And phosphorus pentachloride (PCl) 5 ). The present invention does not require any particular source for the above components, and commercially available products well known to those skilled in the art can be used.
In addition to the above reaction raw materials, the preparation method of the 3 deuterated dansyl chloride further comprises a solvent, an acidifying reagent, an alkaline solution and an extracting agent required by the reaction, wherein the reaction solvent, the acidifying reagent, the alkaline solution and the extracting agent are explained in the following specific steps.
The preparation method of the 3-deuterated dansyl chloride comprises the following steps of:
(1) Carrying out methylation reaction on 5-amino-1-naphthalene sulfonic acid and paraformaldehyde to obtain a material A;
(2) Mixing the material A obtained in the step (1) with sodium borohydride, carrying out reduction reaction, and acidifying to obtain a reduced material B;
(3) Mixing the reduced material B obtained in the step (2) with sodium hydride dispersion liquid, then mixing the obtained mixture with deuterated iodomethane, carrying out a first substitution reaction, and acidifying to obtain a deuterated solid material;
(4) And (3) mixing the deuterated solid material obtained in the step (3) with phosphorus oxychloride and phosphorus pentachloride to perform a second substitution reaction to obtain 3-deuterated dansyl chloride.
The invention carries out methylation reaction on 5-amino-1-naphthalene sulfonic acid and paraformaldehyde to obtain a material A. In the present invention, before the methylation reaction, the 5-amino-1-naphthalenesulfonic acid is preferably subjected to a salination treatment in a manner preferably including:
5-amino-1-naphthalenesulfonic acid is mixed with methanol and sodium methoxide to obtain 5-amino-1-naphthalenesulfonate.
In the present invention, the 5-amino-1-naphthalenesulfonic acid, methanol, and sodium methoxide are preferably used in a ratio of 1.5mg:
(25-35) mL (2.15-2.50) g, more preferably 1.5mg: (28-32) mL (2.17-2.30) g, most preferably 1.5mg: 30mL. In the present invention, the mixing manner of the 5-amino-1-naphthalenesulfonic acid with methanol and sodium methoxide is preferably that the 5-amino-1-naphthalenesulfonic acid is mixed with methanol and then mixed with sodium methoxide.
After salinization, the salinized material is preferably mixed with paraformaldehyde to carry out amide condensation reaction. In the present invention, the molar ratio of the paraformaldehyde to the 5-amino-1-naphthalenesulfonic acid is preferably 3 to 5:1, more preferably 4 to 5:1, and most preferably 5:1.
In the present invention, the condensation reaction temperature is preferably 58 to 65 ℃, more preferably 59 to 63 ℃, and still more preferably 60 to 62 ℃; the time is preferably 1.5 to 3 hours, more preferably 1.8 to 2.5 hours, and still more preferably 2 to 2.2 hours. According to the invention, a material A is obtained through condensation reaction, and the material A has a structure shown in a formula I:
Figure BDA0002080450140000031
after the material A is obtained, the material A is mixed with sodium borohydride for reduction reaction, and a reduction material B is obtained after acidification. In the present invention, the molar ratio of sodium borohydride to 5-amino-1-naphthalenesulfonic acid is preferably 2 to 3:1, more preferably 2.1 to 2.8, and still more preferably 2.3 to 2.5.
In the present invention, the reduction reaction is an exothermic reaction, and in order to smoothly proceed the reaction, the reduction reaction is preferably performed under ice-water bath conditions. In the present invention, when the material a is mixed with sodium borohydride, the sodium borohydride is preferably added to the material a, and more preferably, the sodium borohydride is slowly added to the material a in batches to ensure that the reduction reaction is smoothly performed. The invention has no special requirements on the adding speed of the sodium borohydride and the quality of each batch, so that the reduction reaction can be stably carried out.
After the reduction reaction, acidifying the material after the reduction reaction to obtain a reduced material B; the pH of the acidification is preferably 3 to 4, more preferably 3 to 3.5, and still more preferably 3. In the invention, the acidifying reagent for acidification preferably comprises hydrochloric acid, sulfuric acid, formic acid or acetic acid, and the invention has no special requirement on the concentration of the acidifying reagent and can ensure that the pH value of a material system after reduction reaction reaches the range.
After acidification, the invention preferably performs solid-liquid separation and drying on the acidified material system to obtain a reduced material B, wherein the reduced material B has a structure shown in a formula II:
Figure BDA0002080450140000041
in the present invention, the solid-liquid separation method is preferably suction filtration. The present invention has no special requirement on the specific drying mode, and the drying mode known to those skilled in the art can be adopted.
After the reduction material B is obtained, the reduction material B is mixed with sodium hydride dispersion liquid, then the obtained mixture is mixed with deuterated iodomethane, a first substitution reaction is carried out, and a deuterated solid material is obtained after acidification. In the present invention, the solvent of the sodium hydride dispersion liquid is preferably a nonaqueous solvent, and the nonaqueous solvent preferably includes N, N-dimethylformamide, acetonitrile, or acetone. The invention has no special requirement on the concentration of the sodium hydride dispersion liquid, and can obtain the dispersion liquid with uniformly dispersed sodium hydride.
In the present invention, the mass ratio of the reducing material to the sodium hydride in the sodium hydride dispersion is preferably 1000. According to the invention, sodium hydride is mixed with the reducing material B, an alkaline environment is provided by the sodium hydride, and the sodium hydride reacts with the secondary amino group on the reducing material B to capture the hydrogen on the secondary amino to form a mixture containing a Na salt intermediate, so that favorable conditions are provided for the subsequent substitution reaction of the deuterated iodomethane. In the present invention, the mixing of the reduced material with the sodium hydride dispersion is preferably performed under ice-water bath conditions to avoid splashing of the mixed material liquid.
After the mixture is obtained, the mixture is mixed with deuterated iodomethane to carry out a first substitution reaction, and the deuterated solid material is obtained after acidification. The molar ratio of the deuterated iodomethane to the reducing material B is preferably (3-5): 1, more preferably (3.3-4.5): 1, and even more preferably (3.5-4.0): 1, based on the content of the reducing material B.
In the present invention, the temperature of the first substitution reaction is preferably 30 to 40 ℃, more preferably 32 to 37 ℃, and still more preferably 34 to 36 ℃; the time of the first substitution reaction is preferably 1.5 to 4 hours, more preferably 2 to 3.5 hours, and still more preferably 3 to 3.5 hours; the time of the first substitution reaction is measured after the temperature is raised to the reaction temperature. The present invention has no special requirement on the specific mode of temperature rise, and the mode known to the technicians in the field can be adopted.
In the present invention, the acidification conditions are the same as those required to obtain the reduced material B in the above technical scheme, and are not repeated here. After acidification, the invention preferably performs solid-liquid separation on the acidified material, and then dries the obtained solid to obtain the deuterated solid material. In the present invention, the solid-liquid separation preferably includes suction filtration; the drying mode preferably comprises drying, and the drying temperature is preferably 100-120 ℃, and more preferably 120 ℃; the drying time is preferably 2 to 3 hours, and more preferably 2 hours.
In the present invention, the deuterium carrying solid has the structure shown in formula III:
Figure BDA0002080450140000051
after the deuterated solid material is obtained, the deuterated solid material is mixed with phosphorus oxychloride and phosphorus pentachloride to carry out a second substitution reaction, so as to obtain the 3 deuterated dansyl chloride. In the invention, the molar ratio of the phosphorus oxychloride, the phosphorus pentachloride and the deuterated solid material is preferably (7-10): 1.5-3): 1, and more preferably (8-9.5): and (2-3) 1.
In the invention, the mixing is preferably to mix the deuterated solid material with the phosphorus oxychloride and then mix with the phosphorus pentachloride; the mixing is preferably performed under stirring, and more preferably under magnetic stirring. The invention has no special requirement on the stirring speed, and can ensure that all the components are fully contacted. In the present invention, the phosphorus pentachloride is preferably mixed by batch addition to avoid local overheating caused by single addition. The invention has no special requirements on the batch mode of the phosphorus pentachloride, and can ensure that materials of each component of a mixed system do not splash.
In the present invention, the temperature of the second substitution reaction is preferably room temperature; the time for the second substitution reaction is preferably 20 to 25 hours, more preferably 21 to 24 hours, and still more preferably 24 hours.
After the second substitution reaction, the present invention preferably further comprises performing a post-treatment on the material after the second substitution reaction to obtain 3-deuterated dansyl chloride. In the present invention, the post-treatment preferably comprises:
mixing the reacted materials with ice water, and then extracting with diethyl ether to obtain an organic phase;
sequentially carrying out alkali washing, drying and solvent removal on the organic phase to obtain oily liquid;
and dissolving the oily liquid in hot n-hexane, filtering, and cooling to obtain an orange-yellow crystal, namely the 3-deuterated dansyl chloride.
In the invention, the reacted material is preferably mixed with ice water and then extracted with diethyl ether to obtain an organic phase. Before mixing, the temperature of the reacted materials is preferably reduced to 0 ℃ and then mixed with ice water. In the present invention, the mass ratio of the reacted material to ice water is preferably 0.5 (180-210), more preferably 0.5 (185-205), and still more preferably 0.5. In the invention, the reacted material is preferably mixed with ice water to remove unreacted phosphorus oxychloride and phosphorus pentachloride. After mixing the reaction mass with ice water, the invention was extracted with diethyl ether to obtain an organic phase. The invention has no special requirements on the specific mode of extraction, and the extraction mode known to the skilled person can be adopted. In the specific embodiment of the invention, the dosage of the diethyl ether for extraction is preferably 70-80 mL/time, more preferably 72-77 mL/time, and still more preferably 75 mL/time; the number of extractions is preferably 3 to 4, more preferably 4. In the present invention, the organic phase refers to the sum of organic phases obtained after multiple extractions.
After the organic phase is obtained, the organic phase is sequentially subjected to alkali washing, drying and solvent removal to obtain oily liquid. In the invention, the alkali washing can further remove unreacted phosphorus oxychloride and phosphorus pentachloride. In the present invention, the alkali wash liquid preferably includes a sodium hydroxide solution, and the concentration of the sodium hydroxide solution is preferably 0.08 to 0.12M, and more preferably 0.1M. The method has no special requirements on the dosage of the sodium hydroxide solution and the specific mode of alkaline washing, and can remove unreacted phosphorus oxychloride and phosphorus pentachloride in an organic phase. In a specific embodiment of the present invention, the amount of the sodium hydroxide solution is preferably 45 to 60mL, more preferably 48 to 55mL, and still more preferably 50mL.
After alkali washing, the material obtained after alkali washing is preferably dried, the drying reagent preferably comprises a solid drying agent, and the solid drying agent preferably comprises anhydrous magnesium sulfate; the invention has no special requirements on the specific dosage of the anhydrous magnesium sulfate, and can fully remove the moisture in the material obtained after alkaline washing.
After drying, the present invention also preferably subjects the dried material to a desolvation treatment to obtain an oily liquid. In the present invention, the means for removing the solvent preferably includes concentration by volatilization of nitrogen gas. The oily liquid of the present invention is an orange oily liquid.
After obtaining the oily liquid, the invention preferably dissolves the oily liquid in hot n-hexane, and after filtering and cooling, orange yellow crystals, namely 3 deuterated dansyl chloride, are obtained. In the present invention, the temperature of the hot n-hexane is preferably 60 ℃ to 70 ℃, more preferably (65 ℃). The invention has no special requirement on the dosage of the normal hexane, and can completely dissolve the oily liquid. In the present invention, the end point temperature of the cooling is preferably 5 ℃ or less, more preferably 1 to 4 ℃, and still more preferably 4 ℃. The invention has no special requirements on the filtration mode and the cooling mode, and the mode known by the technical personnel in the field can be adopted
According to the invention, hot n-hexane is preferably used for dissolving the oily liquid, and insoluble impurities in the oily liquid are removed by filtration, so that the purity of the target product is improved. According to the invention, through cooling, oily components dissolved in a hot n-hexane solvent are separated out, so that a target product with higher purity is obtained, and an orange-yellow crystal is 3 deuterated dansyl chloride (expressed by D3-Dns).
To clearly illustrate the preparation process of the present invention, the following reaction formula is provided:
Figure BDA0002080450140000071
in the invention, the 3-deuterated dansyl chloride has a structure shown in a formula IV:
Figure BDA0002080450140000072
the molecular formula of the 3-deuterated dansyl chloride prepared by the invention is C 12 H 9 D 3 ClNO 2 S indicates a relative molecular mass of 272.7613 and a precise molecular mass of 272.0466. In the invention, the 3-deuterated dansyl chloride and the dansyl chloride have more similar properties, the retention time is more stable and consistent during liquid chromatography-mass spectrometry analysis, the matrix effect in the analysis and detection process can be better compensated, and the method is favorable for improving the accuracy of the detection result.
The invention also provides application of the 3-deuterated dansyl chloride in the technical scheme in fluorescence detection or metabonomics. The invention is not particularly limited to the specific manner of use described, as such may be readily adapted by those skilled in the art.
In order to further illustrate the present invention, the following detailed description of the 3-deuterated dansyl chloride provided by the present invention, the preparation method and the application thereof are provided with reference to the accompanying drawings and examples, which should not be construed as limiting the scope of the present invention.
Advantageous technical effects
The preparation method provided by the invention has the advantages that the raw materials are easy to obtain, the intermediate products are few, the 3-deuterated dansyl chloride derivative reagent can be obtained, and the preparation method can be used in fluorescence detection or metabonomics. The results of the examples also show that the method provided by the invention can obtain the 3-deuterated dansyl chloride with higher purity.
Drawings
FIG. 1 is a mass spectrum of positive ion ESI-MS of 3 deuterated dansyl chloride obtained by the invention.
Detailed Description
Example 1
Preparing reaction raw materials according to the following dosage proportion:
the molar ratio of paraformaldehyde to 5-amino-1-naphthalenesulfonic acid is 4.9;
the molar ratio of sodium borohydride to 5-amino-1-naphthalenesulfonic acid is 2.0;
the molar ratio of the deuterated iodomethane to the reduction material B is 5.2;
the molar ratio of phosphorus oxychloride, phosphorus pentachloride and deuterated solid material is 9.1, 2.2, wherein the amount of each component substance is calculated according to the standard of the labeled molecular weight of a commercial product, the relative molecular weight or density parameter of each component is listed in brackets of the following steps, and the specific preparation process comprises the following steps:
step 1: 1.5g (223.25/0.0067 mol) of 5-amino-1-naphthalenesulfonic acid was weighed out and added to 30mL of methanol, and then 2.17g (54.0/0.0434 mol) of sodium methoxide was added. When the solution is brownish red, adding 1g (30 n/0.033 mol) of paraformaldehyde, and sealing the bottle at 60 ℃ for 2 hours to obtain a material A.
Figure BDA0002080450140000091
Step 1
Step 2: weighing 510mg of sodium borohydride (37.83/0.01348 mol), slowly adding the sodium borohydride into the solution in an ice-water bath, stirring for 10min, then adding the next part, slowly adding the sodium borohydride to avoid generating excessive gas, enabling the reaction material to overflow a reaction bottle, adding 6N HCl, diluting the solution until the pH is 3, separating out a solid, performing suction filtration and drying to obtain 930mg of a reduction material B.
Figure BDA0002080450140000092
Step 2
And step 3: sodium hydride solid 448.4mg (24.0/18.68 mol) was suspended in 1mL of N, N-dimethylformamide, and 1g (237.25/0.0042 mol) of reduced material B was added, cooled to 0 ℃ and 3.2g (144.96/0.022 mol) of CD was added 3 After I, heating to 35 ℃, reacting for 2h, adding water in an ice bath, adding 6N HCl to adjust the pH of the solution to 3, separating out a solid, performing suction filtration, and drying for 2h at 120 ℃ to obtain a deuterated solid material of 850mg;
Figure BDA0002080450140000101
step 3
And 4, step 4:500mg of the above-mentioned dried deuterated solid material (254.25/0.00197 mol) and 1.7ml of OCL 3 (1.645 g/mL,153.33, 0.018mol) was mixed at room temperature, and under complete removal of water, 0.92g (208.22/0.0044 mol) of PCl was stirred magnetically all the time 5 Slowly adding the mixture, stirring the resultant paste at room temperature for 24h, cooling the mixture to 0 deg.C, adding 200g of ice water to the mixture, and removing POCl 3 And PCl 5 Extracted with 4X 75mL diethyl ether. The organic layer was washed with 50mL of 0.1M NaOH solution and MgSO 4 After drying, filtering, volatilizing the filtrate by using nitrogen and concentrating. An orange oily liquid formed; dissolving the obtained orange oily liquid in hot n-hexane solution, filtering to remove impurities insoluble in n-hexane, cooling to 4 deg.C, and cooling to form orange yellow crystal 417mg, wherein the yield of the obtained target product is 82%, and the purity is 76%.
Figure BDA0002080450140000102
Step 4
The resulting orange-yellow crystals were characterized by a Qstar Elite mass spectrometer with a positive ion ESI-MS spectrum as shown in FIG. 1. In FIG. 1, a significant [ M + H ] was observed] + Peak, which indicates that C is obtained 12 H 10 D 3 ClNO 2 S + The test value is 273.0551, which is close to the theoretical value 273.0538 with an error of 4.76ppm.
Example 2
3-deuterated dansyl chloride was prepared as in example 1, except that:
the molar ratio of paraformaldehyde to 5-amino-1-naphthalenesulfonic acid is 4:1;
the molar ratio of sodium borohydride to 5-amino-1-naphthalenesulfonic acid was 2:1;
the molar ratio of the deuterated iodomethane to the reduced material B is 4:1;
the molar ratio of phosphorus oxychloride, phosphorus pentachloride and deuterated solid material is 7;
the temperature of the first substitution reaction is 37 ℃, and the reaction time is 1.5h; the yield of the target product was 75% and the purity 80%.
Example 3
3-deuterated dansyl chloride was prepared as in example 1, except that:
the molar ratio of paraformaldehyde to 5-amino-1-naphthalenesulfonic acid is 3.5;
the molar ratio of sodium borohydride to 5-amino-1-naphthalenesulfonic acid is 2.7;
the mol ratio of the deuterated iodomethane to the reduction material B is 4.2;
the molar ratio of phosphorus oxychloride, phosphorus pentachloride and deuterated solid material is 8;
the temperature of the first substitution reaction is 30 ℃, and the time is 2.5h; the yield of the target product was 78% and the purity was 63%.
According to the embodiment, the 3-deuterated dansyl chloride can be prepared by the method, the reaction raw materials are easy to obtain, the preparation method is simple and easy to control, and the yield is high and reaches over 75%; the preparation method has high integral reliability and is suitable for large-scale production and use.
The purity of the 3-deuterated dansyl chloride prepared by the invention is higher and reaches 73-85%. When the obtained 3 deuterated dansyl chloride is used as a derivatization reagent, the 3 deuterated dansyl chloride can be used together with the unmarked derivatization reagent, so that the detection effect of substances containing corresponding functional groups is improved.
Although the present invention has been described in detail with reference to the above embodiments, it is only a part of the embodiments of the present invention, not all of the embodiments, and other embodiments can be obtained without inventive step according to the embodiments, and the embodiments are within the scope of the present invention.

Claims (7)

1. A preparation method of 3 deuterated dansyl chloride is characterized by comprising the following steps:
(1) Carrying out methylation reaction on 5-amino-1-naphthalene sulfonic acid and paraformaldehyde to obtain a material A;
Figure FDA0003854117680000011
(2) Mixing the material A obtained in the step (1) with sodium borohydride, carrying out reduction reaction, and acidifying to obtain a reduced material B;
Figure FDA0003854117680000012
(3) Mixing the reducing material B obtained in the step (2) with sodium hydride dispersion liquid, then mixing the obtained mixture with deuterated iodomethane, and carrying out a first substitution reaction at the temperature of 30-40 ℃ for 1.5-4 h; obtaining a deuterated solid material after acidification;
Figure FDA0003854117680000013
(4) Mixing the deuterated solid material obtained in the step (3) with phosphorus oxychloride and phosphorus pentachloride, and performing a second substitution reaction to obtain 3-deuterated dansyl chloride;
Figure FDA0003854117680000021
2. the method according to claim 1, wherein the reaction mixture,
the molar ratio of the paraformaldehyde to the 5-amino-1-naphthalenesulfonic acid is (3-5) to 1;
the molar ratio of the sodium borohydride to the 5-amino-1-naphthalene sulfonic acid is (2-3) to 1.
3. The production method according to claim 1 or 2,
the molar ratio of the deuterated iodomethane to the reduction material B is 3-5:1;
the molar ratio of the phosphorus oxychloride, the phosphorus pentachloride and the deuterated solid material is (7-10): (1.5-3) 1.
4. The production method according to claim 1 or 2,
the temperature of the methylation reaction is 58-65 ℃; the time is 1.5 to 3 hours;
the temperature of the second substitution reaction is room temperature, and the time is 20-25 h.
5. The method of claim 1 or 2, wherein the pH of acidification in step (2) and step (3) is independently 3 to 4.
6. The method according to claim 5, wherein the acidifying agent used in the steps (2) and (3) is hydrochloric acid, sulfuric acid, formic acid, or acetic acid.
7. The method of claim 1, wherein after performing the second substitution reaction, further comprising post-treating the material after the second substitution reaction to obtain 3-deuterated dansyl chloride;
the post-treatment comprises mixing the reacted materials with ice water, and then extracting with diethyl ether to obtain an organic phase;
sequentially carrying out alkali washing, drying and solvent removal on the organic phase to obtain oily liquid;
and dissolving the oily liquid in hot n-hexane, filtering, and cooling to obtain an orange-yellow crystal, namely the 3-deuterated dansyl chloride.
CN201910469626.XA 2019-05-31 2019-05-31 3-deuterated dansyl chloride and preparation method and application thereof Active CN112010782B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201910469626.XA CN112010782B (en) 2019-05-31 2019-05-31 3-deuterated dansyl chloride and preparation method and application thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201910469626.XA CN112010782B (en) 2019-05-31 2019-05-31 3-deuterated dansyl chloride and preparation method and application thereof

Publications (2)

Publication Number Publication Date
CN112010782A CN112010782A (en) 2020-12-01
CN112010782B true CN112010782B (en) 2023-01-06

Family

ID=73501992

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201910469626.XA Active CN112010782B (en) 2019-05-31 2019-05-31 3-deuterated dansyl chloride and preparation method and application thereof

Country Status (1)

Country Link
CN (1) CN112010782B (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113620847B (en) * 2021-08-11 2022-08-09 复旦大学 Naphthalenesulfonyl compounds, preparation method and application thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102887841A (en) * 2012-11-02 2013-01-23 天津希恩思生化科技有限公司 Preparation method of compound dansyl chloride
CN104945285A (en) * 2015-05-26 2015-09-30 无锡贝塔医药科技有限公司 Synthesis method of isotope labeled dansyl chloride-13C2
CN109180591A (en) * 2018-08-29 2019-01-11 上海化工研究院有限公司 A kind of stable isotope labeling reagent and preparation method thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102887841A (en) * 2012-11-02 2013-01-23 天津希恩思生化科技有限公司 Preparation method of compound dansyl chloride
CN104945285A (en) * 2015-05-26 2015-09-30 无锡贝塔医药科技有限公司 Synthesis method of isotope labeled dansyl chloride-13C2
CN109180591A (en) * 2018-08-29 2019-01-11 上海化工研究院有限公司 A kind of stable isotope labeling reagent and preparation method thereof

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
Enhancing analysis throughput, sensitivity and specificity inLC/ESI–MS/MS assay of plasma 25-hydroxyvitamin D3byderivatization with triplex4-(4-dimethylaminophenyl)-1,2,4-triazoline-3,5-dione (DAPTAD)isotopologues;Shoujiro Ogawaa等;《Journal of Pharmaceutical and Biomedical Analysis》;20171231;第136卷;126-133 *
Fabio Mazzotti等.Light and heavy dansyl reporter groups in food chemistry: amino acid assay in beverages.《J. Mass. Spectrom.》.2012,第47卷932-939. *
Light and heavy dansyl reporter groups in food chemistry: amino acid assay in beverages;Fabio Mazzotti等;《J. Mass. Spectrom.》;20121231;第47卷;932-939 *
Observation of a Stable Monomeric N-Methylene Aromatic Amine;Giancarlo Verardo等;《J. CHEM. SOC.CHEM. COMMUN.》;19851231;1787-1788 *

Also Published As

Publication number Publication date
CN112010782A (en) 2020-12-01

Similar Documents

Publication Publication Date Title
WO2022000881A1 (en) Carboxylic acid compound, and preparation method therefor and application thereof
CN111041203B (en) Mixed extracting agent for nickel-lithium separation and separation method
WO2022110821A1 (en) Carboxylic acid compound, preparation method therefor and use thereof
CN112010782B (en) 3-deuterated dansyl chloride and preparation method and application thereof
CN102766027B (en) The synthetic method of cold labeling dihydroxyphenyl propane or Bisphenol F and derivative thereof
CN112010790A (en) Preparation method of 6-deuterated dansyl chloride
CN109912512B (en) New telmisartan impurity compound and preparation method and application thereof
CN115028603A (en) Preparation method of N-methyl-D3-piperazine hydrochloride
CN112321489B (en) Electrophilic molecular probe based on active sulfydryl and report ions and preparation method and application thereof
CN108409635B (en) Carbazole fluorescent thymine drug labeling reagent, synthesis and application
CN118184552A (en) Preparation method of 6-deuterated dansyl hydrazide
CN110172076B (en) Quinoline derivative containing exocyclic double bond and preparation method thereof
CN113149851A (en) Preparation method of stable isotope labeled chlorpropaline
CN103183599A (en) Method for preparing 2-valproic acid
US20240010595A1 (en) Method for synthesizing labeled pyruvic acid
CN109651239A (en) A kind of multidentate ligand terpyridyl diacetic acid and preparation method thereof
EP4289812A1 (en) Method for synthesizing carbon isotope-labeled pyruvic acid
CN114380750B (en) Synthetic method of deuterated albendazole
CN100387514C (en) Fullerene-based hydrogen storage material C60H36Method of synthesis of
CN110156584B (en) Synthesis method of (2R) -3-bromo-2-hydroxy-2-methylpropanoic acid
CN117430556A (en) Synthesis method of tinidazole deuterated compound
CN110105371B (en) Impurities in doladazole bulk drug and preparation method thereof
CN115043816B (en) Chiral resolution method of selenium octanoic acid
JP2013082636A (en) Magnetic ionic liquid compound and method of dissolving and collecting cellulose using the same
CN116947621A (en) Method for synthesizing pyruvic acid marker by one-pot method

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant