CN109678792A - A kind of preparation method of stable isotope labeling Pyridostigmine Bromide internal standard reagent - Google Patents
A kind of preparation method of stable isotope labeling Pyridostigmine Bromide internal standard reagent Download PDFInfo
- Publication number
- CN109678792A CN109678792A CN201811596217.8A CN201811596217A CN109678792A CN 109678792 A CN109678792 A CN 109678792A CN 201811596217 A CN201811596217 A CN 201811596217A CN 109678792 A CN109678792 A CN 109678792A
- Authority
- CN
- China
- Prior art keywords
- stable isotope
- isotope labeling
- internal standard
- pyridostigmine bromide
- standard reagent
- 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.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/65—One oxygen atom attached in position 3 or 5
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Other Investigation Or Analysis Of Materials By Electrical Means (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to a kind of preparation methods of additive detection stable isotope labeling Pyridostigmine Bromide internal standard reagent illegal in feed, belong to feeding quality safety detection standard substance research and development field.With stable isotope labeling N; dinethylformamide is raw material, is reacted with acylting agent, and the N of stable isotope labeling is generated; N- dimethylaminoethyl chloride; it again under organic solvent existence condition, is reacted with 3- pyridone, generates stable isotope labeling 3- (N; N- formyl oxygen dimethylamino) pyridine; it again under organic solvent existence condition, is reacted with bromomethane, obtains stable isotope labeling Pyridostigmine Bromide.The preparation route of the invention is short, and reaction condition is mild, and raw material needed for synthesizing, intermediate are simple and easy to get, and product quality is able to satisfy the technical requirements of required internal standard reagent in the issued professional standard of the Ministry of Agriculture.It is not yet found that stable isotope labeling Pyridostigmine Bromide internal standard reagent prepares document, development stable isotope labeling Pyridostigmine Bromide internal standard reagent is of great significance to China's feeding quality safety detection and supervision to stable isotope labeling Pyridostigmine Bromide internal standard reagent is developed in the whole world.
Description
Technical field
The present invention relates to a kind of additive detection illegal in feed stable isotope labeling Pyridostigmine Bromide internal standard reagents
Preparation method, belong to feeding quality safety detection standard substance research and development field.
Background technique
Pyridostigmine Bromide (Pyridostigmine, CAS No.:101-26-8), is the derivative of neostigmine, to intend gallbladder
Anticholinesterase in alkali medicine.In aquaculture, Pyridostigmine Bromide be usually used in treat cattle and sheep fore stomach disease, animal constipation and
Childbirth phase and postpartum disease etc., the neuromuscular caused by long-term thrombosis is weak also good efficacy.Pyridostigmine Bromide is only
It is allowed to be directly administered and is used as treatment, according to " feed medicated premix operating specification ", forbid using in feed.But with feeding
Grow that industry is intensive, large-scale development, Pyridostigmine Bromide has and illegal abuses and be added as to treat in feed as therapeutic agent
With the security risk of prevention.For this purpose, the Ministry of Agriculture, China has issued " the measurement liquid of Pyridostigmine Bromide in NY/T 3142-2017 feed
Phase chromatography-tandem mass spectrometry ", and the formal implementation from June 1st, 2018.Wherein, it clearly proposes using stable isotope mark
Remember Pyridostigmine Bromide-D6Inner mark method ration is carried out as internal standard reagent.It can additive medicine in specification feed using this method
Object uses, and provides for the service condition of Pyridostigmine Bromide in monitoring feed and the further investigation of feeding quality security risk assessment
Technical support.
Illegal additive detection stable isotope labeling Pyridostigmine Bromide internal standard reagent in feed involved in the present invention
It develops, is able to satisfy the demand in China's agricultural industry criteria about additive illegal in feed monitoring.The whole world is not yet found at present
There is stable isotope labeling Pyridostigmine Bromide to prepare document, therefore, develops stable isotope labeling Pyridostigmine Bromide internal standard reagent
It is of great significance to China's feeding quality safety detection and supervision.
Summary of the invention
The object of the present invention is to provide a kind of additive detection stable isotope labeling bromine pyrroles illegal suitable for feed
The preparation method of this internal standard reagent.The invention preparation route is short, and reaction condition is simple, and raw material needed for synthesizing, intermediate are simply easy
, product quality is able to satisfy the technical requirements of required internal standard reagent in the issued professional standard of the Ministry of Agriculture.
The purpose of the present invention can be achieved through the following technical solutions:
The illegal additive detection preparation method of stable isotope labeling Pyridostigmine Bromide internal standard reagent in a kind of feed,
Shown in the chemical structure such as formula (I) of the stable isotope labeling Pyridostigmine Bromide internal standard reagent:
Wherein, X is in (I)12C or13C, Y are H or D, and * is14N or15N, synthesis step general line are as follows:
Wherein, X is12C or13C, Y are H or D, and * is14N or15N。
(1) under the conditions of nitrogen protection, stable isotope labeling n,N-Dimethylformamide is added, in -20 DEG C~0 DEG C item
Under part, acylting agent is added, reacts 0.5~3 hour；Obtain the N of stable isotope labeling, N- dimethylaminoethyl chloride, nothing
It needs to handle, carries out next step reaction directly as intermediate.
(2) under organic solvent existence condition, under the conditions of nitrogen protection, 3- pyridone is added, stirring 0.5~2 is small
When；The N for the stable isotope labeling that step (1) is obtained, the organic solution of N- dimethylaminoethyl chloride are added to above-mentioned 3- hydroxyl
In the organic solution of yl pyridines, reacted 2~12 hours under the conditions of 30 DEG C~130 DEG C；TLC tracks reaction raw materials fully reacting
Afterwards, reaction is quenched with water, water phase is extracted with organic solvent, is merged organic phase, is successively washed with water, saturated sodium bicarbonate solution is washed
It washs, desiccant dryness is added in saturated sodium chloride solution washing, and vacuum distillation removes solvent, and residue is chromatographed through column to be stablized
Isotope labelling obtains stable isotope labeling 3- (N, N- formyl oxygen dimethylamino) pyridine.
(3) by the obtained stable isotope labeling 3- of step (2) (N, N- formyl oxygen dimethylamino), pyridine is dissolved in has
In solvent, bromomethane is added under the conditions of -30 DEG C~50 DEG C, reacts 24~72 hours at room temperature, with organic molten after filtering
Stable isotope labeling Pyridostigmine Bromide is washed to obtain in agent.
Compared with prior art, the beneficial effects of the present invention are: stable isotope is used in the detection of illegal additive in feed
The preparation of Pyridostigmine Bromide internal standard reagent is marked, preparation route used in method is short, and reaction condition is simply mild, needed for synthesis
Raw material, intermediate are simple and easy to get, and product quality is able to satisfy the technical requirements of required internal standard reagent in China's agricultural industry criteria.System
Standby stable isotope labeling Pyridostigmine Bromide purity out is greater than 98%, and isotope abundance is greater than 98%.The structural compounds
Preparation route and method be not it has been reported that develop stable isotope labeling Pyridostigmine Bromide internal standard reagent to China's feed matter
Amount safety detection and supervision are of great significance.
Specific embodiment
It is further discussed below the present invention below with reference to embodiment, but it is not any restrictions to the scope of the present invention.
Embodiment 1: the N of stable isotope labeling, N- dimethylaminoethyl chloride-D6Preparation
In 100mL there-necked flask, under nitrogen protection, n,N-Dimethylformamide-D is added7(37.5mL), is cooled to -5
DEG C, it is added thionyl chloride (7.15mL, 0.1mol), and be stirred to react at such a temperature 1 hour；Reaction solution is without processing, directly
Carry out next step reaction.
Embodiment 2:3- (N, N- formyl oxygen dimethylamino) pyridine-D6Preparation
In 500mL there-necked flask, 3- pyridone (9.5g, 0.1mol) and toluene (200mL) is added；Embodiment 1 is added
In stable isotope labeling obtained N, N- dimethylaminoethyl chloride-D6(16.5mL) is heated to return stirring 3 hours；TLC
After tracking reaction raw materials fully reacting, reaction solution is quenched with saturated sodium carbonate solution；Water phase be extracted with ethyl acetate (3 ×
100mL), merge organic phase, be successively washed with water (3 × 100mL), saturated sodium bicarbonate solution washs (3 × 100mL), saturation
Sodium chloride solution washs (3 × 100mL), and anhydrous sodium sulfate drying is added, and vacuum distillation removes solvent, and residue is chromatographed through column
To stable isotope labeling 3- (N, N- formyl oxygen dimethylamino) pyridine-D6(13.9g, yield 81%).
Embodiment 3: stable isotope labeling Pyridostigmine Bromide-D6Preparation
In 100mL there-necked flask, stable isotope labeling 3- (N, N- formyl oxygen dimethylamino) pyridine-D is added6(4g,
23mmol), anhydrous propanone (25mL), is cooled to -10 DEG C；It is added bromomethane (3g, 32mmol), then heats to room temperature, continue
Reaction 36 hours；After TLC tracks reaction raw materials fully reacting, vacuum distillation removes solvent, obtains after residue washed with acetone
Stable isotope labeling Pyridostigmine Bromide-D6(5.2g, yield 85%)；H NMR(DMSO-D6, 300M) and δ ppm 9.35 (s, 1H),
8.72 (d, 2H), 8.38 (m, 2H), 8.26 (d, 1H), 4.42 (s, 3H), MS ESI+267 [M+1].
13C flag and15The Pyridostigmine Bromide synthesis step of N label is the same as stable isotope labeling bromine pyrrole-D in above-described embodiment6
Preparation route.
The above is presently preferred embodiments of the present invention, but the present invention should not be limited to disclosed in the embodiment
Content.So all do not depart from the lower equivalent or modification completed of spirit disclosed in this invention, the model that the present invention protects is both fallen within
It encloses.
Claims (4)
1. the illegal additive detection preparation method of stable isotope labeling Pyridostigmine Bromide internal standard reagent in a kind of feed, should
Shown in the chemical structure such as formula (I) of stable isotope labeling Pyridostigmine Bromide internal standard reagent:
Wherein, X is in (I)12C or13C, Y are H or D, and * is14N or15N, which is characterized in that preparation step is as follows:
(1) under the conditions of nitrogen protection, stable isotope labeling n,N-Dimethylformamide is added, in -20 DEG C~0 DEG C condition
Under, acylting agent is added, reacts 0.5~3 hour；The N of stable isotope labeling is obtained, N- dimethylaminoethyl chloride is not necessarily to
Processing carries out next step reaction directly as intermediate；
(2) under organic solvent existence condition, under the conditions of nitrogen protection, 3- pyridone is added, stirs 0.5~2 hour；It will
The N for the stable isotope labeling that step (1) obtains, the organic solution of N- dimethylaminoethyl chloride are added to above-mentioned 3- pyridone
Organic solution in, reacted 2~12 hours under the conditions of 30 DEG C~130 DEG C；After TLC tracks reaction raw materials fully reacting, water is used
Quenching reaction, water phase are extracted with organic solvent, are merged organic phase, are successively washed with water, saturated sodium bicarbonate solution washing, saturation
Desiccant dryness is added in sodium chloride solution washing, and vacuum distillation removes solvent, and residue chromatographs to obtain stable isotope mark through column
Remember stable isotope labeling 3- (N, N- formyl oxygen dimethylamino) pyridine；
(3) step (2) obtained stable isotope labeling 3- (N, N- formyl oxygen dimethylamino) pyridine is dissolved in organic molten
In agent, bromomethane is added under the conditions of -30 DEG C~50 DEG C, reacts 24~72 hours, is washed after filtering with organic solvent at room temperature
Wash to obtain stable isotope labeling Pyridostigmine Bromide.
2. the preparation method of stable isotope labeling Pyridostigmine Bromide internal standard reagent according to claim 1, feature exist
In the step (1), acylting agent used is thionyl chloride, in oxalyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride
One kind；The N,N-dimethylformamide of stable isotope labeling used be deuterium-labeled N,N-dimethylformamide,13C flag
N,N-dimethylformamide and15One of the N,N-dimethylformamide of N label.
3. the preparation method of stable isotope labeling Pyridostigmine Bromide internal standard reagent according to claim 1, feature exist
In the step (2), organic solvent used is tetrahydrofuran, methyltetrahydrofuran, dioxane, benzene, toluene, acetonitrile, first
One of base tertbutyl ether, methylene chloride；The N of stable isotope labeling used, N- dimethylaminoethyl chloride are deuterium-labeled
N, N- dimethylaminoethyl chloride,13The N of C flag, N- dimethylaminoethyl chloride and15The N of N label, in N- dimethylaminoethyl chloride
One kind.
4. the preparation method of stable isotope labeling Pyridostigmine Bromide internal standard reagent according to claim 1, feature exist
In the step (3), organic solvent used is tetrahydrofuran, methyltetrahydrofuran, dioxane, benzene, toluene, acetonitrile, first
One of base tertbutyl ether, methylene chloride, acetone；The 3- (N, N- formyl oxygen dimethylamino) of stable isotope labeling used
Pyridine be deuterium-labeled 3- (N, N- formyl oxygen dimethylamino) pyridine,133- (N, N- formyl oxygen dimethylamino) pyrrole of C flag
Pyridine and15One of 3- (N, N- formyl oxygen dimethylamino) pyridine of N label.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811596217.8A CN109678792A (en) | 2018-12-26 | 2018-12-26 | A kind of preparation method of stable isotope labeling Pyridostigmine Bromide internal standard reagent |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811596217.8A CN109678792A (en) | 2018-12-26 | 2018-12-26 | A kind of preparation method of stable isotope labeling Pyridostigmine Bromide internal standard reagent |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN109678792A true CN109678792A (en) | 2019-04-26 |
Family
ID=66188566
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811596217.8A Pending CN109678792A (en) | 2018-12-26 | 2018-12-26 | A kind of preparation method of stable isotope labeling Pyridostigmine Bromide internal standard reagent |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109678792A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114950299A (en) * | 2022-04-27 | 2022-08-30 | 浙江海昇药业股份有限公司 | Preparation device and method of pirstine bromide |
-
2018
- 2018-12-26 CN CN201811596217.8A patent/CN109678792A/en active Pending
Non-Patent Citations (4)
| Title |
|---|
| M. D. SCOTT等: "Vilsmeier Adducts of Dimethylformamide", 《JOURNAL OF THE CHEMICAL SOCIETY C: ORGANIC》 * |
| NORBERT SCHINDLER等: "Preparation of carbamoyl chlorides (bromides) by reactions of phosphorus trichloride (bromide) and thionyl chloride (bromide) with formamides", 《CHEMISCHE BERICHTE》 * |
| ULRICH HASSERODT: "Chemistry of sulfur chlorides. II. Reaction of sulfur dichloride, disulfur dichloride, and sulfuryl chloride with (thio)amides to yield (thio)carbamoyl chlorides and mustard oils", 《CHEMISCHE BERICHTE》 * |
| VOLKER HORSTMANN等: "Determination of the structure of products of the reduction of pyridostigmine with sodium borohydride", 《ZEITSCHRIFT FUER NATURFORSCHUNG, TEIL B: ANORGANISCHE CHEMIE, ORGANISCHE CHEMIE》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114950299A (en) * | 2022-04-27 | 2022-08-30 | 浙江海昇药业股份有限公司 | Preparation device and method of pirstine bromide |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| WO2013169553A1 (en) | Method for synthesizing 2-cyano-3, 12-dioxoolean-1,9(11)-dien-28-oic acid methyl ester and derivatives thereof | |
| CN115490697B (en) | Asymmetric synthesis method of chiral azaspiro [4,5] -decylamine | |
| EP2542555B1 (en) | Process for producing pyripyropene derivatives | |
| CN103360444A (en) | Novel synthesis process of antiparasitic drug, namely selamectin | |
| Ghosh et al. | A synthesis of biaryl ketones via the C–S bond cleavage of thiol ester by a Cu/Ag salt | |
| CN109678792A (en) | A kind of preparation method of stable isotope labeling Pyridostigmine Bromide internal standard reagent | |
| Yadav et al. | A facile conversion of tertiary alcohols to olefins | |
| Gayler et al. | Synthetic studies towards the penicisulfuranols: Synthesis of an advanced spirocyclic diketopiperazine intermediate | |
| CN106892928B (en) | A kind of synthetic method of tertiary butyl -8- hydroxyls -5- oxa- -2- azaspiros [3.5] nonane -2- carboxylates | |
| CN106631740B (en) | A kind of amyl- 2- ketenes -4- alcoholic compound of the ring of high cis-selectivity and preparation method thereof | |
| Oohashi et al. | A New Method for the Synthesis of Carboxylic Esters and Lactones with Di-2-thienyl Carbonate (2-DTC) by the Promotion of DMAP and Iodine | |
| CN109694359B (en) | Synthetic method of nitrofuran metabolite-furazolidone AOZ-D4 | |
| CN103467449B (en) | Piperidine derivative, and preparation method and application thereof in preparation of halofuginone | |
| CN114989061A (en) | Preparation method of brivaracetam | |
| CN105884733B (en) | A kind of scopoletin and its synthetic method of stable isotope labeling | |
| JP4251892B2 (en) | Method for esterifying 4-guanidinobenzoic acid or its derivatives | |
| CN101462988A (en) | Technique for synthesizing bicalutamide | |
| CN106749157A (en) | A kind of step of use DDB one prepares the new method of bicyclic alcohols | |
| CN109678787A (en) | A kind of new HCV virus NS3/4A inhibitor synthetic intermediate and synthetic method | |
| CN106957251B (en) | A method of preparing alkyl thiomethyl ester type compound | |
| CN110128422A (en) | The synthetic method of 5- methoxyl group -7- azaindole | |
| Duke et al. | Synthesis of the non-K-region dihydrodiols of 7-methylbenz [c] acridine | |
| Chen et al. | Application of the Curtius Rearrangement in a Convenient Preparation of 3-Aminopyrazinecarboxylic Acid, Methyl Ester | |
| CN115521318B (en) | Preparation method of nalfurorphine diastereoisomer impurity | |
| CN105777766B (en) | The preparation method of the methylnaltrexone bromides of Delta 7 |
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 | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20190426 |
|
| WD01 | Invention patent application deemed withdrawn after publication |